[{"id":"1p19q-codeletion-readout","kind":"biomarker","name":"1p/19q codeletion","aka":["1p/19q codeletion","1p19q codeleted","1p/19q co-deletion","1p19q","whole-arm 1p/19q loss","oligodendroglioma marker"],"tldr":"Loss of one copy each of chromosome arms 1p and 19q, together with an IDH mutation, defines oligodendroglioma in the WHO 2021 classification. It predicts a slower course and a good response to chemotherapy, and separates oligodendroglioma from astrocytoma.","summary":"The whole-arm codeletion is detected by FISH, array or sequencing-based copy-number analysis; partial deletions do not count. WHO CNS5 (2021) requires IDH mutation plus 1p/19q codeletion for the diagnosis of oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grades 2 to 3. The long-term RTOG 9402 and EORTC 26951 results showed that adding PCV chemotherapy to radiotherapy roughly doubled survival in codeleted tumours. Vorasidenib's label covers grade 2 oligodendroglioma by IDH mutation, not by codeletion. As an arm-level change it has no single parent gene and sits under no target here.","asOf":"2026-09-23","links":[{"label":"WHO CNS5 (Louis et al. 2021)","url":"https://doi.org/10.1093/neuonc/noab106"}],"tags":["biomarker","glioma","no-approval"],"related":["idh1-r132","idh2-mutation","mgmt-promoter-methylation"],"cancers":["oligodendroglioma","glioblastoma","idh-mutant-astrocytoma"],"sections":[],"technologies":[],"targets":[],"drugs":["vorasidenib","temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":["1p19q-codeletion","fish","cytogenetics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"noParentReason":"Whole-arm loss of chromosome arms 1p and 19q: hundreds of genes, no single parent gene or protein.","measurement":"copy-number","scoringRule":{"text":"Loss of the whole short arm of chromosome 1 and the whole long arm of chromosome 19 by FISH, chromosomal microarray or sequencing copy-number analysis, in a tumour with an IDH1 or IDH2 mutation.","quote":"Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted","source":"https://doi.org/10.1093/neuonc/noab106","sourceLabel":"Louis et al., The 2021 WHO Classification of Tumors of the Central Nervous System, Neuro-Oncology 2021"},"thresholds":[],"definedBy":{"label":"WHO CNS5 classification (Louis et al., Neuro-Oncology 2021)","url":"https://doi.org/10.1093/neuonc/noab106"},"tests":["caris-mi-profile","foundationone-cdx","tempus-xt"],"assays":[],"companionDiagnostics":[],"forPatient":"If your glioma has an IDH mutation and 1p/19q codeletion it is an oligodendroglioma, which grows more slowly and responds well to chemotherapy with radiotherapy. Without the codeletion the same IDH-mutant tumour is an astrocytoma. Vorasidenib is on label for grade 2 tumours of either type after surgery."},{"id":"pd-ligand-9p24-alteration","kind":"biomarker","name":"9p24.1 alteration of the PD-1 ligand loci","aka":["9p24.1 amplification","CD274 amplification","PDCD1LG2 amplification","PD-1 ligand copy gain","9p24.1 copy gain"],"tldr":"An extra stretch of chromosome 9 that carries both of the molecules a tumour uses to switch off T cells, plus the enzyme that turns them up further. Nearly every classical Hodgkin lymphoma has it, which is why checkpoint drugs work so well there and so poorly in most other lymphomas.","summary":"The 9p24.1 amplicon contains CD274 and PDCD1LG2, the genes for the two PD-1 ligands, and JAK2. Amplifying it raises the ligands twice over, by gene dose and by JAK2-driven transcription, and JAK2 amplification also increases sensitivity to JAK2 inhibition in the laboratory. The alteration is disease-specific: it is restricted to nodular sclerosing Hodgkin lymphoma, the subtype most closely related to mediastinal large B-cell lymphoma, and to mediastinal large B-cell lymphoma itself (Green 2010).\n\nIn 108 newly diagnosed classical Hodgkin lymphomas evaluated by fluorescence in situ hybridisation, 97% had concordant alterations of both loci: polysomy in 5 of 108, copy gain in 61 of 108 and amplification in 39 of 108, and higher-level gain predicted shorter progression-free survival (Roemer 2016). Alongside it, recurrent CIITA fusions, found in 38% of primary mediastinal B-cell lymphomas and 15% of classical Hodgkin lymphomas across 263 B-cell lymphomas, lower MHC class II on the tumour cell and place the ligands under new promoters (Steidl 2011).\n\nThis is the clearest genetic explanation in oncology for why one disease answers checkpoint blockade: PD-1 blockade gave an objective response in 20 of 23 heavily pre-treated Hodgkin patients, 87%, most of whom had already failed both autologous transplant and brentuximab vedotin (Ansell 2015). What predicts complete remission within that group is not MHC class I but MHC class II expression on the Hodgkin and Reed-Sternberg cells, which suggests the effector is a CD4 T cell (Roemer 2018).","asOf":"2026-09-30","links":[{"label":"Green et al., Blood 2010: selective 9p24.1 amplification and PD-1 ligand induction through JAK2 in Hodgkin lymphoma and mediastinal large B-cell lymphoma","url":"https://doi.org/10.1182/blood-2010-05-282780"},{"label":"Roemer et al., J Clin Oncol 2016: PD-L1 and PD-L2 genetic alterations in 108 classical Hodgkin lymphomas","url":"https://doi.org/10.1200/JCO.2016.66.4482"},{"label":"Roemer et al., J Clin Oncol 2018: MHC class II and PD-L1 expression predict outcome after PD-1 blockade in classical Hodgkin lymphoma (CheckMate 205)","url":"https://doi.org/10.1200/JCO.2017.77.3994"},{"label":"Ansell et al., N Engl J Med 2015: nivolumab in relapsed or refractory Hodgkin lymphoma (23 patients)","url":"https://doi.org/10.1056/NEJMoa1411087"}],"tags":["biomarker","lymphoma"],"related":[],"cancers":["hodgkin-lymphoma","primary-mediastinal-b-cell-lymphoma"],"sections":[],"technologies":["cytogenetics-fish","checkpoint-inhibitor"],"targets":["jak2","ciita"],"drugs":["nivolumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","jak-stat","antigen-presentation-immunoediting"],"terms":["lymphoma-bio-hodgkin-microenvironment","gene-amplification","fish"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"noParentReason":"9p24.1 is an amplicon rather than a gene: one copy-number event raises CD274, PDCD1LG2 and JAK2 together, and the result is reported as a change at the locus rather than as a result for any one of them. The protein-level PD-L1 scores that do have a single parent gene are the separate CPS, TPS, IC and TC readouts.","measurement":"copy-number","scoringRule":{"text":"Fluorescence in situ hybridisation on the tumour cells with probes for the 9p24.1 locus and a chromosome 9 centromere control, graded as polysomy, copy gain or amplification by the ratio. It is done on the malignant cells specifically, because in Hodgkin lymphoma they are a small minority of the tissue and a bulk assay would measure the infiltrate instead.","quote":"Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]).","source":"https://doi.org/10.1200/JCO.2016.66.4482","sourceLabel":"Roemer et al., Journal of Clinical Oncology 2016"},"thresholds":[],"definedBy":{"label":"Roemer et al., J Clin Oncol 2016: PD-L1 and PD-L2 genetic alterations in 108 classical Hodgkin lymphomas","url":"https://doi.org/10.1200/JCO.2016.66.4482"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"Nobody is tested for this before being given a checkpoint drug for Hodgkin lymphoma, because almost every case has it. It is the reason these drugs work in Hodgkin lymphoma when they do very little in most other lymphomas, and that is worth knowing when comparing treatments between diseases."},{"id":"akt1-e17k","kind":"biomarker","name":"AKT1 E17K mutation","aka":["AKT1 E17K","AKT1 mutation","E17K","AKT1-mutant"],"tldr":"AKT1 E17K is a single hotspot mutation, in about 3 to 5 percent of hormone-receptor-positive breast cancers, that switches on the AKT kinase directly. It is one of the three alterations that qualify a patient for capivasertib.","summary":"The E17K substitution in the pleckstrin homology domain sends AKT1 to the membrane without PIP3. Capivasertib (Truqap) is labelled with fulvestrant for HR-positive HER2-negative advanced breast cancer with one or more PIK3CA, AKT1 or PTEN alterations as detected by an FDA-approved test (CAPItello-291); FoundationOne CDx carries the three-gene claim. AKT1 E17K also appears in endometrial and rarer cancers, where it is a trial marker only.","asOf":"2026-09-23","links":[{"label":"TRUQAP prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf"}],"tags":["biomarker","pi3k"],"related":["pik3ca-hotspot-mutation","pten-alteration"],"cancers":["breast-hr-positive","endometrial","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":["capivasertib","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["hyperglycaemia"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018","paper-schmid-pakt-capivasertib-tnbc-jco-2020"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: AKT1 mutation in 13% of LAR tumours (Bareche 2018) and 2 to 3% of triple-negative samples overall (cBioPortal); counted in the PAKT altered subgroup (Schmid 2020)."],"target":"akt","measurement":"sequencing-variant","scoringRule":{"text":"The AKT1 c.49G>A (p.E17K) substitution by sequencing of tumour tissue or plasma, reported with PIK3CA and PTEN as the capivasertib selection set.","quote":"PIK3CA/AKT1/PTEN alterations","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"AKT1 alteration (with PIK3CA and PTEN as the qualifying set)","drugId":"capivasertib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf","quote":"with one or more PIK3CA/AKT1/PTEN -alterations as detected by an FDA-approved test","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt"],"assays":["foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["capivasertib","fulvestrant"],"indication":"Breast Cancer - Tissue","pma":"P170019/S048 (11/16/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"An AKT1 E17K result in hormone-receptor-positive breast cancer qualifies you for capivasertib with fulvestrant once hormone therapy has stopped working, the same as a PIK3CA mutation or PTEN loss would. Alpelisib and inavolisib are not approved for AKT1 mutations on their own."},{"id":"alk-fusion","kind":"biomarker","name":"ALK fusion (ALK-positive)","aka":["ALK fusion","ALK rearrangement","ALK-positive","ALK+","EML4-ALK","EML4::ALK","ALK translocation","ALK gene rearrangement"],"tldr":"An ALK fusion, usually EML4::ALK, is a swapped piece of chromosome 2 that turns the ALK kinase on permanently in about 4 percent of lung adenocarcinomas. Seven ALK inhibitors are approved for it, including alectinib after surgery.","summary":"ALK rearrangements are detected by break-apart FISH (Vysis), immunohistochemistry (Ventana D5F3), or DNA and RNA sequencing; the FDA list carries all three routes as companion diagnostics. Crizotinib, ceritinib, alectinib, brigatinib, lorlatinib and ensartinib are labelled for ALK-positive metastatic NSCLC 'as detected by an FDA-approved test', and alectinib for adjuvant treatment after resection of tumours 4 cm or larger or node-positive (ALINA). Crizotinib is also labelled for ALK-positive anaplastic large cell lymphoma and inflammatory myofibroblastic tumour. Alectinib's label allows selection on tumour tissue or plasma.","asOf":"2026-09-23","links":[{"label":"ALECENSA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=42c49deb-713b-427a-9670-08af08adcffb"},{"label":"Lorbrena prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=004f93d7-a1cd-4b67-9207-31cdcb5c5976"}],"tags":["biomarker","fusion"],"related":["ros1-fusion","ret-fusion","ntrk-fusion"],"cancers":["nsclc","pancreatic","kras-wild-type-pdac"],"sections":[],"technologies":[],"targets":[],"drugs":["alectinib","lorlatinib","crizotinib","brigatinib","ceritinib","ensartinib","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["gene-fusion","fish","tki-term"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-singhi-alk-rearrangements-pancreatic-jnccn-2017","paper-philip-kras-wild-type-pancreatic-ccr-2022","paper-soda-eml4-alk-fusion-nature-2007","paper-kris-lung-cancer-mutation-consortium-jama-2014","paper-gainor-alk-resistance-mutations-cancer-discov-2016","paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019","paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Pancreatic ductal adenocarcinoma: ALK fusions in 0.16% of 3,170 tumours, all KRAS wild-type and all in patients under 50 (1.3% of that age group), with benefit from ALK inhibitors in 3 of 4 treated (Singhi 2017).","Lung cancer: 3 to 6% of adenocarcinomas by panel and 8% by fluorescence in situ hybridisation in the Lung Cancer Mutation Consortium, with EML4 the partner in the large majority (Soda 2007, Kris 2014; cBioPortal). Immunohistochemistry is an acceptable screen and a DNA panel that does not bait the breakpoint introns will read wild-type (Lindeman 2018). At progression the gene is read again for resistance mutations, which decide whether a third-generation inhibitor is the right next step (Gainor 2016, Shaw 2019)."],"target":"alk","measurement":"sequencing-variant","scoringRule":{"text":"An ALK gene rearrangement or fusion by break-apart FISH (15 percent or more of cells with split or isolated 3' signals on the Vysis kit), ALK protein expression by the Ventana D5F3 IHC assay, or a fusion transcript or rearrangement by sequencing of tissue or plasma.","quote":"ALK rearrangements","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"ALK-positive (adjuvant, tumours >= 4 cm or node positive)","drugId":"alectinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=42c49deb-713b-427a-9670-08af08adcffb","quote":"adjuvant treatment in adult patients following tumor resection of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) (tumors ≥ 4 cm or node positive) as detected by an FDA-approved test.","status":"current"},{"value":"ALK-positive","drugId":"lorlatinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=004f93d7-a1cd-4b67-9207-31cdcb5c5976","quote":"LORBRENA ® is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.","status":"current"},{"value":"ALK-positive or ROS1-positive","drugId":"crizotinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7","quote":"adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test.","status":"current"},{"value":"ALK-positive","drugId":"brigatinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0fe9ff20-d402-41f3-bc1e-7002ea7007db","quote":"ALUNBRIG is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test","status":"current"},{"value":"ALK-positive, ALK inhibitor-naive","drugId":"ensartinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e1b2f79-678a-472a-b924-66909c8a4b2e","quote":"ENSACOVE is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC)as detected by an FDA-approved test","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive","caris-mi-cancer-seek"],"assays":["alk-vysis-fish","alk-d5f3","foundationone-cdx-panel"],"companionDiagnostics":[{"device":"Vysis ALK Break Apart FISH Probe Kit","maker":"Abbott Molecular","companyId":"abbott","drugs":["crizotinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P110012 (08/26/2011)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Vysis ALK Break Apart FISH Probe Kit","maker":"Abbott Molecular","companyId":"abbott","drugs":["ensartinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P110012/S022 (08/05/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana ALK (D5F3) CDx Assay","maker":"Ventana Medical Systems (Roche)","drugs":["alectinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P140025/S006 (11/06/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana ALK (D5F3) CDx Assay","maker":"Ventana Medical Systems (Roche)","drugs":["lorlatinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P140025/S014 (03/03/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["alectinib","crizotinib","ceritinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P170019 (11/30/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne Liquid CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["alectinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P200006 (10/26/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"ALK-positive lung cancer is treated first with an ALK tablet, usually alectinib or lorlatinib, instead of chemotherapy or immunotherapy, and responses often last years. After surgery, two years of alectinib is on label for larger or node-positive tumours. If one ALK tablet stops working, others are approved after it."},{"id":"alk-resistance-mutation","kind":"biomarker","name":"ALK kinase-domain resistance mutation (G1202R and the rest)","aka":["ALK resistance mutation","G1202R","ALK G1202R","L1196M","ALK secondary mutation","solvent front mutation"],"tldr":"After a lung cancer stops responding to an ALK-blocking tablet, finding a change inside the ALK protein itself is good news: it means the cancer still depends on ALK, and a later-generation tablet is likely to work. Finding none means the opposite.","summary":"Each generation of ALK inhibitor selects its own set of secondary mutations in the ALK kinase domain. Across 103 repeat biopsies, crizotinib was followed by a diverse spectrum (L1196M, G1269A and others) in a minority of patients, while second-generation inhibitors (alectinib, brigatinib, ceritinib) were followed by mutations in the majority, with the solvent-front substitution G1202R rising significantly in frequency (Gainor 2016). The readout is predictive rather than descriptive: in the lorlatinib registration study, among patients who had failed one or more second-generation inhibitors, objective response was 69% with an ALK mutation on tissue genotyping against 27% without, and progression-free survival 11.0 against 5.4 months (hazard ratio 0.47); after crizotinib alone, mutation status made no difference (Shaw 2019). Compound mutations can reverse the ordering entirely: C1156Y with L1198F confers resistance to lorlatinib and restores sensitivity to crizotinib (Shaw 2016).","asOf":"2026-09-25","links":[{"label":"Gainor et al., Cancer Discov 2016: 103 repeat biopsies and the resistance mutations of first- and second-generation ALK inhibitors","url":"https://doi.org/10.1158/2159-8290.CD-16-0596"},{"label":"Shaw et al., J Clin Oncol 2019: ALK resistance mutations and the efficacy of lorlatinib in 198 patients","url":"https://doi.org/10.1200/JCO.18.02236"},{"label":"Shaw et al., N Engl J Med 2016: resensitisation to crizotinib by the lorlatinib resistance mutation ALK L1198F","url":"https://doi.org/10.1056/NEJMoa1508887"}],"tags":["biomarker","resistance"],"related":["alk-fusion"],"cancers":["nsclc"],"sections":[],"technologies":["cgp","liquid-biopsy","kinase-inhibitors"],"targets":["alk"],"drugs":[],"companies":[],"institutions":[],"pathways":["resistance-routes-map","rtk-activation","clonal-evolution"],"terms":["resistance","cross-resistance","gene-fusion","biopsy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-gainor-alk-resistance-mutations-cancer-discov-2016","paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019","paper-shaw-alk-l1198f-resensitisation-nejm-2016"],"journals":[],"dependsOn":[],"notes":[],"target":"alk","measurement":"sequencing-variant","scoringRule":{"text":"Presence of a secondary missense substitution in the ALK kinase domain on tumour tissue or plasma sequencing taken at progression, reported with the specific residue and with the inhibitors already received, since the spectrum differs by generation.","quote":"each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALK G1202R, increases significantly after treatment with second-generation agents","source":"https://doi.org/10.1158/2159-8290.CD-16-0596","sourceLabel":"Gainor et al., Cancer Discovery 2016"},"thresholds":[],"definedBy":{"label":"Shaw et al., J Clin Oncol 2019: ALK resistance mutations and the efficacy of lorlatinib","url":"https://doi.org/10.1200/JCO.18.02236"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A repeat biopsy or blood test when a treatment stops working is not a formality here. Finding a change in the ALK protein usually means another tablet in the same family will work; finding none usually means it is time for a different kind of treatment."},{"id":"ar-amplification","kind":"biomarker","name":"AR amplification (gene and upstream enhancer)","aka":["AR amplification","androgen receptor amplification","AR gain","AR copy number gain","AR enhancer amplification","Xq12 amplification"],"tldr":"Extra copies of the gene for the androgen receptor. It is almost never present before hormone treatment and is found in about half of prostate cancers that have become resistant to it, which is why the stage the sample was taken at matters more than the result itself.","summary":"High-level amplification of AR at Xq12 was the first molecular explanation of endocrine treatment failure in a solid tumour: it was present in 7 of 23 tumours recurring on androgen deprivation and in none of the pre-treatment specimens from the same men (Visakorpi 1995). Recomputed on cBioPortal, it is present in 217 of 444 samples (48.9%) in prad_su2c_2019, 78 of 150 (52.0%) in prad_su2c_2015 and 85 of 149 (57.0%) in prad_fhcrc, all castration-resistant, against 5 of 489 (1.0%) in the TCGA primary cohort and 17 of 424 (4.0%) in the metastatic castration-sensitive cohort prad_mcspc_mskcc_2020. A second amplification that no coding-exon panel can see accompanies it: an intergenic enhancer 624 kb upstream of AR is amplified in 81% of 101 deeply sequenced castration-resistant metastases and correlates with receptor expression (Quigley 2018). In plasma, AR amplification is the commonest finding in castration-resistant disease and adds nothing to standard prognostic markers on its own (Annala 2018); some potential AR resistance alteration, amplification included, was present in 940 of 2,213 evaluable plasma samples, 42% (Tukachinsky 2021).","asOf":"2026-09-25","links":[{"label":"Visakorpi et al., Nat Genet 1995: in vivo amplification of the androgen receptor gene in tumours recurring on androgen deprivation (23 recurrent tumours)","url":"https://doi.org/10.1038/ng0495-401"},{"label":"Quigley et al., Cell 2018: genomic hallmarks and structural variation in 101 metastatic castration-resistant prostate cancers (deep whole genomes)","url":"https://doi.org/10.1016/j.cell.2018.06.039"},{"label":"cBioPortal study prad_su2c_2019 (SU2C/PCF Dream Team, PNAS 2019; 444 metastatic castration-resistant samples from 429 patients, whole exome)","url":"https://www.cbioportal.org/study/summary?id=prad_su2c_2019"}],"tags":["biomarker","resistance"],"related":["ar-v7-splice-variant","ar-ligand-binding-domain-mutation"],"cancers":["prostate","prostate-mcrpc","prostate-mhspc"],"sections":[],"technologies":["cgp","liquid-biopsy"],"targets":["androgen-receptor"],"drugs":[],"companies":[],"institutions":[],"pathways":["ar-signaling","resistance-routes-map","prostate-cancer-signalling"],"terms":["castration-resistance","gene-amplification","copy-number-variation-term","resistance","adt","ctdna"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-visakorpi-androgen-receptor-amplification-nat-genet-1995","paper-quigley-structural-variation-mcrpc-cell-2018","paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018","paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021"],"journals":[],"dependsOn":[],"notes":[],"target":"androgen-receptor","measurement":"copy-number","scoringRule":{"text":"High-level amplification of the AR locus at Xq12 on tumour or plasma sequencing, reported with the disease state at which the sample was taken, since prevalence runs from about 1% before treatment to about half after castration resistance.","quote":"We found high-level AR amplification in seven of 23 (30%) recurrent tumours, but in none of the specimens taken from the same patients prior to therapy.","source":"https://doi.org/10.1038/ng0495-401","sourceLabel":"Visakorpi et al., Nature Genetics 1995"},"thresholds":[],"definedBy":{"label":"Quigley et al., Cell 2018: genomic hallmarks and structural variation in metastatic prostate cancer, including the AR upstream enhancer","url":"https://doi.org/10.1016/j.cell.2018.06.039"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result usually explains why a hormone treatment has stopped working rather than changing what is offered next. It does not mean treatment has run out: the usual next steps are a different kind of treatment altogether, such as chemotherapy, a radioligand or, where the genetics allow it, a PARP inhibitor."},{"id":"ar-ligand-binding-domain-mutation","kind":"biomarker","name":"AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L)","aka":["AR mutation","androgen receptor mutation","L702H","T878A","T877A","H875Y","F877L","F876L","W742C","AR LBD mutation"],"tldr":"A change in the part of the androgen receptor that hormone drugs attach to. Depending on which change it is, another hormone the man is already taking can switch the receptor on, or the blocking drug can start behaving as an activating one.","summary":"Androgen receptor mutations in this domain were first described in metastatic androgen-independent prostate cancer, where 5 of 10 men carried one and two of the mutant receptors could be activated by progesterone and by oestrogen in transfected cells (Taplin 1995). They are almost entirely a property of treated disease: cBioPortal records AR mutation in 61 of 444 samples (13.7%) in prad_su2c_2019 and 27 of 150 (18.0%) in prad_su2c_2015, against 2 of 494 (0.4%) in the TCGA primary cohort, where neither record falls in the ligand-binding domain at all. The spectrum is narrow and it tracks the treatment. In prad_su2c_2019 (72 mutation records): L702H 17, T878A 15, H875Y 11, W742C 8, W742L 4, F877L 3. L702H makes the receptor responsive to glucocorticoid, which matters because abiraterone is given with prednisone or prednisolone; T878A and H875Y open the pocket to progestogens and older antiandrogens; F877L converts enzalutamide and apalutamide from antagonists into agonists. Plasma detects compound and polyclonal combinations that a single biopsy cannot (Tukachinsky 2021).","asOf":"2026-09-25","links":[{"label":"Taplin et al., N Engl J Med 1995: androgen-receptor gene mutation in metastatic androgen-independent prostate cancer (10 patients)","url":"https://doi.org/10.1056/NEJM199505253322101"},{"label":"Tukachinsky et al., Clin Cancer Res 2021: circulating tumour DNA profiling in 3,334 men with advanced prostate cancer, including 1,674 TRITON screening samples","url":"https://doi.org/10.1158/1078-0432.CCR-20-4805"},{"label":"cBioPortal study prad_su2c_2019 (SU2C/PCF Dream Team, PNAS 2019; 444 metastatic castration-resistant samples from 429 patients, whole exome)","url":"https://www.cbioportal.org/study/summary?id=prad_su2c_2019"}],"tags":["biomarker","resistance"],"related":["ar-amplification","ar-v7-splice-variant"],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["cgp","liquid-biopsy"],"targets":["androgen-receptor","cyp17a1"],"drugs":[],"companies":[],"institutions":[],"pathways":["ar-signaling","resistance-routes-map"],"terms":["castration-resistance","resistance","cross-resistance","driver-mutation","ctdna"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995","paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021"],"journals":[],"dependsOn":[],"notes":[],"target":"androgen-receptor","measurement":"sequencing-variant","scoringRule":{"text":"A missense substitution in the AR ligand-binding domain on tumour or plasma sequencing, reported by specific residue rather than as AR mutated, since the clinical meaning differs by allele and more than one allele is often present at once.","quote":"Point mutations in the androgen-receptor gene were identified in metastatic cells from 5 of the 10 patients examined... Functional studies of two of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen.","source":"https://doi.org/10.1056/NEJM199505253322101","sourceLabel":"Taplin et al., New England Journal of Medicine 1995"},"thresholds":[],"definedBy":{"label":"Taplin et al., N Engl J Med 1995: mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer","url":"https://doi.org/10.1056/NEJM199505253322101"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A report that says only that the androgen receptor is mutated has not answered the question. Which change it is decides whether a different hormone tablet is still worth trying, and whether a steroid being taken alongside could be feeding the cancer. It is a question for a specialist centre, because no approval depends on it."},{"id":"ar-v7-splice-variant","kind":"biomarker","name":"AR-V7 splice variant","aka":["AR-V7","AR-V7 positive","androgen receptor splice variant 7","AR-V7 CTC","nuclear AR-V7"],"tldr":"AR-V7 is a shortened androgen receptor that lacks the part hormone drugs bind, so it stays active without testosterone. Found in circulating tumour cells, it predicts poor response to abiraterone and enzalutamide, but no label uses it yet.","summary":"The AR-V7 transcript skips the ligand-binding domain and is detected by RT-PCR of circulating tumour cell RNA or by nuclear AR-V7 protein immunofluorescence in CTCs (the Oncotype DX AR-V7 Nucleus Detect assay, a laboratory-developed test). The prospective PROPHECY trial (NCT02269982) showed that AR-V7-positive men had shorter progression-free and overall survival on abiraterone or enzalutamide, while taxane response was preserved. No regulator has put AR-V7 in a label and no companion diagnostic exists; it is a guideline-discussed, not guideline-mandated, test.","asOf":"2026-09-23","links":[{"label":"PROPHECY (NCT02269982)","url":"https://clinicaltrials.gov/study/NCT02269982"}],"tags":["biomarker","prostate","no-approval"],"related":["psma-pet-expression","ar-amplification","ar-ligand-binding-domain-mutation"],"cancers":["prostate-mcrpc","prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["abiraterone","enzalutamide"],"companies":[],"institutions":[],"pathways":[],"terms":["ar-v7"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-antonarakis-ar-v7-resistance-nejm-2014","paper-prophecy-arv7-validation-jco-2019","paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018"],"journals":[],"dependsOn":[],"notes":["Prevalence, from the two prospective series: AR-V7 messenger RNA was detectable in circulating tumour cells from 12 of 31 men starting enzalutamide, 39%, and 6 of 31 starting abiraterone, 19%, with no PSA response in any AR-V7-positive man in either group (Antonarakis 2014). PROPHECY validated the prognostic effect prospectively in 118 men on two assays that agreed on 82% of samples (Armstrong 2019).","The treatment-selection evidence: in a blinded three-centre series of 142 men, AR-V7-positive men had median overall survival of 14.3 months on a taxane against 7.3 months on a receptor signalling inhibitor, and AR-V7-negative men 19.8 against 12.8 months the other way, hazard ratio 1.67 (Scher 2018).","Mechanistically it belongs with the other four routes to androgen receptor reactivation, gene amplification, enhancer amplification, ligand-binding-domain mutation and receptor overexpression, and more than one is often present in the same man."],"target":"androgen-receptor","measurement":"sequencing-variant","scoringRule":{"text":"Detection of the AR-V7 transcript in circulating tumour cell RNA by RT-PCR, or nuclear-localised AR-V7 protein in circulating tumour cells by immunofluorescence; no label defines a threshold.","quote":"AR-V7 splice variant","source":"https://clinicaltrials.gov/study/NCT02269982","sourceLabel":"PROPHECY trial (NCT02269982): prospective validation of AR-V7 in metastatic castration-resistant prostate cancer"},"thresholds":[],"definedBy":{"label":"PROPHECY: AR-V7 in circulating tumour cells predicting resistance to abiraterone and enzalutamide (ClinicalTrials.gov NCT02269982)","url":"https://clinicaltrials.gov/study/NCT02269982"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"An AR-V7-positive result suggests that abiraterone and enzalutamide are less likely to work and that chemotherapy or a radioligand may be a better next step, but no approval depends on it and it is not routinely offered outside specialist centres. A negative result does not guarantee response."},{"id":"b7-h3-expression","kind":"biomarker","name":"B7-H3 (CD276) expression","aka":["B7-H3","CD276 expression","B7-H3 positive"],"tldr":"B7-H3 is an immune checkpoint protein overexpressed on small-cell lung, prostate and many solid tumours. Ifinatamab deruxtecan is in phase 3 for small-cell lung cancer without an expression cut-off; nothing is approved.","summary":"Ifinatamab deruxtecan (I-DXd) is being compared with topotecan or other chemotherapy in relapsed small-cell lung cancer in IDeate-Lung02 (NCT06203210) with no B7-H3 selection; earlier phase studies found responses across expression levels. Other B7-H3 ADCs and radioligands are in early trials. No regulator has approved a B7-H3-directed drug.","asOf":"2026-09-23","links":[{"label":"ClinicalTrials.gov NCT06203210 (IDeate-Lung02)","url":"https://clinicaltrials.gov/study/NCT06203210"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["dll3-expression"],"cancers":["sclc","extensive-stage-sclc","prostate-mcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":["ifinatamab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"b7h3","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"IDeate-Lung02: ifinatamab deruxtecan versus treatment of physician's choice in relapsed small cell lung cancer","source":"https://clinicaltrials.gov/study/NCT06203210","sourceLabel":"ClinicalTrials.gov NCT06203210 (IDeate-Lung02)"},"thresholds":[],"definedBy":{"label":"IDeate-Lung02 (NCT06203210)","url":"https://clinicaltrials.gov/study/NCT06203210"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"B7-H3 is a research target. If you have small-cell lung cancer that has returned, a trial of ifinatamab deruxtecan may be open to you without any B7-H3 test; ask your team."},{"id":"bcl2-g101v","kind":"biomarker","name":"BCL2 G101V and the other venetoclax binding-site mutations","aka":["BCL2 Gly101Val","BCL2 G101V","venetoclax resistance mutation","BCL2 D103Y"],"tldr":"A change in the pocket of the survival protein BCL-2 where venetoclax has to fit. The protein still works and the drug no longer binds it. It can be detected in blood months before the disease starts growing again.","summary":"Glycine 101 sits in the BH3-binding groove of BCL-2. The valine substitution reduces the affinity of the protein for venetoclax about 180-fold on surface plasmon resonance, so the drug can no longer displace the pro-apoptotic proteins that BCL-2 is holding, while the protein continues to do its job for the cell.\n\nPaired samples from 15 patients progressing on venetoclax in clinical trials showed G101V in seven at progression and in none at study entry. It first became detectable between 19 and 42 months of continuous treatment, and its emergence preceded clinical progression by many months (Blombery 2019). Other substitutions in the same groove have since been described, usually at low allele fraction and often several at once in one patient, which suggests convergent selection rather than a single escape route.","asOf":"2026-09-30","links":[{"label":"Blombery et al., Cancer Discov 2019: the recurrent BCL2 Gly101Val mutation confers resistance to venetoclax","url":"https://doi.org/10.1158/2159-8290.CD-18-1119"}],"tags":["biomarker","resistance","lymphoma"],"related":["btk-c481s","bcl2-rearrangement"],"cancers":["non-hodgkin-lymphoma","mantle-cell-lymphoma"],"sections":[],"technologies":["cgp","liquid-biopsy"],"targets":["bcl2","mcl1"],"drugs":["venetoclax","sonrotoclax"],"companies":[],"institutions":[],"pathways":["apoptosis-bcl2","resistance-routes-map"],"terms":["resistance","ngs","mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"bcl2","measurement":"sequencing-variant","scoringRule":{"text":"Deep targeted sequencing of BCL2 on blood or marrow during or at progression on venetoclax, reported by residue and allele fraction. Standard-depth panels miss these variants, which are typically present in a small subclone when they first appear; serial testing is what makes the result useful, because a rising allele fraction is an early warning rather than a diagnosis of progression.","quote":"The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry.","source":"https://doi.org/10.1158/2159-8290.CD-18-1119","sourceLabel":"Blombery et al., Cancer Discovery 2019"},"thresholds":[],"definedBy":{"label":"Blombery et al., Cancer Discov 2019: the recurrent BCL2 Gly101Val mutation confers resistance to venetoclax","url":"https://doi.org/10.1158/2159-8290.CD-18-1119"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"Finding this change explains why venetoclax has stopped working, and it means the next treatment should work by a different mechanism rather than being a higher dose of the same one. Because it can appear before scans or blood counts change, it is a reason for a conversation rather than for immediate treatment."},{"id":"bcl2-rearrangement","kind":"biomarker","name":"BCL2 rearrangement, t(14;18)","aka":["t(14;18)","IGH::BCL2","BCL2 translocation","BCL2 break-apart FISH","bcl-2 rearrangement"],"tldr":"A swap of DNA that puts the survival gene BCL2 next to an antibody gene, so the cell makes far too much of a protein that stops it dying. It is the founding event of most follicular lymphomas and it happens in the bone marrow, often years before anything is wrong.","summary":"The t(14;18)(q32;q21) translocation joins BCL2 on chromosome 18 to the immunoglobulin heavy-chain locus on chromosome 14, so the anti-apoptotic protein is driven by the enhancer that should be driving antibody production. Sequencing the junctions showed that the breakpoints sit close to the 5' end of the JH segment, carry extraneous N-region nucleotides and lie beside signal-like sequences on chromosome 18, which identifies the translocation as a mistake by the VDJ recombinase at the pre-B-cell stage rather than a late event in a lymphoma (Tsujimoto 1985).\n\nIt is present in the large majority of follicular lymphomas and in 13.5% of 442 unselected diffuse large B-cell lymphomas in the RICOVER cohort, where BCL2 protein was expressed in 79.6% of tumours, far more often than the gene was rearranged (Horn 2013). A cell carrying the translocation can be found in the blood of healthy people, so the result on its own is not a diagnosis.","asOf":"2026-09-30","links":[{"label":"Tsujimoto et al., Science 1985: the t(14;18) translocation results from a mistake in VDJ joining","url":"https://doi.org/10.1126/science.3929382"},{"label":"Horn et al., Blood 2013: MYC, BCL2 and BCL6 rearrangement and expression in 442 RICOVER patients","url":"https://doi.org/10.1182/blood-2012-06-435842"}],"tags":["biomarker","lymphoma"],"related":["double-hit-rearrangement","myc-bcl2-double-expressor"],"cancers":["follicular-lymphoma","dlbcl","non-hodgkin-lymphoma"],"sections":[],"technologies":["cytogenetics-fish","histopathology-ihc"],"targets":["bcl2"],"drugs":["venetoclax"],"companies":[],"institutions":[],"pathways":["apoptosis-bcl2","germinal-centre-reaction"],"terms":["fish","cytogenetics","lymphoma-bio-germinal-centre"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"bcl2","measurement":"fish-ratio","scoringRule":{"text":"A break at the BCL2 locus on interphase fluorescence in situ hybridisation, reported as rearranged or not rearranged, usually with a break-apart probe; a dual-fusion probe additionally confirms the immunoglobulin partner. The result is read alongside MYC and BCL6, because the combination rather than BCL2 alone defines the high-grade entity.","quote":"Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively.","source":"https://doi.org/10.1182/blood-2012-06-435842","sourceLabel":"Horn et al., Blood 2013"},"thresholds":[],"definedBy":{"label":"Alaggio et al., Leukemia 2022: the fifth edition of the WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"On its own this result helps name the lymphoma rather than choose the treatment. It becomes important when it appears together with a MYC rearrangement, which is a different and more aggressive diagnosis and usually means a stronger regimen."},{"id":"bcma-expression","kind":"biomarker","name":"BCMA expression","aka":["BCMA","BCMA-positive","B-cell maturation antigen expression","TNFRSF17 expression","soluble BCMA"],"tldr":"BCMA is the plasma-cell antigen behind the myeloma bispecifics and CAR-T cells. None of their labels requires a BCMA test; expression is near-universal, and loss through BCMA gene deletion is a documented escape route.","summary":"Teclistamab, elranatamab and linvoseltamab (BCMA x CD3 bispecifics), idecabtagene vicleucel and ciltacabtagene autoleucel (BCMA CAR-T) and belantamab mafodotin (BCMA ADC) are labelled for relapsed or refractory multiple myeloma by prior lines of therapy, with BCMA named in the mechanism of action only. Biallelic TNFRSF17 loss and extracellular-domain mutations after BCMA-directed therapy are reported in the literature and motivate GPRC5D- and FcRH5-directed alternatives.","asOf":"2026-09-23","links":[{"label":"TECVAYLI prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=54e0f974-ccee-44ea-9254-40e9883cee1e"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["gprc5d-expression","fcrh5-expression","cd38-expression"],"cancers":["multiple-myeloma","myeloma-relapsed-refractory"],"sections":[],"technologies":[],"targets":[],"drugs":["teclistamab","elranatamab","linvoseltamab","idecabtagene-vicleucel","ciltacabtagene-autoleucel","belantamab-mafodotin"],"companies":[],"institutions":[],"pathways":[],"terms":["antigen-escape"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"bcma","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"TECVAYLI is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=54e0f974-ccee-44ea-9254-40e9883cee1e","sourceLabel":"TECVAYLI prescribing information (DailyMed)"},"thresholds":[],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"No BCMA test is needed before a BCMA bispecific or CAR-T; the antigen is assumed. If myeloma returns after one BCMA-directed treatment, your team may test whether BCMA is still present before choosing another, or move to a drug aimed at GPRC5D."},{"id":"bcr-abl1-t315i","kind":"biomarker","name":"BCR::ABL1 T315I","aka":["T315I","BCR-ABL T315I","ABL1 T315I","T315I mutation","gatekeeper mutation CML"],"tldr":"T315I is the gatekeeper mutation in the ABL1 kinase that defeats imatinib, dasatinib, nilotinib and bosutinib. Ponatinib and asciminib are the two drugs approved for it.","summary":"The threonine-to-isoleucine change at the gatekeeper residue removes a hydrogen bond the first- and second-generation inhibitors need and adds steric bulk. It is detected by Sanger or next-generation sequencing of the kinase domain when BCR::ABL1 levels rise. Ponatinib (Iclusig) is labelled for T315I-positive CML in any phase and T315I-positive Ph+ ALL; asciminib (Scemblix), which binds the myristoyl pocket rather than the ATP site, is labelled for Ph+ CML in chronic phase with the T315I mutation at a higher dose. Allosteric plus ATP-site combinations are in trials for compound mutations.","asOf":"2026-09-23","links":[{"label":"SCEMBLIX prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e33001e7-3650-42b1-ae56-cddb5c43aa2b"},{"label":"Iclusig prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16d804b6-4957-43ee-b18c-3b36ec37c5ac"}],"tags":["biomarker","cml","resistance"],"related":["bcr-abl1-transcript"],"cancers":["cml","cml-chronic-phase","cml-advanced-phase","all-leukemia"],"sections":[],"technologies":[],"targets":[],"drugs":["ponatinib","asciminib"],"companies":[],"institutions":[],"pathways":[],"terms":["abl1-kinase-domain-mutations","gatekeeper-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"bcr-abl","measurement":"sequencing-variant","scoringRule":{"text":"The ABL1 c.944C>T (p.T315I) substitution in the BCR::ABL1 kinase domain by Sanger or next-generation sequencing of blood or marrow RNA.","quote":"Ph+ CML in CP with the T315I mutation.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e33001e7-3650-42b1-ae56-cddb5c43aa2b","sourceLabel":"SCEMBLIX prescribing information"},"thresholds":[{"value":"T315I-positive","drugId":"ponatinib","cancerId":"cml","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16d804b6-4957-43ee-b18c-3b36ec37c5ac","quote":"As monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL.","status":"current","note":"The Iclusig label also covers chronic, accelerated and blast phase CML with the T315I mutation."},{"value":"T315I mutation, chronic phase","drugId":"asciminib","cancerId":"cml-chronic-phase","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e33001e7-3650-42b1-ae56-cddb5c43aa2b","quote":"Ph+ CML in CP with the T315I mutation.","status":"current"}],"tests":["foundationone-heme"],"assays":[],"companionDiagnostics":[],"forPatient":"If your leukaemia's BCR::ABL1 level has risen and sequencing finds T315I, the usual tablets will no longer work; ponatinib or asciminib are the two approved options and a transplant may be discussed. Testing for the mutation is done from a blood sample whenever response is lost."},{"id":"bcr-abl1-transcript","kind":"biomarker","name":"BCR::ABL1 transcript (Philadelphia chromosome, quantitative PCR)","aka":["BCR-ABL1","BCR::ABL1","BCR-ABL","Philadelphia chromosome positive","Ph+","Ph-positive","BCR-ABL1 IS","BCR-ABL1 international scale","MMR","MR4","MR4.5","major molecular response"],"tldr":"The BCR::ABL1 fusion is the Philadelphia chromosome that defines chronic myeloid leukaemia and some acute lymphoblastic leukaemia. Its transcript level in blood, on the international scale, is how response to tyrosine kinase inhibitors is measured and when treatment can be stopped.","summary":"The t(9;22) translocation is confirmed at diagnosis by karyotype, FISH or PCR; thereafter quantitative RT-PCR of BCR::ABL1 mRNA on the International Scale defines response milestones (early molecular response <= 10 percent at 3 months, major molecular response <= 0.1 percent, MR4 <= 0.01 percent, MR4.5 <= 0.0032 percent) under ELN and NCCN. Imatinib, dasatinib, nilotinib, bosutinib, ponatinib and asciminib are labelled for Ph+ CML; the MRDx BCR-ABL Test (MolecularMD) is on the FDA list as the companion for nilotinib's treatment-free remission labelling (K173492, 2017), which requires sustained deep molecular response before stopping.","asOf":"2026-09-23","links":[{"label":"Gleevec prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=211ef2da-2868-4a77-8055-1cb2cd78e24b"},{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"tags":["biomarker","cml"],"related":["bcr-abl1-t315i"],"cancers":["cml","cml-chronic-phase","cml-advanced-phase","all-leukemia","all-paediatric-ph-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib","dasatinib","nilotinib","bosutinib","ponatinib","asciminib"],"companies":[],"institutions":[],"pathways":[],"terms":["philadelphia-chromosome","molecular-response","mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"bcr-abl","measurement":"sequencing-variant","scoringRule":{"text":"BCR::ABL1 mRNA relative to a control gene, reported as a percentage on the International Scale; major molecular response is 0.1 percent or lower, MR4 0.01 percent or lower, MR4.5 0.0032 percent or lower.","quote":"t(9;21) Philadelphia chromosome: BCR - ABL fusion","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"Ph+ CML (BCR::ABL1 present)","drugId":"imatinib","cancerId":"cml-chronic-phase","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=211ef2da-2868-4a77-8055-1cb2cd78e24b","quote":"Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.","status":"current"},{"value":"Ph+ CML; treatment-free remission requires sustained deep molecular response by MRDx BCR-ABL Test","drugId":"nilotinib","cancerId":"cml-chronic-phase","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6093952a-5248-45cb-ad17-33716a411146","quote":"Adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.","status":"current"}],"definedBy":{"label":"European LeukemiaNet 2020 recommendations for treating CML (Hochhaus et al., Leukemia 2020): molecular response milestones","url":"https://doi.org/10.1038/s41375-020-0776-2"},"tests":["foundationone-heme","neotype-profiles"],"assays":[],"companionDiagnostics":[{"device":"MRDx BCR-ABL Test","maker":"MolecularMD","drugs":["nilotinib"],"indication":"Chronic Myeloid Leukemia - Peripheral Blood","pma":"K173492 (12/22/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"The BCR::ABL1 level in your blood is the number that matters in chronic myeloid leukaemia. Below 10 percent at three months is the first milestone; 0.1 percent or lower is a major molecular response; and years at 0.01 percent or lower can allow a supervised attempt to stop treatment. A rising level is the signal to check for a resistance mutation such as T315I."},{"id":"braf-class-ii-iii","kind":"biomarker","name":"BRAF class II and class III mutations (non-V600)","aka":["BRAF class II","BRAF class III","non-V600 BRAF","BRAF K601E","BRAF G469A","BRAF D594G","atypical BRAF mutation","BRAF non-V600E"],"tldr":"Class II and III BRAF mutations sit outside codon 600 and signal as pairs (class II) or by leaning on RAS (class III). Approved BRAF inhibitors do not work on them, and no drug is yet approved for them; pan-RAF inhibitors are in trials.","summary":"Class II mutations (K601E, G469A, L597 and others, plus fusions and in-frame deletions) form RAS-independent dimers; class III mutations (D594, G466, N581) are kinase-impaired and amplify upstream RAS or receptor signalling. Neither responds to the monomer-selective inhibitors vemurafenib, dabrafenib or encorafenib, and the labels state the drugs are not indicated for BRAF wild-type tumours without addressing these classes. No approval exists: tovorafenib, a type II RAF inhibitor, is approved only for paediatric low-grade glioma with BRAF fusion or V600 mutation, and trials of pan-RAF inhibitors and MEK inhibitors (for example the NCI-MATCH sub-protocol of trametinib for non-V600 BRAF, and the tovorafenib FIREFLY-2 programme) define the group. The classification is from Yao et al. (Cancer Cell 2015, Nature 2017).","asOf":"2026-09-23","links":[{"label":"OJEMDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea3a9631-3a66-6a7c-e053-2995a90ae2ad"}],"tags":["biomarker","braf","no-approval"],"related":["braf-v600e","braf-fusion"],"cancers":["melanoma","nsclc","colorectal","thyroid"],"sections":[],"technologies":[],"targets":[],"drugs":["tovorafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":["braf-v600-mutation","driver-passenger-model"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-jones-non-v600-braf-colorectal-jco-2017"],"journals":[],"dependsOn":[],"notes":["Colorectal cancer: non-V600 BRAF mutations occurred in 208 of 9,643 sequenced metastatic patients (2.2%) and accounted for 22% of all BRAF mutations. They define a clinically distinct group: younger (median 58 against 68 years), less often female, lower grade, less often right-sided, and with median overall survival of 60.7 months against 11.4 for V600E and 43.0 for BRAF wild-type (hazard ratio 0.18) (Jones 2017). No colorectal approval covers them, and the encorafenib plus cetuximab label is V600E only.","Lung cancer: class II and class III alleles (G469A, G466V, K601E, D594G, D594N) outnumber V600E about three to one in lung adenocarcinoma, appearing in roughly 3 to 4% of tumours (cBioPortal). Class III alleles are kinase-impaired and signal as RAS-dependent dimers through CRAF, so a V600-directed inhibitor can activate the pathway rather than block it; class II alleles dimerise independently of RAS. Neither class is covered by the licensed V600E indication."],"target":"braf","measurement":"sequencing-variant","scoringRule":{"text":"A BRAF mutation outside codon 600 classified by mechanism: class II (RAS-independent dimers, kinase-activated) or class III (kinase-impaired, RAS-dependent); detected by sequencing.","quote":"BRAF V600 mutations and BRAF fusions","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices (the Ojemda row names V600 mutations and fusions; no companion claim covers class II or III point mutations)"},"thresholds":[],"definedBy":{"label":"Yao et al., Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS, Nature 2017 (the class I to III scheme)","url":"https://doi.org/10.1038/nature23291"},"tests":["foundationone-cdx","tempus-xt","caris-mi-cancer-seek","trusight-oncology-comprehensive"],"assays":[],"companionDiagnostics":[],"forPatient":"A BRAF mutation that is not V600E or V600K usually means the approved BRAF tablets are not expected to work. There is no approved drug for these classes yet; ask about trials of pan-RAF or MEK inhibitors, and about the other treatments for your cancer type, which are unchanged by this result."},{"id":"braf-fusion","kind":"biomarker","name":"BRAF fusion or rearrangement","aka":["BRAF fusion","KIAA1549-BRAF","KIAA1549::BRAF","BRAF rearrangement","BRAF-fused glioma"],"tldr":"A BRAF fusion joins another gene to the BRAF kinase, most often KIAA1549 in paediatric low-grade glioma. Tovorafenib is approved for children whose relapsed low-grade glioma carries a BRAF fusion or V600 mutation.","summary":"KIAA1549::BRAF is the hallmark of pilocytic astrocytoma and most paediatric low-grade gliomas; other partners and rare BRAF fusions occur in melanoma, thyroid and pancreatic acinar cancers. Fusions behave as class II alterations and respond poorly to first-generation BRAF inhibitors, which can paradoxically activate them. Tovorafenib (Ojemda, 2024) is labelled for patients 6 months and older with relapsed or refractory paediatric low-grade glioma harbouring a BRAF fusion or rearrangement or a BRAF V600 mutation; FoundationOne CDx is the listed companion diagnostic (P170019/S054). Detection needs RNA or DNA sequencing that captures rearrangements, or FISH; hotspot PCR misses them.","asOf":"2026-09-23","links":[{"label":"OJEMDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea3a9631-3a66-6a7c-e053-2995a90ae2ad"}],"tags":["biomarker","braf"],"related":["braf-v600e","braf-class-ii-iii"],"cancers":["paediatric-low-grade-glioma","melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["tovorafenib","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["gene-fusion","braf-v600-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"braf","measurement":"sequencing-variant","scoringRule":{"text":"A BRAF gene fusion or rearrangement (for example KIAA1549::BRAF) detected by RNA or DNA sequencing or FISH; hotspot PCR does not detect it.","quote":"BRAF V600 mutations and BRAF fusions","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"BRAF fusion or rearrangement, or BRAF V600 mutation","drugId":"tovorafenib","cancerId":"paediatric-low-grade-glioma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea3a9631-3a66-6a7c-e053-2995a90ae2ad","quote":"OJEMDA is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.","status":"current"}],"tests":["foundationone-cdx","tempus-xt","trusight-oncology-comprehensive","caris-mi-profile"],"assays":["foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["tovorafenib"],"indication":"Low-Grade Glioma - Tissue","pma":"P170019/S054 (01/16/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"In a child's low-grade glioma a BRAF fusion is common and, if the tumour comes back after treatment, makes tovorafenib an on-label option taken by mouth. The first-generation BRAF tablets used for V600E melanoma are not suitable for fusions. Ask whether the test used could see rearrangements, because some panels cannot."},{"id":"braf-v600e","kind":"biomarker","name":"BRAF V600E (and V600K)","aka":["BRAF V600E","V600E","BRAF V600","BRAF V600K","BRAF-mutant","BRAF class I mutation","BRAF V600E-mutant"],"tldr":"V600E is the BRAF change that drives half of melanomas and many thyroid, bowel, lung and brain tumours. BRAF plus MEK inhibitors are approved for it in melanoma, lung, thyroid and, tumour-agnostically, any solid tumour; in bowel cancer it is treated with encorafenib and cetuximab.","summary":"The c.1799T>A (V600E) substitution, and the rarer V600K, are class I BRAF mutations that signal as monomers and respond to BRAF inhibitors. Dabrafenib and vemurafenib are labelled for BRAF V600E melanoma; dabrafenib with trametinib for V600E or V600K melanoma, V600E NSCLC, anaplastic thyroid cancer, paediatric low-grade glioma and V600E solid tumours (tumour-agnostic, 2022); encorafenib with binimetinib for V600E or V600K melanoma and V600E NSCLC, and with cetuximab for V600E colorectal cancer. Companion diagnostics on the FDA list include the cobas 4800 BRAF V600, THxID BRAF, therascreen BRAF V600E, FoundationOne CDx and Liquid CDx, Oncomine Dx Target Test, Guardant360 CDx and Caris MI Cancer Seek. Labels warn the drugs are not for BRAF wild-type tumours.","asOf":"2026-09-23","links":[{"label":"Tafinlar prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fee1e6b1-e1a5-4254-9f2e-a70e0f8dbdea"},{"label":"BRAFTOVI prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=235dfc38-0f0b-4037-b501-7a9f4294740c"}],"tags":["biomarker","braf"],"related":["braf-class-ii-iii","braf-fusion","kras-g12c"],"cancers":["melanoma","advanced-melanoma","colorectal","nsclc","thyroid","anaplastic-thyroid-cancer","paediatric-low-grade-glioma","metastatic-cancer","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["dabrafenib","trametinib","dabrafenib-trametinib","vemurafenib","cobimetinib","encorafenib","binimetinib","cetuximab","therascreen-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["braf-v600-mutation","ngs","tumour-agnostic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014","paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","paper-jones-non-v600-braf-colorectal-jco-2017","paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-breakwater-nejm-2025","paper-giraldo-gallbladder-msk-impact-ccr-2022","paper-kris-lung-cancer-mutation-consortium-jama-2014"],"journals":[],"dependsOn":[],"notes":["Colorectal cancer: V600E in 6 to 18% by cohort and 8.2% of first-line metastatic patients; the threshold is simply the presence of the allele. It does three jobs here. It is prognostic (overall survival hazard ratio 1.91, and the shorter survival of mismatch repair deficiency is itself driven by co-occurring BRAF mutation; Venderbosch 2014). It is predictive, selecting encorafenib plus cetuximab, now first line with chemotherapy (BEACON CRC, BREAKWATER). And it is a reflex test in MLH1-deficient tumours, because BRAF V600E points to sporadic CIMP-associated methylation rather than Lynch syndrome (Weisenberger 2006). Non-V600 BRAF mutations, 22% of all BRAF mutations found, do not qualify for the regimen and carry a far better prognosis (Jones 2017).","Gallbladder cancer: BRAF mutation in 7 of 244 samples (2.9%) in cBioPortal gbc_mskcc_2022; the tumour-agnostic dabrafenib plus trametinib indication applies to V600E.","Lung cancer: 1 to 2% of adenocarcinomas, and, unlike in melanoma, a minority of all BRAF mutations found: 31 of 133 BRAF mutation records in the largest panel cohort and 9 of 45 in the TCGA adenocarcinomas (cBioPortal). A BRAF-mutant lung cancer therefore has to be read allele by allele before the licensed combination is considered."],"target":"braf","measurement":"sequencing-variant","scoringRule":{"text":"The BRAF c.1799T>A (p.V600E) substitution, or c.1798_1799GT>AA (p.V600K) where the label names it, detected by PCR or sequencing in tumour tissue or plasma.","quote":"V600E or V600K","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"BRAF V600E","drugId":"dabrafenib","cancerId":"melanoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fee1e6b1-e1a5-4254-9f2e-a70e0f8dbdea","quote":"TAFINLAR is a kinase inhibitor indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.","status":"current"},{"value":"BRAF V600E","drugId":"dabrafenib-trametinib","cancerId":"paediatric-low-grade-glioma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fee1e6b1-e1a5-4254-9f2e-a70e0f8dbdea","quote":"TAFINLAR is indicated, in combination with trametinib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy","status":"current"},{"value":"BRAF V600E or V600K","drugId":"trametinib","cancerId":"melanoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0002ad27-779d-42ab-83b5-bc65453412a1","quote":"MEKINIST is a kinase inhibitor indicated as a single agent for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.","status":"current"},{"value":"BRAF V600E or V600K","drugId":"encorafenib","cancerId":"melanoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=235dfc38-0f0b-4037-b501-7a9f4294740c","quote":"in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-authorized test.","status":"current"},{"value":"BRAF V600E","drugId":"vemurafenib","cancerId":"melanoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38eea320-7e0c-485a-bc30-98c3c45e2763","quote":"ZELBORAF ® is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.","status":"current"},{"value":"BRAF V600E","drugId":"encorafenib","cancerId":"colorectal","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"BRAF V600E mutations","status":"current","note":"FDA companion diagnostic rows for therascreen BRAF V600E RGQ PCR (P190026), FoundationOne Liquid CDx and Guardant360 CDx with Braftovi in combination with cetuximab in colorectal cancer."}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","caris-mi-cancer-seek","tempus-xt","trusight-oncology-comprehensive"],"assays":["braf-cobas","braf-thxid","braf-therascreen","oncomine-dx"],"companionDiagnostics":[{"device":"cobas 4800 BRAF V600 Mutation Test","maker":"Roche Molecular Systems","drugs":["vemurafenib"],"indication":"Melanoma - Tissue","pma":"P110020 (08/17/2011)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"THxID BRAF Kit","maker":"bioMérieux","drugs":["dabrafenib","trametinib"],"indication":"Melanoma - Tissue","pma":"P120014 (05/29/2013)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"THxID BRAF Kit","maker":"bioMérieux","drugs":["encorafenib","binimetinib"],"indication":"Melanoma - Tissue","pma":"P120014/S008 (06/27/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen BRAF V600E RGQ PCR Kit","maker":"QIAGEN","companyId":"qiagen","drugs":["encorafenib","cetuximab"],"indication":"Colorectal Cancer - Tissue","pma":"P190026 (04/15/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["dabrafenib","trametinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160045 (06/22/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["dabrafenib","trametinib"],"indication":"Anaplastic Thyroid Cancer (ATC) - Tissue","pma":"P160045/S025 (09/29/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["encorafenib","binimetinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P170019/S039 (10/11/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["encorafenib","cetuximab"],"indication":"Colorectal Cancer (CRC) - Plasma","pma":"P200010/S026 (01/15/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A BRAF V600E result opens targeted tablets: a BRAF inhibitor with a MEK inhibitor in melanoma, lung and thyroid cancer and many rarer tumours, and encorafenib with the antibody cetuximab in bowel cancer. In melanoma your team will weigh these against immunotherapy, which also works. A V600K result qualifies for the melanoma combinations; other BRAF changes (class II and III) do not."},{"id":"btk-c481s","kind":"biomarker","name":"BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors","aka":["BTK C481S","BTK Cys481Ser","BTK L528W","BTK T474I","BTK resistance mutation","ibrutinib resistance mutation"],"tldr":"A change in the enzyme BTK at the exact point where the drug grips it. The enzyme keeps working and the drug no longer holds, which is the usual reason a BTK inhibitor stops working after it has been working well.","summary":"Ibrutinib and its covalent successors bind cysteine 481 of BTK irreversibly. Whole-exome sequencing of paired baseline and relapse samples from six patients with acquired resistance found a cysteine-to-serine substitution at that residue in five of them, and three distinct PLCG2 mutations in two; functional work showed that C481S leaves the protein only reversibly inhibited, and that the PLCG2 changes R665W and L845F are gain-of-function lesions producing autonomous B-cell receptor activity. Neither was found in nine patients with prolonged lymphocytosis who were still responding (Woyach 2014).\n\nThe answer to C481S is a non-covalent inhibitor that does not need the cysteine. Pirtobrutinib produced an overall response of 73.3% in 247 patients who had already received a covalent BTK inhibitor, with median progression-free survival of 19.6 months (Mato 2023). Resistance to that in turn runs through different residues: the kinase-dead L528W substitution was found in 7 of 13 patients progressing on zanubrutinib against 1 of 24 on ibrutinib, and in two patients it was enriched further under pirtobrutinib, which is cross-resistance rather than a new event; both of those patients responded to venetoclax afterwards (Blombery 2022).","asOf":"2026-09-30","links":[{"label":"Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib","url":"https://doi.org/10.1056/NEJMoa1400029"},{"label":"Blombery et al., Blood Adv 2022: enrichment of BTK Leu528Trp on zanubrutinib and cross-resistance to pirtobrutinib","url":"https://doi.org/10.1182/bloodadvances.2022008325"},{"label":"Mato et al., N Engl J Med 2023: pirtobrutinib after a covalent BTK inhibitor (BRUIN, 317 patients)","url":"https://doi.org/10.1056/NEJMoa2300696"}],"tags":["biomarker","resistance","lymphoma"],"related":["bcl2-g101v"],"cancers":["mantle-cell-lymphoma","waldenstrom","non-hodgkin-lymphoma","marginal-zone-lymphoma"],"sections":[],"technologies":["cgp","liquid-biopsy"],"targets":["btk","plcg2"],"drugs":["ibrutinib","acalabrutinib","zanubrutinib","pirtobrutinib","venetoclax"],"companies":[],"institutions":[],"pathways":["bcr-signalling","resistance-routes-map"],"terms":["resistance","cross-resistance","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"btk","measurement":"sequencing-variant","scoringRule":{"text":"Deep targeted sequencing of BTK and PLCG2 on blood or marrow at progression, reported by specific residue rather than as BTK mutated, because the residue decides what works next: C481 substitutions are answered by a non-covalent inhibitor, while L528W and T474I are not. Subclonal variants at low allele fraction can appear months before clinical progression, so the depth of the assay matters.","quote":"We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients.","source":"https://doi.org/10.1056/NEJMoa1400029","sourceLabel":"Woyach et al., New England Journal of Medicine 2014"},"thresholds":[],"definedBy":{"label":"Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib","url":"https://doi.org/10.1056/NEJMoa1400029"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"If a BTK inhibitor has stopped working, this test can say whether a different BTK inhibitor is still worth trying or whether the next treatment needs to work in another way altogether, such as venetoclax, a bispecific antibody or CAR-T. A report that says only BTK mutated has not answered the question; the exact change matters."},{"id":"met-overexpression","kind":"biomarker","name":"c-Met protein overexpression (IHC 3+ in >= 50% of tumour cells)","aka":["c-Met overexpression","MET overexpression","c-Met high","MET IHC 3+","c-Met protein overexpression","MET SP44","c-Met-high NSCLC"],"tldr":"c-Met overexpression is a stain, not a gene change: strong (3+) membrane staining in at least half of tumour cells. It selects telisotuzumab vedotin, an antibody-drug conjugate, in previously treated non-squamous lung cancer.","summary":"The VENTANA MET (SP44) RxDx Assay scores c-Met protein on tumour cell membranes and cytoplasm; the telisotuzumab vedotin (Emrelis, May 2025) label defines high c-Met overexpression as 50 percent or more of tumour cells with strong (3+) staining, as determined by an FDA-approved test, in locally advanced or metastatic non-squamous NSCLC after prior systemic therapy (LUMINOSITY). About a quarter of non-squamous, EGFR wild-type lung cancers meet the bar. Overexpression can occur without amplification or exon 14 skipping and the three readouts are scored separately.","asOf":"2026-09-23","links":[{"label":"EMRELIS prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bc04f980-3957-4e35-ab81-8ec2ffe87215"}],"tags":["biomarker","met"],"related":["met-ex14","met-amplification-readout"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["telisotuzumab-vedotin","telisotuzumab-adizutecan"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-awad-met-exon-14-mutations-lung-jco-2016"],"journals":[],"dependsOn":[],"notes":["Lung cancer: c-Met protein staining is a third MET readout, distinct from exon 14 skipping and from amplification. It rises with stage in exon 14-mutant disease (mean H score 253 in stage IV against 155 in earlier stages) and is also high in stage IV exon 14 wild-type tumours at a lower level (142), so the stain and the sequencing result answer different questions (Awad 2016)."],"target":"met","measurement":"ihc-score","scoringRule":{"text":"50 percent or more of tumour cells showing strong (3+) membranous and/or cytoplasmic c-Met staining on the VENTANA MET (SP44) RxDx Assay.","quote":"MET protein expression (>= 50% of tumor cells exhibiting strong membrane and/or cytoplasmic staining 3+)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":">= 50% of tumour cells with strong (3+) staining","drugId":"telisotuzumab-vedotin","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bc04f980-3957-4e35-ab81-8ec2ffe87215","quote":"EMRELIS is indicated for the treatment of adult patients with locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining], as determined by an FDA-approved test, who have received a prior systemic therapy","status":"current"}],"tests":[],"assays":[],"companionDiagnostics":[{"device":"VENTANA MET (SP44) RxDx Assay","maker":"Ventana Medical Systems (Roche Tissue Diagnostics)","drugs":["telisotuzumab-vedotin"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P240037 (05/14/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If the SP44 stain shows strong c-Met in at least half of your non-squamous lung cancer cells, telisotuzumab vedotin is on label after a first treatment has stopped working. This is a protein stain, so a sequencing report that says nothing about MET does not answer the question; ask whether the stain was done."},{"id":"cd19-expression","kind":"biomarker","name":"CD19 expression (CD19-positive)","aka":["CD19-positive","CD19+","CD19 expression","CD19 positive B-ALL","CD19 loss","CD19-negative relapse"],"tldr":"CD19 is the B-cell surface protein that blinatumomab, CAR-T cells and several antibodies aim at. Blinatumomab's label requires CD19-positive leukaemia; the CAR-T labels assume it, and losing CD19 is the commonest way the disease escapes.","summary":"CD19 is read by flow cytometry on blood or marrow blasts, or by immunohistochemistry on lymphoma tissue. Blinatumomab (Blincyto) is labelled for CD19-positive B-cell precursor ALL (in remission with MRD of 0.1 percent or more, in consolidation, and relapsed or refractory); tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel and brexucabtagene autoleucel are CD19-directed CAR-T products whose labels describe the disease by histology rather than by a CD19 threshold; tafasitamab and loncastuximab tesirine are CD19-directed antibodies for DLBCL. Antigen loss or lineage switch after CD19-directed therapy is documented in the labels' clinical sections and is the reason CD22- and CD20-directed options exist.","asOf":"2026-09-23","links":[{"label":"BLINCYTO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38b482a8-960b-4591-9857-5031ecb830aa"},{"label":"Sotillo et al., Cancer Discov 2015: acquired mutations and alternative splicing of CD19 enable resistance to CART-19","url":"https://doi.org/10.1158/2159-8290.CD-15-1020"},{"label":"Plaks et al., Blood 2021: CD19 target evasion as a mechanism of relapse after axicabtagene ciloleucel in large B-cell lymphoma","url":"https://doi.org/10.1182/blood.2021010930"}],"tags":["biomarker","surface-antigen"],"related":["cd22-expression","cd20-expression"],"cancers":["all-leukemia","all-paediatric-relapsed","dlbcl","follicular-lymphoma","mantle-cell-lymphoma","non-hodgkin-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["blinatumomab","tisagenlecleucel","axicabtagene-ciloleucel","lisocabtagene-maraleucel","brexucabtagene-autoleucel","tafasitamab","zynlonta"],"companies":[],"institutions":[],"pathways":[],"terms":["flow-cytometry","antigen-escape","mrd","lymphoma-bio-antigen-escape","lymphoma-bio-lineage-antigen-cost"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: CD19 is not tested before a CD19-directed treatment, because expression is close to universal in B-cell lymphoma; the reason to measure it is after treatment, not before. Relapse with loss of the CD19 epitope follows 10 to 20% of paediatric responses to CD19 CAR-T in B-cell acute lymphoblastic leukaemia, through deletion of the locus, exon 2 mutation, or selection for an alternatively spliced transcript that skips exon 2 and makes a protein the CAR cannot see (Sotillo 2015). Target evasion is also documented after axicabtagene ciloleucel in large B-cell lymphoma (Plaks 2021), but the published lymphoma series are small and the reported shares do not agree, so OnCo holds no figure for it. The cost of hitting the antigen is B-cell aplasia and low immunoglobulin, deeper and longer after CAR-T than after an antibody."],"target":"cd19","measurement":"ihc-score","scoringRule":{"text":"CD19 detected on leukaemia blasts by flow cytometry (the label states CD19-positive without a percentage); for CAR-T and lymphoma antibodies no measurement is required.","quote":"CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38b482a8-960b-4591-9857-5031ecb830aa","sourceLabel":"BLINCYTO prescribing information"},"thresholds":[{"value":"CD19-positive (flow cytometry, no percentage stated)","drugId":"blinatumomab","cancerId":"all-leukemia","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38b482a8-960b-4591-9857-5031ecb830aa","quote":"BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adult and pediatric patients one month and older with: CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.","status":"current"}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"Almost every B-cell leukaemia and lymphoma is CD19-positive, so a positive result mainly confirms that blinatumomab, CAR-T cells and the CD19 antibodies are options. If the disease comes back after one of these treatments, CD19 is re-checked, because a CD19-negative relapse needs a treatment aimed at a different target such as CD22."},{"id":"cd20-expression","kind":"biomarker","name":"CD20 expression (CD20-positive)","aka":["CD20-positive","CD20+","CD20 expression","CD20 positive lymphoma","CD20 loss"],"tldr":"CD20 is the B-cell antigen rituximab made famous. Rituximab and obinutuzumab labels are written for CD20-positive lymphoma and leukaemia; the newer CD20 x CD3 bispecifics assume it.","summary":"CD20 is read by immunohistochemistry or flow cytometry and is present on almost all mature B-cell lymphomas and chronic lymphocytic leukaemia. Rituximab (Rituxan) is labelled as a CD20-directed cytolytic antibody for CD20-positive non-Hodgkin lymphoma and CLL; obinutuzumab (Gazyva) for CLL and follicular lymphoma; mosunetuzumab, glofitamab and epcoritamab are CD20 x CD3 bispecifics labelled by histology. CD20-negative lymphomas (some after rituximab, and entities such as plasmablastic lymphoma) are excluded from the anti-CD20 indications.","asOf":"2026-09-23","links":[{"label":"Rituxan prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563"},{"label":"Hiraga et al., Blood 2009: CD20-negative transformation after rituximab-containing chemotherapy (19 rebiopsied patients)","url":"https://doi.org/10.1182/blood-2008-08-175208"}],"tags":["biomarker","surface-antigen"],"related":["cd19-expression","cd22-expression"],"cancers":["non-hodgkin-lymphoma","dlbcl","follicular-lymphoma","cll","mantle-cell-lymphoma","marginal-zone-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab","obinutuzumab","mosunetuzumab","glofitamab","epcoritamab"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc","flow-cytometry","antigen-escape","lymphoma-bio-antigen-escape","lymphoma-bio-lineage-antigen-cost"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: the stain is part of every diagnostic panel and is not repeated before each dose of rituximab, which is why loss at relapse is under-measured. Of 124 patients treated with rituximab-containing chemotherapy, 36 relapsed or progressed, 19 were rebiopsied and 5 of those, 26.3%, had become CD20-negative, with lower CD20 messenger RNA in the negative cells than in the positive cells from the same patient; all five died within a year (Hiraga 2009). The practical rule is to rebiopsy and restain before giving another CD20-directed drug. CD20 is not internalised, so it carries naked antibodies and T-cell engagers but no antibody-drug conjugate."],"target":"cd20","measurement":"ihc-score","scoringRule":{"text":"CD20 detected on lymphoma or leukaemia cells by immunohistochemistry or flow cytometry; the labels state CD20-positive without a percentage.","quote":"RITUXAN is a CD20-directed cytolytic antibody indicated for the treatment of: Adult patients with Non-Hodgkin's Lymphoma (NHL)","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563","sourceLabel":"Rituxan prescribing information"},"thresholds":[{"value":"CD20-positive","drugId":"rituximab","cancerId":"non-hodgkin-lymphoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b172773b-3905-4a1c-ad95-bab4b6126563","quote":"RITUXAN is a CD20-directed cytolytic antibody indicated for the treatment of: Adult patients with Non-Hodgkin's Lymphoma (NHL)","status":"current","note":"The full indication text specifies CD20-positive follicular, low-grade and diffuse large B-cell lymphoma and CD20-positive CLL."}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A CD20-positive result is expected in nearly every B-cell lymphoma and means rituximab or obinutuzumab will be part of treatment, with the CD20-directed bispecific antibodies as later options. A CD20-negative result, which can happen after previous rituximab, steers the team to drugs aimed at other targets."},{"id":"cd22-expression","kind":"biomarker","name":"CD22 expression (CD22-positive)","aka":["CD22-positive","CD22+","CD22 expression","CD22 positive ALL"],"tldr":"CD22 is a second B-cell antigen, kept even when CD19 is lost. Inotuzumab ozogamicin is labelled for CD22-positive acute lymphoblastic leukaemia.","summary":"CD22 is measured by flow cytometry on blasts; more than 90 percent of B-ALL is CD22-positive. Inotuzumab ozogamicin (Besponsa) is a CD22-directed antibody-drug conjugate labelled for relapsed or refractory CD22-positive B-cell precursor ALL in adults and children aged one and over. CD22-directed CAR-T cells are in trials for CD19-negative relapse after blinatumomab or CD19 CAR-T.","asOf":"2026-09-23","links":[{"label":"Besponsa prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cc7014b1-c775-411d-b374-8113248b4077"}],"tags":["biomarker","surface-antigen"],"related":["cd19-expression"],"cancers":["all-leukemia","all-paediatric-relapsed","non-hodgkin-lymphoma","dlbcl"],"sections":[],"technologies":[],"targets":[],"drugs":["inotuzumab-ozogamicin"],"companies":[],"institutions":[],"pathways":[],"terms":["flow-cytometry","antigen-escape"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: CD22 is expressed on most B-cell non-Hodgkin lymphomas and recycles rapidly between the surface and the endosome, which suits conjugate delivery, but the licensed conjugate is in acute lymphoblastic leukaemia rather than in lymphoma. In lymphoma its main use is as a second address after CD19-directed treatment has failed, and the limiting factor is surface density rather than presence."],"target":"cd22","measurement":"ihc-score","scoringRule":{"text":"CD22 detected on leukaemia blasts by flow cytometry; the label states CD22-positive without a percentage.","quote":"BESPONSA is a CD22-directed antibody and cytotoxic drug conjugate","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cc7014b1-c775-411d-b374-8113248b4077","sourceLabel":"Besponsa prescribing information"},"thresholds":[{"value":"CD22-positive","drugId":"inotuzumab-ozogamicin","cancerId":"all-leukemia","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cc7014b1-c775-411d-b374-8113248b4077","status":"current","note":"Besponsa indication: relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia in adults and pediatric patients 1 year and older."}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"If your leukaemia is CD22-positive, inotuzumab ozogamicin is an on-label option when the disease has come back or not responded, and it remains usable if CD19 has been lost after blinatumomab or CAR-T. Liver toxicity, especially before a transplant, is the main thing your team will weigh."},{"id":"cd30-expression","kind":"biomarker","name":"CD30 expression (CD30-positive)","aka":["CD30-positive","CD30+","CD30 expression","CD30-expressing","CD30 IHC"],"tldr":"CD30 is the antigen of Hodgkin Reed-Sternberg cells and anaplastic large cell lymphoma. Brentuximab vedotin is labelled for Hodgkin lymphoma without a CD30 test and for peripheral T-cell lymphomas that express it.","summary":"CD30 is read by immunohistochemistry; classical Hodgkin lymphoma and ALCL are uniformly positive, other T-cell lymphomas variably so. Brentuximab vedotin (Adcetris) is a CD30-directed antibody-drug conjugate labelled for classical Hodgkin lymphoma (first-line with chemotherapy, consolidation, relapsed), systemic ALCL and CD30-expressing peripheral T-cell lymphomas (ECHELON-2 required at least 10 percent of cells positive) and CD30-expressing mycosis fungoides or primary cutaneous ALCL. No numeric threshold appears in the indications.","asOf":"2026-09-23","links":[{"label":"ADCETRIS prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3904f8dd-1aef-3490-e48f-bd55f32ed67f"},{"label":"Kuppers, Nat Rev Cancer 2009: the biology of Hodgkin's lymphoma","url":"https://doi.org/10.1038/nrc2542"}],"tags":["biomarker","surface-antigen"],"related":["cd19-expression"],"cancers":["hodgkin-lymphoma","peripheral-t-cell-lymphoma","cutaneous-t-cell-lymphoma","primary-mediastinal-b-cell-lymphoma","non-hodgkin-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["brentuximab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc","lymphoma-bio-hodgkin-microenvironment","lymphoma-bio-lineage-antigen-cost"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: CD30 is the closest thing in lymphoma to an antigen restricted to the tumour, because resting lymphocytes do not carry it and only activated T and B cells and monocytes do. That is why brentuximab vedotin does not empty a normal compartment the way anti-CD20 does, and why its dose-limiting toxicity is the auristatin payload, as cumulative peripheral neuropathy, rather than the antigen. In classical Hodgkin lymphoma essentially every Reed-Sternberg cell carries it, which is remarkable given that those cells make up a small minority of the tissue (Kuppers 2009)."],"target":"cd30","measurement":"ihc-score","scoringRule":{"text":"CD30 detected on tumour cells by immunohistochemistry; the Hodgkin indications assume it, the T-cell lymphoma indications say CD30-expressing without a percentage (ECHELON-2 used 10 percent or more).","quote":"ADCETRIS is a CD30-directed antibody and microtubule inhibitor conjugate indicated for treatment of: • Adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3904f8dd-1aef-3490-e48f-bd55f32ed67f","sourceLabel":"ADCETRIS prescribing information"},"thresholds":[{"value":"CD30-expressing (no percentage in the label; ECHELON-2 used >= 10%)","drugId":"brentuximab-vedotin","cancerId":"peripheral-t-cell-lymphoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3904f8dd-1aef-3490-e48f-bd55f32ed67f","status":"current","note":"Adcetris indication for previously untreated systemic ALCL or other CD30-expressing peripheral T-cell lymphomas in combination with cyclophosphamide, doxorubicin and prednisone."}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"In Hodgkin lymphoma CD30 is taken as read and brentuximab vedotin is an option without further testing. In a T-cell lymphoma the pathologist reports whether the cells express CD30; if they do, brentuximab vedotin with chemotherapy is on label as first treatment."},{"id":"cd33-expression","kind":"biomarker","name":"CD33 expression (CD33-positive)","aka":["CD33-positive","CD33+","CD33 expression","CD33 positive AML"],"tldr":"CD33 is a myeloid antigen on the blasts of about 90 percent of acute myeloid leukaemias. Gemtuzumab ozogamicin's label requires CD33-positive disease.","summary":"CD33 is measured by flow cytometry on marrow or blood blasts. Gemtuzumab ozogamicin (Mylotarg) is a CD33-directed antibody-drug conjugate labelled for newly diagnosed CD33-positive AML with chemotherapy in adults and children from one month, and relapsed or refractory CD33-positive AML; the label does not set a percentage, though trials used 20 percent or more of blasts and benefit is greatest in favourable-risk cytogenetics. CD33 is also the target of bispecifics and CAR-T cells in trials.","asOf":"2026-09-23","links":[{"label":"Mylotarg prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=32fd2bb2-1cfa-4250-feb8-d7956c794e05"}],"tags":["biomarker","surface-antigen"],"related":["flt3-itd","npm1-mutation"],"cancers":["aml","aml-paediatric"],"sections":[],"technologies":[],"targets":[],"drugs":["gemtuzumab-ozogamicin"],"companies":[],"institutions":[],"pathways":[],"terms":["flow-cytometry","cytogenetics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"cd33","measurement":"ihc-score","scoringRule":{"text":"CD33 detected on leukaemia blasts by flow cytometry; the label states CD33-positive without a percentage.","quote":"MYLOTARG is a CD33-directed antibody and cytotoxic drug conjugate indicated for: • treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients 1 month and older","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=32fd2bb2-1cfa-4250-feb8-d7956c794e05","sourceLabel":"Mylotarg prescribing information"},"thresholds":[{"value":"CD33-positive","drugId":"gemtuzumab-ozogamicin","cancerId":"aml","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=32fd2bb2-1cfa-4250-feb8-d7956c794e05","quote":"treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients 1 month and older","status":"current"}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A CD33-positive result, present in most acute myeloid leukaemias, means gemtuzumab ozogamicin can be added to your first chemotherapy or used if the disease returns; it helps most when the leukaemia's chromosomes are in the favourable group, so both results are read together."},{"id":"cd38-expression","kind":"biomarker","name":"CD38 expression","aka":["CD38","CD38-positive","CD38 expression myeloma"],"tldr":"CD38 is on almost every myeloma cell, so daratumumab and isatuximab are given without testing for it. The stain matters afterwards: CD38 falls after treatment and can confuse flow cytometry and blood typing.","summary":"Daratumumab and isatuximab are CD38-directed antibodies labelled for multiple myeloma by line of therapy, not by CD38 level; every label describes the antigen only in the mechanism section. CD38 expression is near-universal on plasma cells and drops for months after anti-CD38 therapy, which is why laboratories use alternative gating in flow cytometry and why the drugs interfere with indirect antiglobulin tests.","asOf":"2026-09-23","links":[{"label":"DARZALEX prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d0efe9-5e54-467e-9eb4-56fa7d53b60b"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["bcma-expression","gprc5d-expression"],"cancers":["multiple-myeloma","myeloma-transplant-eligible","myeloma-transplant-ineligible","myeloma-relapsed-refractory","non-hodgkin-lymphoma","peripheral-t-cell-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["daratumumab","isatuximab"],"companies":[],"institutions":[],"pathways":[],"terms":["flow-cytometry"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: there is no approved anti-CD38 indication in lymphoma. CD38 is expressed on a minority of T-cell and NK-cell lymphomas and on plasmablastic tumours, and the evidence there is case series and small trials rather than randomised data. The result that matters in practice is a laboratory one: an anti-CD38 antibody binds CD38 on red cells and makes the indirect antiglobulin test positive, masking genuine alloantibodies, so the transfusion laboratory must be told before a crossmatch."],"target":"cd38","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"DARZALEX is a CD38-directed cytolytic antibody","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d0efe9-5e54-467e-9eb4-56fa7d53b60b","sourceLabel":"DARZALEX prescribing information (DailyMed)"},"thresholds":[],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"You will not usually be tested for CD38 before daratumumab or isatuximab; the antigen is present on virtually all myeloma cells. Tell any hospital laboratory you are on an anti-CD38 antibody, because it interferes with blood-matching tests for transfusion."},{"id":"cd79b-itam-mutation","kind":"biomarker","name":"CD79B ITAM mutation","aka":["CD79B mutation","CD79B Y196","CD79A ITAM mutation","ITAM mutation"],"tldr":"A change in the signalling tail of part of the B-cell receptor that leaves the receptor switched on without needing anything to bind it. It marks a group of large B-cell lymphomas that depend on that signal, and therefore on the enzyme BTK.","summary":"The B-cell receptor signals through the ITAM motifs of CD79a and CD79b. In activated B-cell-like diffuse large B-cell lymphoma, the receptor signals continuously: the receptors form slow-diffusing clusters in the membrane like those of an antigen-stimulated normal B cell, and knocking down IgM, Ig-kappa, CD79A, CD79B or BTK kills the cell while leaving other lymphomas alone. Somatic mutations of the ITAM modules were detected frequently in activated B-cell-like biopsies, rarely in other diffuse large B-cell lymphomas and never in Burkitt or MALT lymphoma; the mutations raise surface receptor expression and blunt LYN, the kinase that normally damps the signal down (Davis 2010).\n\nCD79B mutation with MYD88 L265P is what names the MCD genetic subtype (Schmitz 2018). CD79b protein itself is expressed on more than 95% of diffuse large B-cell lymphomas regardless of mutation status, which is why polatuzumab vedotin, the anti-CD79b conjugate, is given without a test.","asOf":"2026-09-30","links":[{"label":"Davis et al., Nature 2010: chronic active B-cell receptor signalling in diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/nature08638"},{"label":"Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB)","url":"https://doi.org/10.1056/NEJMoa1801445"}],"tags":["biomarker","lymphoma"],"related":["myd88-l265p"],"cancers":["dlbcl","primary-cns-lymphoma","non-hodgkin-lymphoma"],"sections":[],"technologies":["cgp"],"targets":["cd79b","btk","myd88"],"drugs":["ibrutinib","polatuzumab-vedotin"],"companies":[],"institutions":[],"pathways":["bcr-signalling","inflammation-nfkb"],"terms":["lymphoma-bio-lymphgen","cell-of-origin","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"cd79b","measurement":"sequencing-variant","scoringRule":{"text":"Targeted sequencing of the CD79B ITAM region, reported as mutated or wild-type, usually as part of a lymphoma gene panel rather than alone. It is a different question from CD79b protein expression, which is near-universal in large B-cell lymphoma and is not tested before polatuzumab vedotin.","quote":"In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated.","source":"https://doi.org/10.1038/nature08638","sourceLabel":"Davis et al., Nature 2010"},"thresholds":[],"definedBy":{"label":"Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB)","url":"https://doi.org/10.1056/NEJMoa1801445"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result does not change a licensed treatment today. Together with MYD88 it puts a lymphoma in the group that has shown the most response to BTK inhibitor drugs in research studies, so it may make a trial relevant."},{"id":"ceacam5-expression","kind":"biomarker","name":"CEACAM5 expression","aka":["CEACAM5","CEACAM5-positive","CEACAM5 high","CEA cell adhesion molecule 5 expression"],"tldr":"CEACAM5 is the cell-surface form of the tumour marker CEA, high on many lung and bowel cancers. Tusamitamab ravtansine was tested in CEACAM5-high lung cancer but failed its phase 3 and no approval exists.","summary":"The CARMEN-LC03 trial (NCT04154956) selected non-squamous NSCLC with CEACAM5 expression at 2+ intensity in 50 percent or more of tumour cells by IHC; it did not meet its endpoints and development stopped in 2023. Newer CEACAM5 ADCs and bispecifics are in early trials with similar IHC gates. No label names CEACAM5.","asOf":"2026-09-23","links":[{"label":"ClinicalTrials.gov NCT04154956 (CARMEN-LC03)","url":"https://clinicaltrials.gov/study/NCT04154956"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["trop2-expression"],"cancers":["nsclc","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["tusamitamab-ravtansine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"ceacam5","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"CARMEN-LC03: tusamitamab ravtansine versus docetaxel in CEACAM5-positive non-squamous NSCLC","source":"https://clinicaltrials.gov/study/NCT04154956","sourceLabel":"ClinicalTrials.gov NCT04154956 (CARMEN-LC03)"},"thresholds":[],"definedBy":{"label":"CARMEN-LC03 (NCT04154956): CEACAM5 IHC 2+ in >= 50% of tumour cells","url":"https://clinicaltrials.gov/study/NCT04154956"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"CEACAM5 staining is not a routine test and no approved drug depends on it; the one late-stage antibody-drug conjugate aimed at it did not succeed. Trials of newer CEACAM5 drugs may use the stain to select patients."},{"id":"ctdna-tumour-fraction","kind":"biomarker","name":"Circulating tumour DNA fraction (and what a negative plasma result means)","aka":["ctDNA fraction","circulating tumour DNA fraction","tumour fraction","ctDNA%","cfDNA tumour content","plasma tumour fraction"],"tldr":"How much of the DNA floating in a blood sample came from the cancer. Above a few per cent, a plasma test finds what a biopsy would find; below it, a negative result means the test could not see, not that there is nothing there.","summary":"The number that decides whether a plasma genomic result can be believed. In 45 men with metastatic castration-resistant prostate cancer whose plasma was taken on the day of a metastatic tissue biopsy, 75.6% of samples had a circulating tumour DNA proportion above 2% of total cell-free DNA; in those samples, every somatic mutation found in the matched tissue was also present in plasma, the ranking of variant allele fractions was closely similar, and copy-number calls in actionable genes agreed 88.9% of the time (Wyatt 2017). At scale, 3,129 of 3,334 men with advanced prostate cancer, 94%, had detectable circulating tumour DNA at a median tumour fraction of 7.5%, and 67 of the 72 BRCA1 or BRCA2 mutations found in tissue were also found in plasma, 93%, including 100% of the variants predicted to be germline (Tukachinsky 2021). Two things confound the reading. Tumour fraction tracks disease burden, so plasma performs worst in the low-volume disease where an early answer would help most. And clonal haematopoiesis contributes variants that look somatic: at a 2% threshold, 13 of 69 men had such variants, and 7, 10%, had one in a gene used to decide PARP inhibitor candidacy, most often ATM, with clonal haematopoiesis accounting for almost half of all somatic repair-gene variants detected (Jensen 2021).","asOf":"2026-09-25","links":[{"label":"Wyatt et al., J Natl Cancer Inst 2017: concordance of circulating tumour DNA and matched metastatic tissue biopsy in 45 men with mCRPC","url":"https://doi.org/10.1093/jnci/djx118"},{"label":"Tukachinsky et al., Clin Cancer Res 2021: circulating tumour DNA profiling in 3,334 men with advanced prostate cancer, including 1,674 TRITON screening samples","url":"https://doi.org/10.1158/1078-0432.CCR-20-4805"},{"label":"Jensen et al., JAMA Oncol 2021: clonal haematopoiesis in DNA repair genes interfering with prostate cancer plasma cell-free DNA testing (69 men, paired whole-blood control)","url":"https://doi.org/10.1001/jamaoncol.2020.5161"}],"tags":["biomarker","prostate"],"related":["hrr-gene-mutation","ar-amplification","ctdna-mrd-positive"],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["liquid-biopsy","cgp"],"targets":["brca","androgen-receptor","atm"],"drugs":[],"companies":[],"institutions":[],"pathways":["clonal-evolution","homologous-recombination-repair","clonal-haematopoiesis"],"terms":["ctdna","cfdna","germline-vs-somatic","vus","biopsy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-wyatt-ctdna-tissue-concordance-mcrpc-jnci-2017","paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021","paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018"],"journals":[],"dependsOn":[],"notes":[],"measurement":"ctdna-detection","scoringRule":{"text":"The estimated proportion of cell-free DNA in plasma that derives from tumour, reported with the genomic result; below the assay's tumour-fraction floor a negative result is uninformative rather than negative, and any repair-gene variant used for treatment selection should be checked against a paired whole-blood control.","quote":"Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA.","source":"https://doi.org/10.1093/jnci/djx118","sourceLabel":"Wyatt et al., Journal of the National Cancer Institute 2017"},"thresholds":[],"definedBy":{"label":"Tukachinsky et al., Clin Cancer Res 2021: circulating tumour DNA profiling in 3,334 men with advanced prostate cancer","url":"https://doi.org/10.1158/1078-0432.CCR-20-4805"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A blood test for cancer genes is easier than a bone biopsy and often gives the same answer. If it comes back with nothing found, that is not the same as nothing being there: it can mean the cancer was not shedding enough DNA into the blood that day, and a tissue sample may still be needed."},{"id":"cldn18-2-expression","kind":"biomarker","name":"Claudin 18.2 expression (>= 75% of tumour cells, moderate to strong)","aka":["CLDN18.2","Claudin 18.2 positive","CLDN18.2-positive","claudin 18.2 expression","CLDN18 IHC","CLDN18.2 >= 75%"],"tldr":"Claudin 18.2 is a tight-junction protein exposed on stomach cancer cells. Zolbetuximab requires at least 75 percent of tumour cells to stain moderately or strongly, the strictest expression threshold in any current label.","summary":"Zolbetuximab (Vyloy) is labelled with fluoropyrimidine and platinum chemotherapy for first-line HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2 positive as determined by an FDA-approved test; the SPOTLIGHT and GLOW trials and the VENTANA CLDN18 (43-14A) RxDx Assay define positivity as 75 percent or more of tumour cells with moderate to strong membranous staining. About 38 percent of screened patients met the bar. CLDN18.2 ADCs and CAR-T cells in trials use lower or different cut-offs.","asOf":"2026-09-23","links":[{"label":"VYLOY prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e7695a21-abb6-47ac-93f8-0ece5a9c4409"}],"tags":["biomarker","surface-antigen"],"related":["her2-ihc-3-plus","pd-l1-cps"],"cancers":["gastric","gastric-cldn18-2-positive","pancreatic"],"sections":[],"technologies":[],"targets":[],"drugs":["zolbetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"cldn18-2","measurement":"ihc-score","scoringRule":{"text":"75 percent or more of viable tumour cells with moderate to strong membranous CLDN18 staining on the VENTANA CLDN18 (43-14A) RxDx Assay.","quote":"CLDN18.2 positivity (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining) was determined by immunohistochemistry on gastric or GEJ tumor tissue specimens from all patients with the VENTANA CLDN18 (43‑14A) RxDx Assay performed in a central laboratory.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e7695a21-abb6-47ac-93f8-0ece5a9c4409","sourceLabel":"VYLOY prescribing information"},"thresholds":[{"value":">= 75% of tumour cells with moderate to strong membranous staining","drugId":"zolbetuximab","cancerId":"gastric-cldn18-2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e7695a21-abb6-47ac-93f8-0ece5a9c4409","quote":"VYLOY is a claudin 18.2-directed cytolytic antibody and is indicated in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive as determined by an FDA-approved test","status":"current"}],"tests":[],"assays":["cldn18-ventana"],"companionDiagnostics":[{"device":"VENTANA CLDN18 (43-14A) RxDx Assay","maker":"Ventana Medical Systems (Roche)","drugs":["zolbetuximab"],"indication":"Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma - Tissue","pma":"P230018 (10/18/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If at least three quarters of your stomach cancer cells stain moderately or strongly for claudin 18.2, zolbetuximab can be added to first-line chemotherapy, provided the cancer is HER2-negative. A lower percentage does not qualify under the label, though trials of other claudin 18.2 drugs may accept it. Nausea and vomiting during the first infusions are common and expected."},{"id":"ctdna-mrd-positive","kind":"biomarker","name":"ctDNA MRD positivity (molecular residual disease after curative treatment)","aka":["ctDNA MRD","ctDNA positive","ctDNA-positive","molecular residual disease","MRD-positive ctDNA","Signatera positive","ctDNA detected after surgery"],"tldr":"A ctDNA MRD test looks for the tumour's own mutations in blood after surgery. Detection predicts relapse months before scans, and in 2026 the FDA approved Signatera as the companion test selecting bladder cancer patients for adjuvant atezolizumab.","summary":"Tumour-informed assays (Signatera, RaDaR, NeXT Personal) sequence the tumour first and track a personalised set of variants in plasma; tumour-naive assays (Guardant Reveal) use mutations and methylation without a tumour sample. A positive result is any detection above the assay's calling threshold, reported as detected or not detected with a level. IMvigor011 showed a survival benefit for atezolizumab over placebo in ctDNA-positive muscle-invasive bladder cancer after cystectomy, and the FDA list carries Signatera CDx as the companion diagnostic for Tecentriq in that setting (P260004, 15 May 2026); the Tecentriq label read on 20 May 2026 predates the indication text in the openFDA copy, so the threshold here is quoted from the FDA list. In colorectal cancer the DYNAMIC trial and the ongoing CIRCULATE trials use ctDNA to guide adjuvant chemotherapy. As a genome-wide readout it sits under no target.","asOf":"2026-09-23","links":[{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"label":"TECENTRIQ prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee"},{"label":"Scherer et al., Sci Transl Med 2016: ctDNA genotyping classifies cell of origin and tracks genome evolution in lymphoma (92 patients)","url":"https://doi.org/10.1126/scitranslmed.aai8545"},{"label":"Kurtz et al., Nat Biotechnol 2021: PhasED-seq, phased variants for residual disease detection in B-cell lymphoma (213 participants)","url":"https://doi.org/10.1038/s41587-021-00981-w"}],"tags":["biomarker","genome-wide","ctdna"],"related":["tmb-high","esr1-mutation-ctdna"],"cancers":["urothelial","colorectal","tnbc","nsclc","breast-cancer","tnbc-early","pancreatic","resectable-pdac","dlbcl","non-hodgkin-lymphoma","hodgkin-lymphoma"],"sections":[],"technologies":["ctdna-lymphoma-monitoring"],"targets":[],"drugs":["atezolizumab","signatera","guardant-reveal","radar-mrd","oncodetect","clonoseq"],"companies":[],"institutions":[],"pathways":[],"terms":["ctdna","mrd","tumour-informed-assay","cfdna"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","paper-magbanua-ispy2-ctdna-neoadjuvant-ann-oncol-2021","paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","paper-stecklein-ctdna-rcb-tnbc-residual-disease-npj-2023","paper-garcia-murillas-molecular-relapse-detection-jama-oncol-2019","paper-sausen-ctdna-pancreatic-resection-nat-commun-2015","paper-groot-kras-ctdna-clinical-test-resected-pancreatic-ccr-2019","paper-lee-ctdna-adjuvant-benefit-localized-pancreatic-ann-oncol-2019","paper-pietrasz-ctdna-prognostic-pancreatic-ccr-2017","paper-bernard-ctdna-exodna-pancreatic-gastroenterology-2019","paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016","paper-reinert-ctdna-ultradeep-sequencing-colorectal-jama-oncol-2019","paper-henriksen-ctdna-stage-iii-colorectal-improve-it-ccr-2022","paper-dynamic-nejm-2022","paper-galaxy-signatera-nat-med-2023"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: post-neoadjuvant ctDNA detection carried a distant disease-free survival hazard ratio of 2.99 in BRE12-158 (Radovich 2020) and 3.71 independent of residual cancer burden in an 80-patient registry, positive in 33% overall and 57% of RCB-III (Stecklein 2023); every pathological complete responder in I-SPY 2 was ctDNA-negative (Magbanua 2021). Prospective surveillance in c-TRAK TN detected ctDNA in 27.3% by 12 months but 72% already had metastases and pembrolizumab cleared none (Turner 2023); brain-only relapse escapes detection (1 of 6; Garcia-Murillas 2019). No TNBC approval uses ctDNA; it is a stratification factor in ASCENT-05 and the ZEST design.","Pancreatic ductal adenocarcinoma: ctDNA is detectable in 43 to 62% of localised disease before surgery and in 37 to 49% of patients after it, where it predicts recurrence with 90% sensitivity and 88% specificity at a median lead time of 84 days (Groot 2019) or 6.5 months against computed tomography (Sausen 2015); all 13 patients with postoperative ctDNA recurred, including 7 given adjuvant gemcitabine (Lee 2019). In advanced disease detection means overall survival 6.5 against 19.0 months, with the allele fraction grading the risk (Pietrasz 2017) and exosome DNA adding to it (Bernard 2019). Most assays track only KRAS codon 12, 13 and 61, so the 6 to 12% of KRAS wild-type tumours are invisible; no pancreatic approval or guideline uses ctDNA.","Colorectal cancer: this is the disease where tumour-informed residual disease testing was invented and where it has its only randomised evidence. Postoperative detection carries recurrence hazard ratios of 7 to 18 (Tie 2016, Reinert 2019, Henriksen 2022) and week-4 positivity a hazard ratio of 10 with 18-month disease-free survival of 38.4% against 90.5% (Kotani 2023); detection after adjuvant chemotherapy is worse still (hazard ratios 17.5 and 50.8) and 16 of 20 such patients relapsed despite treatment. DYNAMIC showed that a ctDNA-guided policy cut adjuvant chemotherapy use from 28% to 15% with non-inferior two-year recurrence-free survival in stage II colon cancer (Tie 2022). What is still missing is evidence that escalating treatment on a positive result improves survival, and a negative result is not a cure: 16 of 164 ctDNA-negative stage II patients recurred (Tie 2016).","Lymphoma: plasma sequencing does three different jobs here. It genotypes, including the cell-of-origin call, directly from blood; it measures burden at diagnosis, which correlated with clinical indices and independently predicted outcome across 92 lymphoma patients profiled by CAPP-Seq (Scherer 2016); and it measures residual disease, where PhasED-seq, which uses several somatic mutations carried on the same DNA fragment, reaches the parts-per-million range and found residual disease in a further 25% of participants who were negative by the earlier method after two cycles, and those participants did worse (Kurtz 2021). What is missing is a decision: no lymphoma approval depends on a ctDNA result and no randomised trial has yet changed treatment on one."],"measurement":"ctdna-detection","scoringRule":{"text":"Detection of tumour-derived DNA in plasma above the assay's validated calling threshold after curative treatment (Signatera: two or more of 16 patient-specific variants detected), reported as MRD-positive with a mean tumour molecules per millilitre level.","quote":"Circulating tumor DNA (ctDNA) molecular residual disease (MRD): Signatera CDx (Natera, Inc.) Muscle Invasive Bladder Cancer (MIBC) - Plasma TECENTRIQ (atezolizumab), TECENTRIQ HYBREZA BLA 761347 P260004 (05/15/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"ctDNA MRD-positive by Signatera CDx after cystectomy","drugId":"atezolizumab","cancerId":"urothelial","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"Circulating tumor DNA (ctDNA) molecular residual disease (MRD): ctDNA MRD","status":"current","note":"FDA companion diagnostic row P260004 (15 May 2026) for Tecentriq in muscle-invasive bladder cancer; the atezolizumab label copy read on DailyMed on 23 Sept 2026 (effective 20 May 2026) is the label version to check for the indication text."}],"tests":["signatera","guardant-reveal","radar-mrd","next-personal"],"assays":["signatera-mrd"],"companionDiagnostics":[{"device":"Signatera CDx","maker":"Natera","companyId":"natera","drugs":["atezolizumab"],"indication":"Muscle Invasive Bladder Cancer (MIBC) - Plasma","pma":"P260004 (05/15/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A positive ctDNA test after surgery means traces of the cancer's DNA are still in your blood and relapse is likely without more treatment. In muscle-invasive bladder cancer a positive Signatera result now selects a year of atezolizumab; in bowel cancer it is used in trials and by some teams to decide on chemotherapy. A negative result is reassuring but not a guarantee, and testing is usually repeated over time."},{"id":"dll3-expression","kind":"biomarker","name":"DLL3 expression","aka":["DLL3","DLL3-positive","delta-like ligand 3 expression","DLL3 IHC"],"tldr":"DLL3 sits on the surface of about 85 percent of small-cell lung cancers and almost no normal adult tissue. Tarlatamab is given without a DLL3 test.","summary":"Tarlatamab (Imdelltra) is a DLL3 x CD3 bispecific labelled for extensive-stage small-cell lung cancer after platinum chemotherapy; the DeLLphi trials enrolled without DLL3 selection and the label names DLL3 only as the target. DLL3-directed ADCs, radioligands and CAR-T cells in trials likewise do not gate on expression, and a DLL3 PET tracer is under study.","asOf":"2026-09-23","links":[{"label":"IMDELLTRA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e7b6163-5d83-42ea-82c9-cf7620cdc782"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["b7-h3-expression"],"cancers":["sclc","extensive-stage-sclc","prostate-nepc"],"sections":[],"technologies":[],"targets":[],"drugs":["tarlatamab"],"companies":[],"institutions":[],"pathways":[],"terms":["sclc-molecular-subtypes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-baine-sclc-subtype-immunohistochemistry-jto-2020","paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019"],"journals":[],"dependsOn":[],"notes":["Small-cell lung cancer: DLL3 is switched on downstream of ASCL1, so its expression follows the transcriptional subtype. The ASCL1-dominant (69%) and NEUROD1-dominant (17%) tumours are neuroendocrine-marker high, TTF-1 high and DLL3 high, while the POU2F3 subtype (7%) and the other double-negative tumours are low for all three (Baine 2020). A DLL3-directed medicine is therefore addressed to the neuroendocrine-high majority rather than to the whole disease, and subtype is the reason a DLL3 stain is negative when it is negative."],"target":"dll3","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"IMDELLTRA is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e7b6163-5d83-42ea-82c9-cf7620cdc782","sourceLabel":"IMDELLTRA prescribing information (DailyMed)"},"thresholds":[],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"Tarlatamab does not require a DLL3 test; the target is present in most small-cell lung cancers. Treatment starts in hospital because of the risk of cytokine release in the first cycle."},{"id":"dmmr-ihc","kind":"biomarker","name":"dMMR (mismatch repair deficiency by IHC)","aka":["dMMR","MMR-deficient","mismatch repair deficient","MMRd","loss of MLH1","loss of MSH2","loss of MSH6","loss of PMS2","MMR IHC","MMR protein loss"],"tldr":"dMMR means one of the four mismatch repair proteins is missing from the tumour cell nuclei on a stain. It is the tissue-level twin of MSI-high and opens checkpoint immunotherapy in endometrial, bowel and many other cancers.","summary":"Immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 is read as retained or lost nuclear staining in tumour cells against an internal positive control; loss of any protein is mismatch repair deficient. Paired losses (MLH1 with PMS2, MSH2 with MSH6) reflect the heterodimers. Labels for pembrolizumab (tumour-agnostic, colorectal, endometrial), dostarlimab (endometrial and tumour-agnostic), nivolumab and ipilimumab (colorectal) and durvalumab (endometrial with chemotherapy) use 'MSI-H or dMMR' and name FDA-authorised tests; the VENTANA MMR RxDx Panel and the Agilent MMR IHC Panel pharmDx are the listed companion diagnostics. The dostarlimab label advises testing the primary tumour before temozolomide in gliomas because chemotherapy can alter dMMR results.","asOf":"2026-09-23","links":[{"label":"KEYTRUDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287"},{"label":"Jemperli prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=095eab9f-545a-4f12-bfb7-19477fb901a5"}],"tags":["biomarker","mmr"],"related":["msi-high","tmb-high"],"cancers":["endometrial","endometrial-mmr-deficient","colorectal","gastric-msi-high","metastatic-cancer","tnbc","pancreatic","msi-high-pdac","gallbladder","cholangiocarcinoma","prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","dostarlimab","nivolumab","ipilimumab","durvalumab","ventana-mmr-rxdx"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","mlh1-promoter-methylation","ihc","tumour-agnostic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ren-tnbc-mmr-msi-440-front-oncol-2021","paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021","paper-moreira-lynch-syndrome-identification-jama-2012","paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017","paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019","paper-wardell-biliary-drivers-germline-j-hepatol-2018","paper-guedes-msh2-loss-primary-prostate-ccr-2017","paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: one mismatch repair-deficient tumour (MSH2 loss) among 440 by immunohistochemistry (Ren 2021); yield is too low for routine four-protein staining outside a Lynch syndrome history.","Pancreatic ductal adenocarcinoma: four-protein immunohistochemistry is the recommended first test, with MSI PCR where the result is doubtful and next-generation sequencing where tissue is limited (Luchini 2021); loss of MLH1, MSH2, MSH6 or PMS2 was found in 7 of 833 patients, all with Lynch syndrome (Hu 2018).","Colorectal cancer: four-protein immunohistochemistry (MLH1, MSH2, MSH6, PMS2) on every colorectal cancer is the guideline route, with MSI PCR where the stain is equivocal (Sepulveda 2017). Testing everyone found 100% of Lynch syndrome carriers against 87.8% for the Bethesda guidelines, at the cost of about a third more tests (Moreira 2012). The reflex step matters: loss of MLH1 with PMS2 prompts BRAF V600E or MLH1 promoter methylation testing, because the sporadic route is CIMP-associated methylation rather than a germline variant (Herman 1998, Weisenberger 2006).","Gallbladder and biliary cancer: mismatch repair deficiency is rare (about 1 to 2.5%), and germline MLH1 or MSH2 variants were among the predisposing mutations found in 11% of biliary tract cancer patients (Wardell 2018), so a lost stain should prompt germline testing.","Prostate cancer: MSH2 protein loss in 14 of 1,176 prostatic carcinomas, 1.2%, concentrated in the highest-grade tumours at 8% of 91 with primary Gleason pattern 5 against 0.4% of 1,042 with any other score, and in 2 of 43 small cell carcinomas. Loss was homogeneous within tumours, so it is an early clonal event and the diagnostic block is an adequate place to look; sequencing confirmed loss of function in all 12 tested, with biallelic inactivation and hypermutation in 83% each and germline MSH2 mutation in 3 of 12, 25% (Guedes 2017)."],"target":"mmr","measurement":"ihc-score","scoringRule":{"text":"Loss of nuclear staining for one or more of MLH1, PMS2, MSH2 and MSH6 in tumour cells, with retained staining in internal control cells, is mismatch repair deficient.","quote":"Deficient mismatch repair (dMMR) proteins: MLH1, PMS2, MSH2 and MSH6","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"MSI-H or dMMR, tumour-agnostic","drugId":"pembrolizumab","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.","status":"current"},{"value":"MSI-H or dMMR","drugId":"pembrolizumab","cancerId":"endometrial-mmr-deficient","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation","status":"current"},{"value":"dMMR","drugId":"dostarlimab","cancerId":"endometrial-mmr-deficient","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=095eab9f-545a-4f12-bfb7-19477fb901a5","quote":"Monotherapy Adults with dMMR recurrent or advanced EC and dMMR recurrent or advanced solid tumors 500 mg a JEMPERLI every 3 weeks for 4 cycles followed by 1,000 mg a JEMPERLI every 6 weeks for all cycles thereafter.","status":"current","note":"Dosing table wording; the indications section names dMMR recurrent or advanced endometrial cancer and dMMR solid tumours as determined by an FDA-approved test."},{"value":"MSI-H or dMMR","drugId":"nivolumab","cancerId":"colorectal","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394","quote":"OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC)","status":"current"}],"tests":[],"assays":["mmr-ventana"],"companionDiagnostics":[{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["dostarlimab"],"indication":"Endometrial Carcinoma (EC) - Tissue","pma":"P200019 (04/22/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["dostarlimab"],"indication":"Solid Tumors","pma":"P210001 (08/17/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["pembrolizumab"],"indication":"Solid Tumors","pma":"P210001/S001 (03/21/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["durvalumab"],"indication":"Endometrial Carcinoma (EC) - Tissue","pma":"P210001/S013 (12/18/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"MMR IHC Panel pharmDx (Dako Omnis)","maker":"Agilent Technologies","companyId":"agilent","drugs":["nivolumab","ipilimumab"],"indication":"Colorectal Cancer (CRC) - Tissue","pma":"P250004 (08/15/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your report shows loss of MLH1, PMS2, MSH2 or MSH6, your cancer is mismatch repair deficient. That opens immunotherapy (pembrolizumab, dostarlimab, nivolumab with ipilimumab depending on the cancer) and, because dMMR can be inherited as Lynch syndrome, your team should offer a germline test and advice for relatives. Loss of MLH1 alone is often caused by methylation rather than inheritance; a follow-up test tells the two apart."},{"id":"myc-bcl2-double-expressor","kind":"biomarker","name":"Double expressor: MYC and BCL2 protein together by immunohistochemistry","aka":["Double expressor lymphoma","DEL","MYC and BCL2 co-expression","MYC IHC","BCL2 IHC"],"tldr":"A stain showing that a lymphoma makes a lot of both the growth protein MYC and the survival protein BCL2, without the genes being rearranged. It predicts a worse course, but on its own it does not change the treatment.","summary":"Protein co-expression is several times commoner than rearrangement and is not the same thing. In a 167-patient training cohort treated with R-CHOP, MYC protein was detected in 29% and BCL2 protein in 44%, with both together in 21%; MYC protein correlated with high MYC messenger RNA and with MYC translocation, but the translocation was present in only 11%. MYC protein predicted inferior overall and progression-free survival only when BCL2 protein was present as well, and the finding held in an independent cohort of 140 patients after adjustment for other risk factors (Johnson 2012). In the 442-patient RICOVER series, MYC protein above the 40% threshold was found in 31.8% of tumours, BCL2 in 79.6% and BCL6 in 82.8% (Horn 2013).\n\nThe thresholds are not standardised across laboratories, the antibodies differ, and reading is subjective, which is the main reason this remains a prognostic observation rather than a decision point.","asOf":"2026-09-30","links":[{"label":"Johnson et al., J Clin Oncol 2012: concurrent MYC and BCL2 protein expression in diffuse large B-cell lymphoma treated with R-CHOP","url":"https://doi.org/10.1200/JCO.2011.41.0985"},{"label":"Horn et al., Blood 2013: MYC, BCL2 and BCL6 rearrangement and expression in 442 RICOVER patients","url":"https://doi.org/10.1182/blood-2012-06-435842"}],"tags":["biomarker","lymphoma"],"related":["double-hit-rearrangement","bcl2-rearrangement"],"cancers":["dlbcl","non-hodgkin-lymphoma"],"sections":[],"technologies":["histopathology-ihc"],"targets":["myc-gene","bcl2"],"drugs":[],"companies":[],"institutions":[],"pathways":["myc","apoptosis-bcl2"],"terms":["ihc","cell-of-origin"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"myc-gene","measurement":"ihc-score","scoringRule":{"text":"Immunohistochemistry for MYC and BCL2 read as the percentage of tumour nuclei or cytoplasm staining, with commonly used cut-offs of 40% for MYC and 50% for BCL2; a double expressor is positive for both. The thresholds are not harmonised between laboratories and the stains are read by eye, so two centres can call the same block differently.","quote":"MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001).","source":"https://doi.org/10.1200/JCO.2011.41.0985","sourceLabel":"Johnson et al., Journal of Clinical Oncology 2012"},"thresholds":[],"definedBy":{"label":"Johnson et al., J Clin Oncol 2012: concurrent MYC and BCL2 protein expression in diffuse large B-cell lymphoma treated with R-CHOP","url":"https://doi.org/10.1200/JCO.2011.41.0985"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This is a prognostic label, not a different disease. It does not by itself mean a stronger regimen, and it is not the same as a double hit, which is found by a different test and does change the plan. It is worth asking which of the two a report means, because the names are easy to confuse."},{"id":"double-hit-rearrangement","kind":"biomarker","name":"Double-hit and triple-hit: MYC with BCL2 and BCL6 rearrangement","aka":["Double hit lymphoma","Triple hit lymphoma","DHL","HGBL-DH","high-grade B-cell lymphoma with MYC and BCL2 rearrangements","MYC rearrangement FISH"],"tldr":"A lymphoma that carries a rearrangement of MYC, the gene that drives growth, together with one of BCL2 or BCL6, the genes that stop a cell dying. Having both is far worse than having either, and it usually means a stronger treatment than standard R-CHOP.","summary":"MYC was mapped to the chromosome 8 region translocated to chromosome 2, 14 or 22 in Burkitt lymphoma cells in 1982, and the partner is always an immunoglobulin locus (Dalla-Favera 1982). In Burkitt lymphoma MYC is the defining lesion. In large B-cell lymphoma it is a minority event that matters mostly through what accompanies it: in 442 patients treated on the RICOVER study, MYC was rearranged in 8.8%, BCL2 in 13.5% and BCL6 in 28.7%, and MYC translocation predicted worse survival independently of the International Prognostic Index (Horn 2013).\n\nA double hit is MYC plus BCL2; a triple hit adds BCL6. The two lesions are complementary: MYC drives proliferation and would ordinarily trigger apoptosis, and BCL2 removes that safeguard. The WHO fifth edition recognises high-grade B-cell lymphoma with MYC and BCL2 rearrangements as a separate entity rather than a variant of diffuse large B-cell lymphoma (Alaggio 2022).\n\nThe partner matters. A MYC rearrangement to an immunoglobulin partner carries a worse outlook than one to a non-immunoglobulin partner, which is an argument for a dual-fusion probe rather than a break-apart probe alone.","asOf":"2026-09-30","links":[{"label":"Dalla-Favera et al., PNAS 1982: human c-myc lies in the chromosome 8 region translocated in Burkitt lymphoma","url":"https://doi.org/10.1073/pnas.79.24.7824"},{"label":"Horn et al., Blood 2013: MYC, BCL2 and BCL6 rearrangement and expression in 442 RICOVER patients","url":"https://doi.org/10.1182/blood-2012-06-435842"},{"label":"Alaggio et al., Leukemia 2022: the fifth edition of the WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"}],"tags":["biomarker","lymphoma"],"related":["bcl2-rearrangement","myc-bcl2-double-expressor"],"cancers":["dlbcl","burkitt-lymphoma","non-hodgkin-lymphoma"],"sections":[],"technologies":["cytogenetics-fish"],"targets":["myc-gene","bcl2","bcl6"],"drugs":[],"companies":[],"institutions":[],"pathways":["myc","apoptosis-bcl2","germinal-centre-reaction"],"terms":["fish","cytogenetics","lymphoma-tx-cns-prophylaxis","lymphoma-bio-germinal-centre"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"myc-gene","measurement":"fish-ratio","scoringRule":{"text":"Interphase fluorescence in situ hybridisation for MYC, BCL2 and BCL6, reported as rearranged or not for each. Double hit means MYC plus BCL2 rearrangement, triple hit means MYC plus BCL2 plus BCL6. Most laboratories screen on MYC protein expression and run the full panel where it exceeds the local threshold, which will miss a minority of rearranged cases with low protein.","quote":"MYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab (R)-CHOP treated patients.","source":"https://doi.org/10.1182/blood-2012-06-435842","sourceLabel":"Horn et al., Blood 2013"},"thresholds":[],"definedBy":{"label":"Alaggio et al., Leukemia 2022: the fifth edition of the WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result usually changes the plan. A double-hit lymphoma is generally treated with a more intensive regimen than R-CHOP and with treatment aimed at protecting the brain and spinal cord, because this type reaches them more often. The evidence for the stronger regimen comes from comparisons between groups of patients rather than from a randomised trial, which is worth knowing when weighing the extra side effects."},{"id":"egfr-c797s","kind":"biomarker","name":"EGFR C797S (and its phase with T790M)","aka":["C797S","EGFR C797S","C797S in cis","C797S in trans","Cys797Ser"],"tldr":"A change in the EGFR protein that removes the anchor point the newest lung cancer pills grip. Whether it can be worked around depends on whether it sits on the same copy of the gene as the earlier resistance change or on the other copy.","summary":"Osimertinib and the other third-generation EGFR inhibitors bind covalently to the cysteine at position 797. Substituting serine for that cysteine removes the covalent bond and confers resistance, and it was first identified in plasma from patients progressing on osimertinib (Thress 2015). It was found in 9 of 41 tumours sequenced at osimertinib resistance, 22%, and occurred in the third of patients who retained T790M (Oxnard 2018); cBioPortal records it in 19 of 2,653 lung adenocarcinoma samples in luad_mskcc_2023_met_organotropism and 20 of 2,621 in nsclc_ctdx_msk_2022, cohorts made largely of treated patients resequenced at progression. The result that matters is not the presence of C797S but its allelic phase relative to T790M: in trans, a first-generation and a third-generation inhibitor together can cover both alleles; in cis, neither can, and the options are a fourth-generation or allosteric inhibitor in a trial, an EGFR-MET bispecific antibody, or chemotherapy. Phase can be called from sequencing reads when both variants fall within one read pair, and plasma assays report it inconsistently.","asOf":"2026-09-25","links":[{"label":"Thress et al., Nat Med 2015: acquired EGFR C797S mediates resistance to osimertinib in T790M-positive lung cancer","url":"https://doi.org/10.1038/nm.3854"},{"label":"Oxnard et al., JAMA Oncol 2018: resistance mechanisms after osimertinib in T790M-positive lung cancer (143 and 110 patients)","url":"https://doi.org/10.1001/jamaoncol.2018.2969"},{"label":"cBioPortal study luad_mskcc_2023_met_organotropism (MSK, Cancer Cell 2023; 2,653 MSK-IMPACT lung adenocarcinoma samples, 2,422 with copy number and structural variants)","url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism"}],"tags":["biomarker","resistance"],"related":["egfr-t790m","egfr-exon-19-deletion","egfr-l858r"],"cancers":["nsclc"],"sections":[],"technologies":["cgp","liquid-biopsy"],"targets":["egfr"],"drugs":[],"companies":[],"institutions":[],"pathways":["resistance-routes-map","rtk-activation"],"terms":["resistance","egfr-mutation-subtypes","ctdna"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-thress-nat-med","paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018"],"journals":[],"dependsOn":[],"notes":[],"target":"egfr","measurement":"sequencing-variant","scoringRule":{"text":"Presence of the EGFR p.Cys797Ser substitution on tumour or plasma sequencing, reported together with T790M status and, where the reads allow it, with the allelic phase of the two variants.","quote":"acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M","source":"https://doi.org/10.1038/nm.3854","sourceLabel":"Thress et al., Nature Medicine 2015"},"thresholds":[],"definedBy":{"label":"Oxnard et al., JAMA Oncology 2018: resistance mechanisms after osimertinib in T790M-positive lung cancer","url":"https://doi.org/10.1001/jamaoncol.2018.2969"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result explains why a targeted tablet has stopped working. It does not close off treatment: which options remain depends on a further detail of the sequencing report, and a specialist centre or a trial is often the next step."},{"id":"egfr-exon-19-deletion","kind":"biomarker","name":"EGFR exon 19 deletion","aka":["EGFR ex19del","exon 19 deletion","EGFR del19","E746_A750del","EGFR exon 19 del","classical EGFR mutation"],"tldr":"An exon 19 deletion removes a few amino acids from the EGFR kinase and leaves it switched on. With L858R it makes up about 85 percent of EGFR-mutant lung cancer and is the classic gate for osimertinib and the other EGFR inhibitors.","summary":"In-frame deletions in exon 19 (most often E746_A750del) are the commonest sensitising EGFR mutation in lung adenocarcinoma. Every EGFR tyrosine kinase inhibitor label (osimertinib, erlotinib, gefitinib, afatinib, dacomitinib, and amivantamab with lazertinib) names 'exon 19 deletions or exon 21 L858R substitution mutations' detected by an FDA-approved test; osimertinib is also labelled as adjuvant therapy after resection and with chemoradiation in stage III disease. The cobas EGFR Mutation Test v2 (tissue and plasma), therascreen EGFR RGQ PCR, Oncomine Dx Target Test, FoundationOne CDx and Liquid CDx and Guardant360 CDx are companion diagnostics; the FDA list groups the TKIs under one device indication. Exon 19 deletions respond somewhat better to TKIs than L858R in the pooled trial data.","asOf":"2026-09-23","links":[{"label":"TAGRISSO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7"},{"label":"Rybrevant prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1466c070-9f97-4fa4-a955-6a6b59981fb8"}],"tags":["biomarker","egfr"],"related":["egfr-l858r","egfr-t790m","egfr-exon-20-insertion"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["osimertinib","erlotinib","gefitinib","afatinib","dacomitinib","amivantamab","lazertinib","cobas-egfr-mutation-test","therascreen-cdx","oncomine-dx-target-test","foundationone-cdx","guardant360-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["egfr-exon19-l858r","egfr-mutation-subtypes","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020","paper-zhang-lung-cancer-never-smokers-nat-genet-2021","paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Lung cancer: present in 13 to 19% of adenocarcinomas by cohort, 14.4% of 2,653 in the largest panel series, 18.9% in East Asian disease and 16.4% in never-smoker whole genomes, with E746_A750del the commonest variant (cBioPortal). It is the more responsive of the two classical alleles: exon 19 deletion leads L858R roughly 4 to 3 in Western cohorts and trails it in East Asian disease, and responds more deeply to every generation of inhibitor. Immunohistochemistry is not acceptable for the call (Lindeman 2018)."],"target":"egfr","measurement":"sequencing-variant","scoringRule":{"text":"An in-frame deletion within exon 19 of EGFR detected by PCR or sequencing of tumour tissue, or of plasma cell-free DNA with tissue testing if plasma is negative.","quote":"Exon 19 deletion or exon 21 L858R substitution mutation","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"EGFR exon 19 deletion or exon 21 L858R","drugId":"osimertinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7","quote":"adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.","status":"current"},{"value":"EGFR exon 19 deletion or exon 21 L858R","drugId":"amivantamab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1466c070-9f97-4fa4-a955-6a6b59981fb8","quote":"in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.","status":"current"},{"value":"EGFR exon 19 deletion or exon 21 L858R","drugId":"gefitinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=827d60e8-7e07-41b7-c28b-49ef1c4a5a41","quote":"IRESSA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test","status":"current"},{"value":"EGFR exon 19 deletion or exon 21 L858R","drugId":"dacomitinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4ab27d2f-e385-4e9c-b324-fa69c10b855a","quote":"VIZIMPRO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive","caris-mi-cancer-seek"],"assays":["egfr-cobas-v2","egfr-therascreen","oncomine-dx","foundationone-cdx-panel","guardant360-cdx"],"companionDiagnostics":[{"device":"cobas EGFR Mutation Test v2","maker":"Roche Molecular Systems","drugs":["osimertinib","erlotinib","gefitinib","afatinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue or Plasma","pma":"P120019/S031 (10/27/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen EGFR RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["afatinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P120022 (07/12/2013)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen EGFR RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["dacomitinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P120022/S018 (09/27/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["osimertinib","erlotinib","gefitinib","afatinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P170019 (11/30/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["osimertinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P200010 (08/07/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["gefitinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160045 (06/22/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"An exon 19 deletion means an EGFR tablet, most often osimertinib, or amivantamab with lazertinib, is the first treatment for advanced lung cancer rather than chemotherapy or immunotherapy; after surgery, osimertinib for three years is also on label. Immunotherapy alone does not work well against these tumours, so the labels for PD-1 drugs exclude them."},{"id":"egfr-exon-20-insertion","kind":"biomarker","name":"EGFR exon 20 insertion","aka":["EGFR ex20ins","exon 20 insertion","EGFR exon 20 insertion mutation","EGFR ex20ins NSCLC"],"tldr":"Exon 20 insertions add amino acids after the C-helix of EGFR and make the kinase resistant to the usual EGFR tablets. They account for about a tenth of EGFR mutations and have their own drugs: amivantamab with chemotherapy and sunvozertinib.","summary":"In-frame insertions or duplications in exon 20 (A767_V769dup, D770_N771insSVD and others) are structurally distinct from the classical mutations and do not respond to first- or third-generation TKIs at tolerated doses. Amivantamab is labelled with carboplatin and pemetrexed for first-line NSCLC with EGFR exon 20 insertion mutations (PAPILLON) and alone after platinum chemotherapy; sunvozertinib (Zegfrovy, 2025) is labelled after platinum chemotherapy with the Oncomine Dx Express Test as companion; mobocertinib was withdrawn in 2023. Guardant360 CDx and the Oncomine Dx Target Test carry exon 20 insertion claims for amivantamab. PCR hotspot kits miss many exon 20 insertions, so sequencing is preferred.","asOf":"2026-09-23","links":[{"label":"Rybrevant prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1466c070-9f97-4fa4-a955-6a6b59981fb8"}],"tags":["biomarker","egfr"],"related":["egfr-exon-19-deletion","her2-mutation"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["amivantamab","sunvozertinib","mobocertinib","zipalertinib","guardant360-cdx","oncomine-dx-target-test"],"companies":[],"institutions":[],"pathways":[],"terms":["egfr-exon20-insertion","egfr-mutation-subtypes","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Lung cancer: 1 to 3% of adenocarcinomas and about 5 to 6% of EGFR-mutant cases, 3.4% in never smokers (cBioPortal). The insertion locks the kinase active without opening the drug pocket, so this class does not respond to the inhibitors that work on exon 19 deletions and L858R and needs different medicines. It is also heterogeneous: A767_V769dup, S768_D770dup and the various D770 insertions behave differently, so the specific variant should be reported rather than the class alone."],"target":"egfr","measurement":"sequencing-variant","scoringRule":{"text":"An in-frame insertion or duplication within exon 20 of EGFR (excluding T790M) detected by next-generation sequencing of tumour tissue or plasma.","quote":"Exon 20 insertion mutations","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"EGFR exon 20 insertion","drugId":"amivantamab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1466c070-9f97-4fa4-a955-6a6b59981fb8","status":"current","note":"Rybrevant indications 1.2 and 1.3: with carboplatin and pemetrexed for first-line, and as a single agent after platinum chemotherapy, in NSCLC with EGFR exon 20 insertion mutations as detected by an FDA-approved test."}],"tests":["foundationone-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive"],"assays":["oncomine-dx","guardant360-cdx"],"companionDiagnostics":[{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["amivantamab"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P200010/S001 (05/21/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["amivantamab"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160045/S027 (12/01/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Express Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["sunvozertinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P240040 (07/02/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"An exon 20 insertion is an EGFR mutation that the common EGFR tablets do not treat well. The on-label first treatment is amivantamab with chemotherapy; after chemotherapy, amivantamab alone or sunvozertinib. Make sure the mutation was found by sequencing, because older hotspot tests can miss it."},{"id":"egfr-l858r","kind":"biomarker","name":"EGFR L858R","aka":["L858R","EGFR exon 21 L858R","exon 21 substitution","EGFR L858R mutation","p.L858R"],"tldr":"L858R is a single letter change in exon 21 of EGFR that keeps the kinase active. It is the second commonest sensitising mutation and shares every EGFR inhibitor label with the exon 19 deletion.","summary":"The c.2573T>G substitution in exon 21 replaces leucine 858 with arginine in the activation loop. Labels for osimertinib, erlotinib, gefitinib, afatinib, dacomitinib and amivantamab plus lazertinib name 'exon 21 L858R substitution mutations' alongside exon 19 deletions, and the same companion diagnostics detect both. Trial subgroup analyses (FLAURA, MARIPOSA) show shorter progression-free survival for L858R than for exon 19 deletions on the same drugs, and L858R more often co-occurs with other EGFR variants, which is why some guidelines discuss combination therapy for it.","asOf":"2026-09-23","links":[{"label":"TAGRISSO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7"}],"tags":["biomarker","egfr"],"related":["egfr-exon-19-deletion","egfr-t790m"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["osimertinib","erlotinib","gefitinib","afatinib","dacomitinib","amivantamab","lazertinib","cobas-egfr-mutation-test"],"companies":[],"institutions":[],"pathways":[],"terms":["egfr-exon19-l858r","egfr-mutation-subtypes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020","paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Lung cancer: present in 9 to 21% of adenocarcinomas, 20.9% in the East Asian cohort against 10.9% in the largest Western panel series (cBioPortal). It is the commoner classical allele in East Asian disease and the less responsive one everywhere, which is why combination approaches have shown their largest gains in this group rather than in exon 19 deletion."],"target":"egfr","measurement":"sequencing-variant","scoringRule":{"text":"The EGFR exon 21 c.2573T>G (p.L858R) substitution detected by PCR or sequencing in tumour tissue or plasma.","quote":"Exon 19 deletion or exon 21 L858R substitution mutation","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"EGFR exon 21 L858R (or exon 19 deletion)","drugId":"osimertinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7","quote":"whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.","status":"current"},{"value":"EGFR exon 21 L858R (or exon 19 deletion)","drugId":"lazertinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c417f9ee-2027-4ed5-92ad-3c19266de16c","quote":"LAZCLUZE, in combination with amivantamab, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive"],"assays":["egfr-cobas-v2","egfr-therascreen","oncomine-dx"],"companionDiagnostics":[{"device":"cobas EGFR Mutation Test v2","maker":"Roche Molecular Systems","drugs":["osimertinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P120019/S007 (11/13/2015)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne Liquid CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["osimertinib","erlotinib","gefitinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P190032 (08/26/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"L858R opens the same EGFR treatments as an exon 19 deletion: osimertinib, or amivantamab with lazertinib, as first treatment for advanced lung cancer, and osimertinib after surgery. Responses tend to be a little shorter than with exon 19 deletions, which is one reason your team may discuss adding chemotherapy."},{"id":"egfr-t790m","kind":"biomarker","name":"EGFR T790M","aka":["T790M","EGFR T790M mutation","gatekeeper mutation EGFR","EGFR exon 20 T790M"],"tldr":"T790M is the gatekeeper mutation that lung cancers acquire to escape first- and second-generation EGFR inhibitors. Finding it, in tissue or blood, is the historic gate for osimertinib after an earlier EGFR drug.","summary":"The c.2369C>T (T790M) substitution in exon 20 enlarges the ATP-binding pocket's affinity for ATP and confers resistance to erlotinib, gefitinib and afatinib; it arose in about half of patients progressing on those drugs. Osimertinib's 2015 accelerated approval (AURA) was for metastatic EGFR T790M-positive NSCLC after an EGFR TKI, detected by the cobas EGFR Mutation Test v2 in tissue or plasma, the first plasma companion diagnostic. That indication remains on the label, though first-line osimertinib has made acquired T790M uncommon. FoundationOne CDx and Guardant360 CDx also list T790M in their EGFR claims.","asOf":"2026-09-23","links":[{"label":"TAGRISSO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7"}],"tags":["biomarker","egfr","resistance"],"related":["egfr-exon-19-deletion","egfr-l858r"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["osimertinib","cobas-egfr-mutation-test"],"companies":[],"institutions":[],"pathways":[],"terms":["gatekeeper-mutation","egfr-mutation-subtypes","c797s"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","paper-pao-egfr-t790m-acquired-resistance-plos-med-2005","paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013","paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018","paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Lung cancer: the gatekeeper substitution, found in 98 of 155 rebiopsies after a first-generation inhibitor, 63% (Yu 2013), and first described in one patient who relapsed after two years of remission (Kobayashi 2005) and independently in progressing tumours that had not carried it before treatment (Pao 2005). The guideline requires an assay sensitive to 5% allele fraction for this call (Lindeman 2018). At the next progression the question reverses: T790M was retained in only 32% of tumours resistant to osimertinib, and losing it predicted earlier progression (6.1 against 15.2 months) and a heterogeneous set of competing mechanisms (Oxnard 2018)."],"target":"egfr","measurement":"sequencing-variant","scoringRule":{"text":"The EGFR exon 20 c.2369C>T (p.T790M) substitution detected in tumour tissue or plasma cell-free DNA; a negative plasma result should prompt tissue testing.","quote":"EGFR exon 19 deletions, EGFR exon 21 L858R, and T790M","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"EGFR T790M after prior EGFR TKI","drugId":"osimertinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7","status":"current","note":"Indication 1.4 of the osimertinib label: metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy."}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx"],"assays":["egfr-cobas-v2"],"companionDiagnostics":[{"device":"cobas EGFR Mutation Test v2","maker":"Roche Molecular Systems","drugs":["osimertinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P150044 (09/28/2016)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your lung cancer grew on erlotinib, gefitinib or afatinib and a T790M mutation is found, osimertinib is the on-label next step. The mutation can often be detected in a blood sample; if the blood test is negative the tumour should be biopsied, because blood misses it in a fair share of patients."},{"id":"er-status","kind":"biomarker","name":"ER status (oestrogen receptor by IHC)","aka":["ER status","ER-positive","ER positive","ER+","ER-negative","estrogen receptor status","oestrogen receptor status","ER low positive","ER >= 1%","ER 1-10%"],"tldr":"ER status is whether the tumour's cells carry the oestrogen receptor, read by staining nuclei. One percent or more of stained nuclei is positive and means hormone-blocking treatment can work; 1 to 10 percent is 'low positive' and behaves more like negative.","summary":"The ASCO/CAP 2020 guideline calls a breast cancer ER-positive when at least 1 percent of tumour cell nuclei stain by validated immunohistochemistry, ER-negative below 1 percent, and introduces 'ER low positive' for 1 to 10 percent with a comment that these tumours often behave like ER-negative disease. Every endocrine therapy label (tamoxifen, aromatase inhibitors, fulvestrant) and the CDK4/6 inhibitor, PI3K, AKT and oral SERD labels are written for hormone-receptor-positive or ER-positive disease without restating the 1 percent rule, so the guideline threshold is what laboratories apply. The same 1 percent rule is used for the progesterone receptor.","asOf":"2026-09-23","links":[{"label":"ASCO/CAP estrogen and progesterone receptor testing guideline, 2020 update (Allison et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.19.02309"}],"tags":["biomarker","hormone-receptor"],"related":["pr-status","ki-67-index","esr1-mutation-ctdna"],"cancers":["breast-hr-positive","breast-cancer","hr-positive-early-high-risk","hr-positive-metastatic-post-cdk46","endometrial"],"sections":[],"technologies":[],"targets":[],"drugs":["tamoxifen","letrozole","fulvestrant","palbociclib","ribociclib","abemaciclib","elacestrant","alpelisib","capivasertib"],"companies":[],"institutions":[],"pathways":[],"terms":["hormone-receptor-status","ihc","serd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"estrogen-receptor","measurement":"ihc-score","scoringRule":{"text":"ER-positive: at least 1 percent of tumour cell nuclei stain positive by IHC. ER low positive: 1 to 10 percent. ER-negative: less than 1 percent or no staining, with internal and external controls behaving as expected.","quote":"ER-positive... if ≥ 1% of tumor cell nuclei are immunoreactive","source":"https://doi.org/10.1200/JCO.19.02309","sourceLabel":"ASCO/CAP estrogen and progesterone receptor testing guideline, 2020 update (Allison et al., J Clin Oncol)"},"thresholds":[{"value":"ER-positive (guideline >= 1% nuclei)","drugId":"elacestrant","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa66ae5c-2bd2-4444-8178-b55651e054ef","quote":"ORSERDU is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)‑negative, ESR1 -mutated advanced or metastatic breast cancer","status":"current"},{"value":"Hormone receptor-positive (guideline >= 1% nuclei)","drugId":"alpelisib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b20b4e18-7a4b-4500-a08f-06c6dab0ee5b","quote":"PIQRAY is indicated in combination with fulvestrant for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer","status":"current"},{"value":"Hormone receptor-positive (guideline >= 1% nuclei)","drugId":"capivasertib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf","quote":"in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN -alterations","status":"current"}],"definedBy":{"label":"ASCO/CAP estrogen and progesterone receptor testing guideline, 2020 update (Allison et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.19.02309"},"tests":["oncotype-dx-breast"],"assays":[],"companionDiagnostics":[],"forPatient":"If 1 percent or more of your tumour cells stain for the oestrogen receptor, the cancer is ER-positive and hormone-blocking drugs (tamoxifen, aromatase inhibitors, fulvestrant) are part of treatment, usually with a CDK4/6 inhibitor when the cancer has spread. A result between 1 and 10 percent is 'low positive'; your team may treat it more like ER-negative disease and discuss chemotherapy."},{"id":"esr1-mutation-ctdna","kind":"biomarker","name":"ESR1 mutation (ligand-binding domain, usually in ctDNA)","aka":["ESR1 mutation","ESR1-mutated","ESR1 Y537S","ESR1 D538G","ESR1m","ESR1 mutant breast cancer","acquired ESR1 mutation"],"tldr":"ESR1 mutations arise in the oestrogen receptor's ligand-binding domain after aromatase inhibitor treatment, letting the receptor work without oestrogen. They are usually found in a blood test and select the oral SERDs elacestrant and imlunestrant.","summary":"Mutations between codons 310 and 547 (Y537S, Y537N, D538G, E380Q and others) are acquired under aromatase inhibitors in 30 to 40 percent of metastatic HR-positive breast cancers and are best detected in plasma cell-free DNA because they are subclonal and heterogeneous. Elacestrant (Orserdu, 2023) is labelled for ER-positive HER2-negative ESR1-mutated advanced breast cancer after at least one line of endocrine therapy, as detected by an FDA-authorised test; imlunestrant (Inluriyo, 2025) for the same population; vepdegestrant was added to the Guardant360 CDx claims in 2026. Guardant360 CDx is the listed companion diagnostic for all three. Guidelines recommend repeat plasma testing at each progression because the mutation appears over time.","asOf":"2026-09-23","links":[{"label":"ORSERDU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa66ae5c-2bd2-4444-8178-b55651e054ef"},{"label":"Inluriyo prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5bc172e4-e8a2-441a-be52-279a7f890196"}],"tags":["biomarker","hormone-receptor","resistance"],"related":["er-status","pik3ca-hotspot-mutation"],"cancers":["breast-hr-positive","hr-positive-metastatic-post-cdk46"],"sections":[],"technologies":[],"targets":[],"drugs":["elacestrant","imlunestrant","camizestrant","guardant360-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["esr1-mutation","ctdna","serd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"estrogen-receptor","measurement":"sequencing-variant","scoringRule":{"text":"An ESR1 missense mutation between codons 310 and 547 (or the listed hotspots E380, V422del, S463, L469, L536, Y537, D538) in plasma cell-free DNA or tumour tissue by sequencing.","quote":"ESR1 missense mutations between codons 310 and 547","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"ESR1-mutated, after at least one line of endocrine therapy","drugId":"elacestrant","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa66ae5c-2bd2-4444-8178-b55651e054ef","quote":"ORSERDU is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)‑negative, ESR1 -mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.","status":"current"},{"value":"ESR1-mutated, after at least one line of endocrine therapy","drugId":"imlunestrant","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5bc172e4-e8a2-441a-be52-279a7f890196","quote":"INLURIYO is indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 ( ESR1 )-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.","status":"current"}],"tests":["guardant360-cdx","foundationone-liquid-cdx","foundationone-cdx","tempus-xt"],"assays":["guardant360-cdx","foundationone-liquid-cdx"],"companionDiagnostics":[{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["elacestrant"],"indication":"Breast Cancer - Plasma","pma":"P200010/S010 (01/27/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["imlunestrant"],"indication":"Breast Cancer - Plasma","pma":"P200010/S021 (09/25/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If a blood test finds an ESR1 mutation after your cancer has progressed on an aromatase inhibitor, elacestrant or imlunestrant tablets are on label as the next hormone treatment. The mutation is usually not present at diagnosis, so the blood test is repeated each time the cancer grows; a negative result now does not rule out a positive one later."},{"id":"ezh2-y646-mutation","kind":"biomarker","name":"EZH2 gain-of-function mutation (Tyr646, originally Tyr641)","aka":["EZH2 Y646","EZH2 Y641","EZH2 mutation","EZH2 Tyr641","EZH2-mutant follicular lymphoma"],"tldr":"A change in an enzyme that puts a chemical silencing mark on DNA. The altered enzyme adds too much of the mark, which keeps a lymphoma cell locked in the state it should have grown out of. It is the one lymphoma mutation that currently selects a tablet.","summary":"EZH2 is the catalytic subunit of polycomb repressive complex 2 and writes the H3K27 trimethyl mark. In lymphoma the mutations replace a single tyrosine in the SET domain, Tyr641 in the original numbering and Tyr646 in current usage. They are not simple activating mutations: the altered enzyme is better at converting the di-methyl mark to the tri-methyl mark and worse at making the first methylation, so a cell with one mutant and one wild-type allele accumulates H3K27me3 and holds the germinal-centre programme shut. This is the opposite direction to the loss-of-function EZH2 mutations found in myeloid disease, which is a standing source of confusion in the literature.\n\nThe substitutions occur in 21.7% of germinal-centre diffuse large B-cell lymphomas and 7.2% of follicular lymphomas, and are absent from the activated B-cell-like subtype (Morin 2010). EZH2 mutation with BCL2 translocation defines the EZB genetic subtype (Schmitz 2018).","asOf":"2026-09-30","links":[{"label":"Morin et al., Nat Genet 2010: somatic EZH2 Tyr641 mutations in follicular and germinal-centre diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/ng.518"},{"label":"Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB)","url":"https://doi.org/10.1056/NEJMoa1801445"}],"tags":["biomarker","lymphoma"],"related":["bcl2-rearrangement"],"cancers":["follicular-lymphoma","dlbcl","non-hodgkin-lymphoma"],"sections":[],"technologies":["cgp"],"targets":["ezh2","bcl2"],"drugs":["tazemetostat"],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","germinal-centre-reaction"],"terms":["lymphoma-bio-germinal-centre","lymphoma-bio-lymphgen","flipi","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"ezh2","measurement":"sequencing-variant","scoringRule":{"text":"Targeted sequencing of the EZH2 SET domain, reported as mutated or wild-type. Sensitivity matters because the mutation is usually heterozygous and may be subclonal; it is normally reported from a lymphoma gene panel on tissue.","quote":"These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs.","source":"https://doi.org/10.1038/ng.518","sourceLabel":"Morin et al., Nature Genetics 2010"},"thresholds":[],"definedBy":{"label":"Morin et al., Nat Genet 2010: somatic EZH2 Tyr641 mutations in follicular and germinal-centre diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/ng.518"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"In relapsed follicular lymphoma this result can open a treatment: tazemetostat, a tablet that blocks the altered enzyme. Response rates are higher in people whose lymphoma carries the mutation than in those whose does not, which is why the test is worth asking about at relapse."},{"id":"fcrh5-expression","kind":"biomarker","name":"FcRH5 expression","aka":["FcRH5","FCRL5 expression","FcRH5-positive"],"tldr":"FcRH5 is a third myeloma surface target after BCMA and GPRC5D. Cevostamab, the FcRH5 x CD3 bispecific, is in phase 3; no approval or threshold exists yet.","summary":"FcRH5 is expressed on nearly all myeloma cells and gained on 1q21. Cevostamab is being tested in the phase 3 CAMMA 2 trial (NCT05535244) against standard combinations in relapsed or refractory myeloma after BCMA-directed therapy; trials enrol without an FcRH5 expression threshold. No regulator has approved an FcRH5-directed drug.","asOf":"2026-09-23","links":[{"label":"ClinicalTrials.gov NCT05535244 (CAMMA 2)","url":"https://clinicaltrials.gov/study/NCT05535244"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["bcma-expression","gprc5d-expression"],"cancers":["multiple-myeloma","myeloma-relapsed-refractory"],"sections":[],"technologies":[],"targets":[],"drugs":["cevostamab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"fcrh5","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"Cevostamab in relapsed or refractory multiple myeloma (CAMMA 2)","source":"https://clinicaltrials.gov/study/NCT05535244","sourceLabel":"ClinicalTrials.gov NCT05535244 (CAMMA 2)"},"thresholds":[],"definedBy":{"label":"CAMMA 2: cevostamab versus standard therapy in relapsed or refractory multiple myeloma (NCT05535244)","url":"https://clinicaltrials.gov/study/NCT05535244"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"FcRH5 is not something you will be tested for today; it is the target of cevostamab, an experimental bispecific antibody available in trials for myeloma that has come back after BCMA-directed treatment."},{"id":"fgfr2-fusion-rearrangement","kind":"biomarker","name":"FGFR2 fusion or rearrangement","aka":["FGFR2 fusion","FGFR2 rearrangement","FGFR2-BICC1","FGFR2::BICC1","FGFR2 fusion-positive cholangiocarcinoma","FGFR2 alteration"],"tldr":"FGFR2 fusions occur in 10 to 15 percent of intrahepatic bile duct cancers and almost nowhere else. Pemigatinib and futibatinib are approved for them after a first chemotherapy.","summary":"FGFR2 fusions (BICC1 is the commonest partner) and other rearrangements are detected by RNA or DNA sequencing or FISH. Pemigatinib (Pemazyre, 2020) is labelled for previously treated unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test, FoundationOne CDx being the companion diagnostic; futibatinib (Lytgobi, 2022) for intrahepatic cholangiocarcinoma harbouring FGFR2 gene fusions or other rearrangements. Infigratinib's US approval was withdrawn in 2024. Acquired kinase-domain mutations (N550, V565F) drive resistance and are the target of next-generation FGFR2 inhibitors in trials.","asOf":"2026-09-23","links":[{"label":"PEMAZYRE prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9e1f2222-1d89-4e63-989c-ccebe2ab1eb4"},{"label":"LYTGOBI prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b1332a1-0581-4707-9bf6-1eccfa39bef4"}],"tags":["biomarker","fgfr"],"related":["fgfr3-alteration"],"cancers":["cholangiocarcinoma","intrahepatic-cholangiocarcinoma","biliary-tract-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["pemigatinib","futibatinib","infigratinib","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["fgfr2-fusion","gene-fusion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"fgfr2","measurement":"sequencing-variant","scoringRule":{"text":"An FGFR2 gene fusion or other rearrangement involving the kinase domain, by DNA or RNA sequencing or FISH.","quote":"FGFR2 fusions and select rearrangements","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"FGFR2 fusion or other rearrangement","drugId":"pemigatinib","cancerId":"cholangiocarcinoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9e1f2222-1d89-4e63-989c-ccebe2ab1eb4","quote":"for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.","status":"current"},{"value":"FGFR2 gene fusion or other rearrangement","drugId":"futibatinib","cancerId":"intrahepatic-cholangiocarcinoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b1332a1-0581-4707-9bf6-1eccfa39bef4","quote":"LYTGOBI is indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","tempus-xt","trusight-oncology-comprehensive","caris-mi-profile"],"assays":["foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["pemigatinib"],"indication":"Cholangiocarcinoma - Tissue","pma":"P170019/S013 (04/17/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"An FGFR2 fusion in bile duct cancer means pemigatinib or futibatinib, both tablets, are on label after first chemotherapy. They raise blood phosphate and can affect the eyes, so monitoring is part of treatment. Because the fusion is found in about one in eight intrahepatic cases, every patient with this cancer should have the tumour sequenced."},{"id":"fgfr3-alteration","kind":"biomarker","name":"FGFR3 alteration (mutation or fusion)","aka":["FGFR3 mutation","FGFR3 fusion","FGFR3-TACC3","FGFR3::TACC3","FGFR3 S249C","FGFR3 R248C","FGFR3 Y373C","susceptible FGFR3 genetic alterations","FGFR alteration bladder"],"tldr":"FGFR3 point mutations and TACC3 fusions drive about 15 to 20 percent of advanced bladder cancers. Erdafitinib is approved for tumours with these 'susceptible' alterations after one prior treatment.","summary":"The erdafitinib (Balversa) label covers locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations after at least one line of systemic therapy (THOR); the original 2019 approval also covered FGFR2 fusions, dropped in 2024. The therascreen FGFR RGQ RT-PCR Kit is the companion diagnostic and detects the point mutations R248C, S249C, G370C and Y373C and the FGFR3::TACC3 v1 and v3 fusions from RNA. Sequencing panels report a wider set; the label's word 'susceptible' refers to alterations shown to respond in the trials.","asOf":"2026-09-23","links":[{"label":"BALVERSA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee"}],"tags":["biomarker","fgfr"],"related":["fgfr2-fusion-rearrangement"],"cancers":["urothelial"],"sections":[],"technologies":[],"targets":[],"drugs":["erdafitinib","therascreen-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["fgfr3","gene-fusion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"fgfr3-receptor","measurement":"sequencing-variant","scoringRule":{"text":"An FGFR3 point mutation (R248C, S249C, G370C, Y373C) or FGFR3::TACC3 fusion by the therascreen FGFR RGQ RT-PCR Kit, or a susceptible FGFR3 alteration by sequencing.","quote":"Exon 7: R248C (c.742C>T), S249C (c.746C>G); exon 10: G370C (c.1108G>T) and Y373C (c.1118A>G); and fusions ( FGFR3 - TACC3v1 and FGFR3 - TACC3v3 )","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"Susceptible FGFR3 genetic alteration","drugId":"erdafitinib","cancerId":"urothelial","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a8aa5c0-6c92-4566-8c45-e8f4d1fc20ee","quote":"BALVERSA is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy.","status":"current"}],"tests":["foundationone-cdx","tempus-xt","trusight-oncology-comprehensive","caris-mi-profile"],"assays":["fgfr-therascreen"],"companionDiagnostics":[{"device":"therascreen FGFR RGQ RT-PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["erdafitinib"],"indication":"Urothelial Cancer - Tissue","pma":"P180043 (04/12/2019)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your bladder cancer carries one of the FGFR3 changes the label calls susceptible, erdafitinib tablets are on label after one prior treatment (usually chemotherapy or immunotherapy). Eye checks and phosphate monitoring are part of the treatment. Tumours with FGFR3 alterations may respond less well to immunotherapy, which shapes the order of treatments."},{"id":"flt3-itd","kind":"biomarker","name":"FLT3-ITD (internal tandem duplication)","aka":["FLT3-ITD","FLT3 ITD","FLT3 internal tandem duplication","FLT3-ITD positive","FLT3-ITD allelic ratio","ITD-positive AML"],"tldr":"FLT3-ITD is a duplicated stretch of the FLT3 receptor gene found in about a quarter of acute myeloid leukaemias; it makes relapse more likely and is treated with midostaurin, quizartinib or gilteritinib.","summary":"Internal tandem duplications in the juxtamembrane domain are detected by PCR fragment analysis (the LeukoStrat CDx FLT3 Mutation Assay reports ITD and the TKD mutations D835 and I836) or by sequencing; the allelic ratio once used in ELN risk stratification was dropped in ELN 2022. Midostaurin (Rydapt) is labelled for newly diagnosed FLT3 mutation-positive AML with induction and consolidation chemotherapy; quizartinib (Vanflyta, 2023) specifically for FLT3-ITD-positive newly diagnosed AML including maintenance; gilteritinib (Xospata) for relapsed or refractory AML with a FLT3 mutation. All three name an FDA-approved test, and the LeukoStrat assay is the companion diagnostic for each.","asOf":"2026-09-23","links":[{"label":"VANFLYTA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29cdbcfe-497d-4e78-bb7b-2d4acafe8e86"},{"label":"RYDAPT prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11fa3fc9-6776-49a6-b1c1-653f627c3e58"}],"tags":["biomarker","flt3"],"related":["flt3-tkd","npm1-mutation"],"cancers":["aml","aml-flt3"],"sections":[],"technologies":[],"targets":[],"drugs":["midostaurin","quizartinib","gilteritinib"],"companies":[],"institutions":[],"pathways":[],"terms":["flt3-itd-allelic-ratio"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"flt3","measurement":"sequencing-variant","scoringRule":{"text":"An internal tandem duplication in FLT3 exons 14 to 15 detected by PCR fragment analysis (LeukoStrat CDx) or sequencing of blood or marrow; the assay's positivity uses a signal ratio cut-off of 0.05.","quote":"ITD mutations and TKD mutations D835 and I836","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"FLT3-ITD-positive","drugId":"quizartinib","cancerId":"aml-flt3","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29cdbcfe-497d-4e78-bb7b-2d4acafe8e86","quote":"VANFLYTA is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive as detected by an FDA-approved test","status":"current"},{"value":"FLT3 mutation-positive (ITD or TKD)","drugId":"midostaurin","cancerId":"aml-flt3","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11fa3fc9-6776-49a6-b1c1-653f627c3e58","quote":"Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.","status":"current"},{"value":"FLT3 mutation (ITD or TKD), relapsed or refractory","drugId":"gilteritinib","cancerId":"aml-flt3","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5ff59aa-9c0d-49a8-9053-1f179b482383","quote":"XOSPATA is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.","status":"current"}],"tests":["foundationone-heme","neotype-profiles"],"assays":["flt3-leukostrat"],"companionDiagnostics":[{"device":"LeukoStrat CDx FLT3 Mutation Assay","maker":"Invivoscribe Technologies","drugs":["midostaurin"],"indication":"Acute Myelogenous Leukemia - Peripheral Blood or Bone Marrow","pma":"P160040 (04/28/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"LeukoStrat CDx FLT3 Mutation Assay","maker":"Invivoscribe Technologies","drugs":["gilteritinib"],"indication":"Acute Myelogenous Leukemia - Peripheral Blood or Bone Marrow","pma":"P160040/S002 (11/28/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"LeukoStrat CDx FLT3 Mutation Assay","maker":"Invivoscribe Technologies","drugs":["quizartinib"],"indication":"Acute Myeloid Leukemia (AML) - Peripheral Blood or Bone Marrow","pma":"P160040/S011 (07/20/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A FLT3-ITD result at diagnosis means a FLT3 inhibitor (midostaurin or quizartinib) is added to chemotherapy from the first cycle, and it strengthens the case for a stem cell transplant in first remission. If the leukaemia comes back, gilteritinib tablets are on label. The test must be back within days, so ask that it be sent at diagnosis."},{"id":"flt3-tkd","kind":"biomarker","name":"FLT3-TKD (D835 and I836 tyrosine kinase domain mutations)","aka":["FLT3-TKD","FLT3 TKD","FLT3 D835","FLT3 D835Y","FLT3 I836","FLT3 tyrosine kinase domain mutation"],"tldr":"FLT3-TKD mutations are point changes in the kinase's activation loop, found in about 7 percent of acute myeloid leukaemias. Midostaurin and gilteritinib labels cover them; quizartinib's does not.","summary":"D835 substitutions and I836 deletions in exon 20 activate FLT3 without the duplication seen in ITD; their prognostic weight is neutral in ELN 2022. The LeukoStrat CDx assay detects D835 and I836 alongside ITD, which is why midostaurin (newly diagnosed 'FLT3 mutation-positive' AML) and gilteritinib (relapsed or refractory 'with a FLT3 mutation') cover TKD mutations, while quizartinib is labelled for FLT3-ITD only. TKD mutations, especially D835, also arise as resistance to type II inhibitors such as quizartinib and sorafenib.","asOf":"2026-09-23","links":[{"label":"XOSPATA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5ff59aa-9c0d-49a8-9053-1f179b482383"}],"tags":["biomarker","flt3"],"related":["flt3-itd"],"cancers":["aml","aml-flt3"],"sections":[],"technologies":[],"targets":[],"drugs":["midostaurin","gilteritinib","quizartinib"],"companies":[],"institutions":[],"pathways":[],"terms":["gatekeeper-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"flt3","measurement":"sequencing-variant","scoringRule":{"text":"A FLT3 D835 or I836 mutation in the tyrosine kinase domain by the LeukoStrat CDx assay or sequencing of blood or marrow.","quote":"ITD mutations and TKD mutations D835 and I836","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"FLT3 mutation-positive (includes TKD)","drugId":"midostaurin","cancerId":"aml-flt3","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11fa3fc9-6776-49a6-b1c1-653f627c3e58","quote":"Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test","status":"current"},{"value":"FLT3 mutation (includes TKD), relapsed or refractory","drugId":"gilteritinib","cancerId":"aml-flt3","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5ff59aa-9c0d-49a8-9053-1f179b482383","quote":"relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test","status":"current"}],"tests":["foundationone-heme","neotype-profiles"],"assays":["flt3-leukostrat"],"companionDiagnostics":[{"device":"LeukoStrat CDx FLT3 Mutation Assay","maker":"Invivoscribe Technologies","drugs":["midostaurin","gilteritinib"],"indication":"Acute Myelogenous Leukemia - Peripheral Blood or Bone Marrow","pma":"P160040 (04/28/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A FLT3-TKD mutation means midostaurin can be added to your first chemotherapy and gilteritinib is on label if the leukaemia returns; quizartinib is not approved for TKD-only disease. A TKD mutation that appears later, during treatment with quizartinib, is a sign of resistance and a reason to switch."},{"id":"folr1-expression","kind":"biomarker","name":"Folate receptor alpha expression (FRα-positive, PS2+ >= 75%)","aka":["FRα","FRa","folate receptor alpha positive","FOLR1 expression","FRα-positive","PS2+ >= 75%","FOLR1 IHC"],"tldr":"Folate receptor alpha is a surface protein on most high-grade serous ovarian cancers. Mirvetuximab soravtansine requires FRα-positive disease, scored as at least 75 percent of cells with moderate or strong staining on the Ventana FOLR1 assay.","summary":"Mirvetuximab soravtansine (Elahere) is labelled for FRα-positive platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer after one to three prior regimens, selected with an FDA-approved test; the VENTANA FOLR1 (FOLR-2.1) RxDx Assay scores positive at 75 percent or more of viable tumour cells with moderate (2+) or strong (3+) membrane staining (PS2+ >= 75 percent), the SORAYA and MIRASOL definition. About 35 to 40 percent of high-grade serous cancers are FRα-high by this rule.","asOf":"2026-09-23","links":[{"label":"ELAHERE prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00c424b5-6ccd-48ab-9e88-1986451120e2"}],"tags":["biomarker","surface-antigen"],"related":["brca-somatic","hrd-positive"],"cancers":["ovarian","platinum-resistant-ovarian-cancer","high-grade-serous-ovarian-cancer","endometrial"],"sections":[],"technologies":[],"targets":[],"drugs":["mirvetuximab-soravtansine"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc","platinum-sensitivity"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"folr1","measurement":"ihc-score","scoringRule":{"text":"75 percent or more of viable tumour cells with moderate (2+) or strong (3+) membrane staining intensity (PS2+ >= 75 percent) on the VENTANA FOLR1 (FOLR-2.1) RxDx Assay.","quote":"Select patients for the treatment of platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer with ELAHERE based on the presence of FRα tumor expression","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00c424b5-6ccd-48ab-9e88-1986451120e2","sourceLabel":"ELAHERE prescribing information"},"thresholds":[{"value":"FRα-positive (PS2+ >= 75% on the Ventana FOLR1 assay)","drugId":"mirvetuximab-soravtansine","cancerId":"platinum-resistant-ovarian-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00c424b5-6ccd-48ab-9e88-1986451120e2","quote":"ELAHERE ® is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.","status":"current"}],"tests":[],"assays":["folr1-ventana"],"companionDiagnostics":[{"device":"Ventana FOLR1 (FOLR-2.1) RxDx Assay","maker":"Ventana Medical Systems (Roche)","drugs":["mirvetuximab-soravtansine"],"indication":"Epithelial Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer - Tissue","pma":"P220006 (11/14/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your ovarian cancer is platinum-resistant and at least three quarters of the cells stain moderately or strongly for folate receptor alpha, mirvetuximab soravtansine is on label. Eye examinations before and during treatment are required because the drug can blur vision. Lower expression does not qualify under the current label."},{"id":"brca-germline","kind":"biomarker","name":"Germline BRCA1/2 pathogenic variant (gBRCAm)","aka":["gBRCA","gBRCAm","germline BRCA","germline BRCA1","germline BRCA2","BRCA carrier","inherited BRCA mutation","deleterious germline BRCA mutation"],"tldr":"A germline BRCA1 or BRCA2 variant is inherited and present in every cell, found by a blood test. It selects PARP inhibitors in breast, ovarian, pancreatic and prostate cancer and tells relatives they may carry it too.","summary":"Germline testing sequences BRCA1 and BRCA2 from blood or saliva and classifies variants as pathogenic, likely pathogenic, uncertain, likely benign or benign; labels use 'deleterious or suspected deleterious'. Olaparib is labelled for gBRCAm HER2-negative high-risk early breast cancer (adjuvant, OlympiA), gBRCAm HER2-negative metastatic breast cancer, first-line maintenance of gBRCAm metastatic pancreatic cancer, and germline or somatic BRCA-mutated ovarian cancer; talazoparib for gBRCAm HER2-negative advanced breast cancer; niraparib for recurrent gBRCAm ovarian cancer maintenance. BRACAnalysis CDx (Myriad) is the blood companion diagnostic on the FDA list for olaparib, talazoparib and rucaparib. A germline result triggers cascade testing of relatives and risk-reducing surgery discussions.","asOf":"2026-09-23","links":[{"label":"Lynparza prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa"},{"label":"Talzenna prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13839d4f-6acf-4ffb-a128-79df59319273"}],"tags":["biomarker","brca"],"related":["brca-somatic","hrd-positive","hrr-gene-mutation"],"cancers":["breast-cancer","tnbc","breast-hr-positive","ovarian","high-grade-serous-ovarian-cancer","pancreatic","prostate-mcrpc","tnbc-early","tnbc-metastatic","brca-palb2-pdac","metastatic-pdac","prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["olaparib","talazoparib","niraparib","rucaparib","bracanalysis-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["gbrca-mutation","germline-vs-somatic","hrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-couch-tnbc-germline-17-genes-jco-2015","paper-hahnen-geparsixto-germline-brca-jama-oncol-2017","paper-sharma-tnbc-registry-germline-brca-bcrt-2014","paper-bedrosian-asco-sso-germline-testing-breast-jco-2024","paper-conroy-nhs-r208-mainstream-testing-audit-breast-j-2026","paper-tutt-nat-med","paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","paper-shindo-germline-sporadic-pancreatic-jco-2017","paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022","paper-golan-brca-pancreatic-platinum-survival-bjc-2014","paper-lowery-prospective-germline-exocrine-pancreatic-jnci-2018","paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","paper-castro-germline-brca-prostate-outcomes-jco-2013","paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019","paper-isaacsson-velho-intraductal-germline-dna-repair-prostate-2018"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: germline BRCA1/2 in 11.2% of 1,824 unselected patients (BRCA1 8.5%, BRCA2 2.7%; Couch 2015), 15.4% of 207 registry patients (Sharma 2014) and 17.2% in GeparSixto (Hahnen 2017), so guidelines test every TNBC diagnosis: ASCO-SSO for all breast cancer at 65 or under and any PARP inhibitor candidate (Bedrosian 2024); in England through the National Genomic Test Directory R208 (mainstream breast testing) and R444.1 (PARP inhibitor eligibility) criteria (Conroy 2026). The result selects adjuvant olaparib after residual disease (OlympiA), olaparib or talazoparib in metastatic disease, and carboplatin, which doubled the response rate in carriers in TNT (Tutt 2018).","Pancreatic ductal adenocarcinoma: germline BRCA2 in 1.4 to 2% and BRCA1 in 0.4 to 1% of patients, with any susceptibility gene in 4 to 10% and no family history in most carriers, which is why every diagnosis is offered germline testing (Hu 2018, Shindo 2017, Lowery 2018). The POLO threshold is a deleterious or suspected deleterious germline BRCA1 or BRCA2 variant plus no progression after at least 16 weeks of first-line platinum: maintenance olaparib gave progression-free survival 7.4 against 3.8 months (hazard ratio 0.53) with no significant overall survival difference (19.0 versus 19.2 months) but 3-year survival 33.9% against 17.8% (Golan 2019, Kindler 2022). The same result also selects platinum chemotherapy (Golan 2014).","Prostate cancer: germline BRCA2 in 37 of 692 men with metastatic disease, 5.3%, and BRCA1 in 6, 0.9%, with no difference by family history of prostate cancer or age at diagnosis, which is why testing is offered to every man with metastatic disease rather than to those with a suggestive family history (Pritchard 2016).","Carrying a germline BRCA mutation changes the disease and not only the options: cause-specific survival 15.7 years in non-carriers against 8.6 years in carriers, hazard ratio 1.8, with five-year metastasis-free survival in localised disease 93% against 77% (Castro 2013).","Only 30.7% of positive germline results in a 3,607-man referral cohort were in BRCA1 or BRCA2, so a BRCA-only panel misses most of the inherited findings in this disease (Nicolosi 2019)."],"target":"brca","measurement":"sequencing-variant","scoringRule":{"text":"A pathogenic or likely pathogenic (deleterious or suspected deleterious) BRCA1 or BRCA2 variant detected in germline DNA from blood by sequencing and large rearrangement analysis.","quote":"deleterious or suspected deleterious gBRCAm human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","sourceLabel":"Lynparza prescribing information"},"thresholds":[{"value":"Deleterious or suspected deleterious gBRCAm","drugId":"olaparib","cancerId":"breast-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"Lynparza is indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCA m human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.","status":"current"},{"value":"Deleterious or suspected deleterious gBRCAm","drugId":"olaparib","cancerId":"pancreatic","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.","status":"current"},{"value":"Deleterious or suspected deleterious gBRCAm","drugId":"talazoparib","cancerId":"breast-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13839d4f-6acf-4ffb-a128-79df59319273","quote":"As a single agent, for the treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated (g BRCA m) HER2-negative locally advanced or metastatic breast cancer.","status":"current"},{"value":"Deleterious or suspected deleterious gBRCAmut","drugId":"niraparib","cancerId":"ovarian","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7f675e2-159c-490c-b6f4-3f16d9492b7d","quote":"ZEJULA is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated (g BRCA mut) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.","status":"current"}],"tests":["mychoice-cdx","tempus-xt"],"assays":["bracanalysis-cdx"],"companionDiagnostics":[{"device":"BRACAnalysis CDx","maker":"Myriad Genetic Laboratories","companyId":"myriad-genetics","drugs":["olaparib"],"indication":"Breast Cancer - Whole Blood","pma":"P140020/S012 (01/12/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"BRACAnalysis CDx","maker":"Myriad Genetic Laboratories","companyId":"myriad-genetics","drugs":["talazoparib"],"indication":"Breast Cancer - Whole Blood","pma":"P140020/S015 (10/16/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"BRACAnalysis CDx","maker":"Myriad Genetic Laboratories","companyId":"myriad-genetics","drugs":["olaparib"],"indication":"Ovarian Cancer - Whole Blood","pma":"P140020 (12/19/2014)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"BRACAnalysis CDx","maker":"Myriad Genetic Laboratories","companyId":"myriad-genetics","drugs":["olaparib"],"indication":"Pancreatic Cancer - Whole Blood","pma":"P140020/S019 (12/27/2019)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"BRACAnalysis CDx","maker":"Myriad Genetic Laboratories","companyId":"myriad-genetics","drugs":["olaparib"],"indication":"Metastatic Castrate Resistant Prostate Cancer (mCRPC) - Whole Blood","pma":"P140020/S020 (05/19/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A pathogenic germline BRCA result means the change is inherited. For your treatment it opens PARP inhibitor tablets (olaparib, talazoparib, niraparib or rucaparib depending on the cancer), including a year of olaparib after chemotherapy in high-risk early breast cancer. For your family it means close relatives can be tested and, if positive, offered screening or preventive surgery. A 'variant of uncertain significance' is not a positive result."},{"id":"gprc5d-expression","kind":"biomarker","name":"GPRC5D expression","aka":["GPRC5D","GPRC5D-positive","GPRC5D expression myeloma"],"tldr":"GPRC5D is a receptor on myeloma cells and in hair follicles, nails and taste buds. Talquetamab targets it without any test, and the side effects on skin, nails and taste follow from where it is expressed.","summary":"Talquetamab (Talvey) is a GPRC5D x CD3 bispecific labelled for relapsed or refractory multiple myeloma after at least four prior lines; the label names GPRC5D only as the target. Expression on plasma cells is high and independent of BCMA, which is why GPRC5D-directed therapy works after BCMA failure; GPRC5D loss at relapse has been described.","asOf":"2026-09-23","links":[{"label":"TALVEY prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9001355e-003d-4d4e-b4ce-337e0fd14952"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["bcma-expression","fcrh5-expression"],"cancers":["multiple-myeloma","myeloma-relapsed-refractory"],"sections":[],"technologies":[],"targets":[],"drugs":["talquetamab"],"companies":[],"institutions":[],"pathways":[],"terms":["antigen-escape"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"gprc5d","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"TALVEY is a bispecific GPRC5D-directed CD3 T-cell engager","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9001355e-003d-4d4e-b4ce-337e0fd14952","sourceLabel":"TALVEY prescribing information (DailyMed)"},"thresholds":[],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"Talquetamab is given without a GPRC5D test. Because the same receptor sits in your skin, nails and taste buds, changes in taste, dry mouth, rash and nail problems are expected and are managed rather than treated as a sign the drug is not working."},{"id":"h3-k27m","kind":"biomarker","name":"H3 K27M mutation","aka":["H3 K27M","H3K27M","H3F3A K27M","H3-3A K27M","K27M","H3 K27-altered","H3 K27M-mutant diffuse midline glioma"],"tldr":"H3 K27M is a single change in a histone that defines diffuse midline glioma, including the brain-stem tumour DIPG. In 2025 dordaviprone became the first drug approved for tumours carrying it.","summary":"The K27M substitution in H3-3A (or H3C2/H3C3, the H3.1 genes) is detected by a mutation-specific antibody on immunohistochemistry or by sequencing; WHO CNS5 groups these tumours as diffuse midline glioma, H3 K27-altered, grade 4. Dordaviprone (Modeyso, August 2025, accelerated approval) is labelled for adult and paediatric patients from one year with diffuse midline glioma harbouring an H3 K27M mutation and progressive disease after prior therapy. Radiotherapy remains the first treatment; the ACTION trial (NCT05580562) tests dordaviprone after radiotherapy.","asOf":"2026-09-23","links":[{"label":"MODEYSO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ad45b43e-fdef-47ad-9c34-055b41bdc576"}],"tags":["biomarker","glioma","paediatric"],"related":["mgmt-promoter-methylation","idh1-r132"],"cancers":["dipg-dmg","paediatric-high-grade-glioma"],"sections":[],"technologies":[],"targets":[],"drugs":["dordaviprone"],"companies":[],"institutions":[],"pathways":[],"terms":["h3k27m"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"h3-3a","measurement":"sequencing-variant","scoringRule":{"text":"The H3 K27M substitution by immunohistochemistry with a mutation-specific antibody (with loss of H3K27me3 staining) or by sequencing of H3-3A, H3C2 or H3C3.","quote":"MODEYSO is indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ad45b43e-fdef-47ad-9c34-055b41bdc576","sourceLabel":"MODEYSO prescribing information"},"thresholds":[{"value":"H3 K27M mutation, progressive disease after prior therapy","drugId":"dordaviprone","cancerId":"dipg-dmg","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ad45b43e-fdef-47ad-9c34-055b41bdc576","quote":"MODEYSO is indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy.","status":"current"}],"tests":["caris-mi-profile","foundationone-cdx","tempus-xt"],"assays":[],"companionDiagnostics":[],"forPatient":"An H3 K27M result confirms a diffuse midline glioma. Radiotherapy is still the first treatment, and if the tumour grows afterwards dordaviprone capsules are now on label for adults and children over one year. Trials of dordaviprone given straight after radiotherapy are recruiting."},{"id":"her2-mutation","kind":"biomarker","name":"HER2 (ERBB2) activating mutation","aka":["HER2 mutation","ERBB2 mutation","HER2-mutant NSCLC","ERBB2 exon 20 insertion","HER2 tyrosine kinase domain mutation","HER2 YVMA insertion","HER2 TKD mutation"],"tldr":"A HER2 mutation is a change in the gene's kinase domain, most often an exon 20 insertion, found in about 2 to 3 percent of lung adenocarcinomas. It is a different thing from HER2 amplification or overexpression, and it selects trastuzumab deruxtecan and, since 2025, zongertinib in lung cancer.","summary":"Activating ERBB2 mutations cluster in the tyrosine kinase domain (exons 18 to 21), the commonest being the exon 20 insertion A775_G776insYVMA; they are detected by sequencing of tumour tissue or plasma. Trastuzumab deruxtecan's label covers unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations in tumour or plasma specimens after prior systemic therapy (DESTINY-Lung02). Zongertinib (Hernexeos), approved in 2025, is labelled for non-squamous NSCLC with HER2 (ERBB2) tyrosine kinase domain activating mutations detected by an FDA-authorised test, testing plasma first and tissue if plasma is negative. The FDA list carries the Oncomine Dx Target Test and Guardant360 CDx for both drugs.","asOf":"2026-09-23","links":[{"label":"ENHERTU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6"},{"label":"HERNEXEOS prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d3fabf12-354e-4e5c-b5de-20fdb579b783"}],"tags":["biomarker","her2"],"related":["her2-ihc-3-plus","her2-ish-amplified","egfr-exon-20-insertion"],"cancers":["nsclc","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","zongertinib","oncomine-dx-target-test","guardant360-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["ngs","egfr-exon20-insertion","her2-testing-in-biliary-cancer"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-mondaca-erbb2-gallbladder-us-chile-jco-go-2024","paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-kris-lung-cancer-mutation-consortium-jama-2014","paper-zhang-lung-cancer-never-smokers-nat-genet-2021"],"journals":[],"dependsOn":[],"notes":["Gallbladder cancer: ERBB2 mutation without amplification in 4% of 260 patients, plus 1.5% with both and 0.4% fusion (Mondaca 2024); the extracellular S310F/Y hotspot predominated among Indian ERBB2 alterations (Suryavanshi 2025). These are not seen by IHC or ISH and fall outside the zanidatamab label; they were among the HER2-expressing or mutant tumours in the tumour-agnostic trastuzumab deruxtecan programme only where IHC was also positive.","Lung cancer: exon 20 insertions in 1.9 to 2.2% of adenocarcinomas and 3.4% of never-smoker cases, with Y772_A775dup the dominant allele; any ERBB2 mutation reaches about 4% (cBioPortal; Kris 2014). This is the licensed HER2 readout in lung cancer, and it is separate from amplification and from immunohistochemistry, neither of which selects the oral HER2 inhibitors here. Kinase-domain missense variants (L755P, V777L, V842I) and the extracellular S310F are further separate classes not covered by the exon 20 indications."],"target":"her2","measurement":"sequencing-variant","scoringRule":{"text":"Presence of an activating ERBB2 mutation (single nucleotide variants in exons 18 to 21 of the tyrosine kinase domain or exon 20 insertions) by sequencing of tumour tissue or plasma; a negative plasma result should be followed by tissue testing.","quote":"ERBB2/HER2 activating mutations (SNVs in exons 18-21 within the tyrosine kinase domain and exon 20 insertions)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"Activating HER2 (ERBB2) mutation, tumour or plasma","drugId":"trastuzumab-deruxtecan","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens","status":"current"},{"value":"HER2 (ERBB2) tyrosine kinase domain activating mutation","drugId":"zongertinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d3fabf12-354e-4e5c-b5de-20fdb579b783","quote":"HERNEXEOS is indicated for the treatment of adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations, as detected by an FDA-authorized test","status":"current"}],"tests":["foundationone-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive"],"assays":["oncomine-dx","guardant360-cdx"],"companionDiagnostics":[{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["trastuzumab-deruxtecan"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160045/S035 (08/11/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["trastuzumab-deruxtecan"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P200010/S008 (08/11/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["zongertinib"],"indication":"Non-Small Cell Lung cancer (NSCLC) - Tissue","pma":"P160045/S049 (08/08/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["zongertinib"],"indication":"Non-small cell lung cancer (NSCLC) - Plasma","pma":"P200010/S027 (06/10/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A HER2 mutation in lung cancer is found by a gene sequencing test, not by the HER2 stain used in breast cancer. If your report shows one, zongertinib is an on-label first treatment and trastuzumab deruxtecan is on label after prior treatment. If only a blood test was done and it was negative, the label asks for the tumour tissue to be tested too."},{"id":"her2-ihc-0","kind":"biomarker","name":"HER2 IHC 0 (HER2-negative, including ultralow)","aka":["HER2 IHC 0","HER2 0","IHC 0","HER2-negative IHC","HER2 null","IHC 0 with membrane staining"],"tldr":"IHC 0 is no HER2 staining, or faint staining in 10 percent or fewer cells. It is HER2-negative, but the label now separates true zero from 'IHC 0 with membrane staining', the ultralow group that trastuzumab deruxtecan can treat in hormone-receptor-positive breast cancer.","summary":"The ASCO/CAP 0 band covers no staining and incomplete faint staining in 10 percent or fewer of tumour cells; the guideline treats it as a single negative category. DESTINY-Breast06 split it: tumours with any faint, incomplete membrane staining in 10 percent or fewer cells ('HER2-ultralow') responded to trastuzumab deruxtecan like HER2-low tumours, and the US label was expanded in January 2025 to HER2-low or HER2-ultralow (IHC 0 with membrane staining) HR-positive breast cancer after endocrine therapy. A true 0 with no staining at all remains outside every HER2-directed label. Distinguishing 0 from ultralow at the low end of the scale is the hardest read in HER2 pathology and the reason AI-assisted scoring is being validated.","asOf":"2026-09-23","links":[{"label":"ENHERTU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6"},{"label":"ASCO/CAP HER2 testing in breast cancer guideline, 2018 focused update (Wolff et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.2018.77.8738"}],"tags":["biomarker","her2"],"related":["her2-ultralow","her2-ihc-1-plus","her2-low-ihc"],"cancers":["breast-cancer","her2-low-metastatic-breast-cancer","breast-hr-positive","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","her2-testing-assays"],"companies":[],"institutions":[],"pathways":[],"terms":["her2-low","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"her2","measurement":"ihc-score","scoringRule":{"text":"0: no staining, or incomplete faint membrane staining in 10 percent or fewer of tumour cells. 'IHC 0 with membrane staining' (ultralow) is the sub-band with faint incomplete staining in 10 percent or fewer cells.","quote":"HER2-ultralow (IHC 0 with membrane staining) breast cancer","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","sourceLabel":"ENHERTU prescribing information; scoring band from the ASCO/CAP 2018 guideline"},"thresholds":[{"value":"IHC 0 with membrane staining (ultralow), HR-positive","drugId":"trastuzumab-deruxtecan","cancerId":"her2-low-metastatic-breast-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression","status":"current"}],"tests":[],"assays":["her2-herceptest","her2-pathway-4b5"],"companionDiagnostics":[{"device":"PATHWAY anti-Her2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan"],"indication":"Breast Cancer - Tissue","pma":"P990081/S055 (01/27/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A 0 result means HER2-directed antibodies such as trastuzumab are not used. If your breast cancer is hormone-receptor-positive, ask whether the 0 was a true zero or 'with membrane staining' (ultralow), because the ultralow group can now receive trastuzumab deruxtecan once hormone therapy has stopped working."},{"id":"her2-ihc-1-plus","kind":"biomarker","name":"HER2 IHC 1+","aka":["HER2 IHC 1+","HER2 1+","IHC 1+","HER2 1+ breast cancer"],"tldr":"IHC 1+ is faint, incomplete HER2 staining. It was called HER2-negative for twenty years; since 2022 it is the larger half of HER2-low, which trastuzumab deruxtecan treats in breast cancer.","summary":"1+ is incomplete, faint or barely perceptible membrane staining in more than 10 percent of tumour cells. Under the ASCO/CAP guideline it is HER2-negative for trastuzumab purposes, and no gene test is needed. The DESTINY-Breast04 trial (2022) and DESTINY-Breast06 (2025) defined HER2-low as IHC 1+ or IHC 2+/ISH-, and trastuzumab deruxtecan's US label adopts that wording, so a 1+ result now selects for an antibody-drug conjugate that the parent antibody trastuzumab would not be given for. About half of breast cancers once labelled HER2-negative fall into 1+.","asOf":"2026-09-23","links":[{"label":"ENHERTU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6"},{"label":"ASCO/CAP HER2 testing in breast cancer guideline, 2018 focused update (Wolff et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.2018.77.8738"}],"tags":["biomarker","her2"],"related":["her2-low-ihc","her2-ihc-0","her2-ihc-2-plus"],"cancers":["breast-cancer","her2-low-metastatic-breast-cancer","breast-hr-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","her2-testing-assays"],"companies":[],"institutions":[],"pathways":[],"terms":["her2-low","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"her2","measurement":"ihc-score","scoringRule":{"text":"1+: incomplete membrane staining that is faint or barely perceptible in more than 10 percent of tumour cells; HER2-negative under ASCO/CAP, HER2-low for trastuzumab deruxtecan.","quote":"HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","sourceLabel":"ENHERTU prescribing information; scoring band from the ASCO/CAP 2018 guideline"},"thresholds":[{"value":"IHC 1+ (HER2-low)","drugId":"trastuzumab-deruxtecan","cancerId":"her2-low-metastatic-breast-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression","status":"current"}],"tests":[],"assays":["her2-herceptest","her2-pathway-4b5"],"companionDiagnostics":[{"device":"PATHWAY anti-Her2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan"],"indication":"Breast Cancer - Tissue","pma":"P990081/S047 (09/30/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A 1+ result still counts as HER2-negative for trastuzumab, but in breast cancer it now means HER2-low, and trastuzumab deruxtecan is on label once the cancer has spread and earlier chemotherapy or hormone therapy has stopped working. If your report is older than 2022 the 1+ score may not have been mentioned to you; it is worth asking."},{"id":"her2-ihc-2-plus","kind":"biomarker","name":"HER2 IHC 2+ (equivocal, reflex to ISH)","aka":["HER2 IHC 2+","HER2 2+","IHC 2+","HER2 equivocal","2+/ISH","IHC 2+/ISH-negative","IHC 2+/ISH+"],"tldr":"IHC 2+ is the in-between HER2 result: moderate staining that cannot be called positive or negative by eye, so the laboratory runs an ISH gene test. 2+ with amplification is HER2-positive; 2+ without it is HER2-low.","summary":"A 2+ score is weak to moderate complete membrane staining in more than 10 percent of tumour cells (or intense complete staining in 10 percent or fewer) and is equivocal under ASCO/CAP; reflex in situ hybridisation decides. The result matters twice over: IHC 2+/ISH+ counts as HER2-positive for trastuzumab, pertuzumab, trastuzumab emtansine and trastuzumab deruxtecan, while IHC 2+/ISH- is one of the two HER2-low categories for trastuzumab deruxtecan after chemotherapy (DESTINY-Breast04) or after endocrine therapy (DESTINY-Breast06). In gastric cancer the trastuzumab label defines positivity as IHC 3+ or IHC 2+ with a positive ISH.","asOf":"2026-09-23","links":[{"label":"ENHERTU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6"},{"label":"ASCO/CAP HER2 testing in breast cancer guideline, 2018 focused update (Wolff et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.2018.77.8738"}],"tags":["biomarker","her2"],"related":["her2-ihc-3-plus","her2-ish-amplified","her2-low-ihc"],"cancers":["breast-cancer","her2-low-metastatic-breast-cancer","gastric-her2-positive","gallbladder","biliary-tract-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","trastuzumab","her2-testing-assays"],"companies":[],"institutions":[],"pathways":[],"terms":["her2-positive","her2-low","fish","ihc","her2-testing-in-biliary-cancer"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-angerilli-her2-ihc-cish-biliary-hum-pathol-2026","paper-harding-lancet-oncol"],"journals":[],"dependsOn":[],"notes":["Gallbladder and biliary cancer: IHC 2+ was 8.6% of 140 resected biliary cancers and only a subset were amplified on chromogenic ISH, with a lower mean ERBB2/CEP17 ratio (3.9) than 3+ tumours (6.2) (Angerilli 2026). HERIZON-BTC-01 counted ISH-confirmed 2+ as HER2-positive (Harding 2023), but the zanidatamab label is written at IHC 3+, so a 2+ result needs ISH and, even when amplified, is off-label in the United States."],"target":"her2","measurement":"ihc-score","scoringRule":{"text":"2+: weak to moderate complete membrane staining in more than 10 percent of tumour cells, or intense complete staining in 10 percent or fewer; classified equivocal and reflexed to in situ hybridisation.","quote":"HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","sourceLabel":"ENHERTU prescribing information; scoring band from the ASCO/CAP 2018 guideline"},"thresholds":[{"value":"IHC 2+/ISH+ (HER2-positive)","drugId":"trastuzumab-deruxtecan","cancerId":"gastric-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH+)","status":"current"},{"value":"IHC 2+/ISH- (HER2-low)","drugId":"trastuzumab-deruxtecan","cancerId":"her2-low-metastatic-breast-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy","status":"current"}],"tests":[],"assays":["her2-herceptest","her2-pathway-4b5","her2-ish"],"companionDiagnostics":[{"device":"PATHWAY anti-Her2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan"],"indication":"Breast Cancer - Tissue","pma":"P990081/S047 (09/30/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A 2+ result is not final. Your pathologist should run an ISH gene test on the same sample: if the HER2 gene is amplified the cancer is HER2-positive and trastuzumab-based treatment applies; if it is not, the cancer is HER2-low, which in breast cancer opens trastuzumab deruxtecan after earlier treatment."},{"id":"her2-ihc-3-plus","kind":"biomarker","name":"HER2 IHC 3+ (HER2-positive by immunohistochemistry)","aka":["HER2 IHC 3+","HER2 3+","IHC 3+","HER2 overexpression","HER2-positive IHC","HER2 protein overexpression"],"tldr":"IHC 3+ means strong, complete membrane staining for HER2 in more than 10 percent of tumour cells. It is HER2-positive without needing a gene test and is the gate for trastuzumab, its combinations and antibody-drug conjugates in breast, stomach, biliary and, since 2024, any solid tumour.","summary":"Under the ASCO/CAP guideline an IHC score of 3+ is circumferential membrane staining that is complete, intense and in more than 10 percent of tumour cells; 3+ is HER2-positive on its own, 2+ is equivocal and goes to in situ hybridisation, 0 and 1+ are negative for trastuzumab purposes. Trastuzumab, pertuzumab, trastuzumab emtansine, tucatinib, margetuximab and neratinib are labelled for HER2-positive (overexpressing or amplified) breast cancer; trastuzumab is labelled for HER2-overexpressing gastric or GEJ adenocarcinoma, where the gastric scoring rules allow incomplete basolateral staining. Trastuzumab deruxtecan is labelled for HER2-positive (IHC 3+ or ISH+) breast cancer and, tumour-agnostically, for HER2-positive (IHC 3+) solid tumours after prior therapy, where the label notes no FDA-authorised test yet exists. Zanidatamab is labelled for HER2-positive (IHC 3+) biliary tract cancer and, with chemotherapy, IHC 3+ gastro-oesophageal adenocarcinoma.","asOf":"2026-09-23","links":[{"label":"ENHERTU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6"},{"label":"Herceptin prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=492dbdb2-077e-4064-bff3-372d6af0a7a2"},{"label":"ASCO/CAP HER2 testing in breast cancer guideline, 2018 focused update (Wolff et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.2018.77.8738"}],"tags":["biomarker","her2"],"related":["her2-ihc-2-plus","her2-ihc-1-plus","her2-ihc-0","her2-low-ihc","her2-ultralow","her2-ish-amplified","her2-mutation"],"cancers":["breast-her2-positive","her2-positive-early-breast-cancer","gastric-her2-positive","biliary-tract-cancer","metastatic-cancer","colorectal","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","pertuzumab","trastuzumab-emtansine","trastuzumab-deruxtecan","tucatinib","margetuximab","neratinib","zanidatamab","her2-testing-assays"],"companies":[],"institutions":[],"pathways":[],"terms":["her2-positive","ihc","dual-her2-blockade","her2-testing-in-biliary-cancer"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-valtorta-her2-scoring-colorectal-heracles-mod-pathol-2015","paper-richman-her2-amplification-quasar-focus-piccolo-j-pathol-2016","paper-harding-lancet-oncol","paper-angerilli-her2-ihc-cish-biliary-hum-pathol-2026","paper-hiraoka-her2-status-biliary-hum-pathol-2020","paper-oh-destiny-pantumor02-biliary-pancreatic-esmo-open-2026"],"journals":[],"dependsOn":[],"notes":["Colorectal cancer: the colorectal-specific rule requires intense membranous staining in more than 50% of cells, against the 10% used in gastric cancer, because the colorectal-specific criteria were written and validated separately on 256 archival and 830 screening samples (Valtorta 2015). Overexpression was found in 2.2% of stage IV and 1.3% of stage II-III patients, and rose to 5.2% in KRAS and BRAF wild-type stage IV disease (Richman 2016).","Gallbladder and biliary cancer: HERIZON-BTC-01 confirmed ERBB2 amplification by central in situ hybridisation and treated IHC 2+ or 3+ as HER2-positive (Harding 2023); the zanidatamab label requires IHC 3+ with the Ventana PATHWAY 4B5 assay. Scoring follows the gastro-oesophageal guideline, which accepts incomplete basolateral staining. In 140 resected biliary cancers 6.4% were 3+, every 3+ tumour was amplified, and staining often involved under half of tumour cells (Angerilli 2026); heterogeneity was seen in 83% of HER2-positive biliary cancers, with loss in deeper invasive areas (Hiraoka 2020). In the DESTINY-PanTumor02 biliary cohort the objective response rate was 56.3% in centrally confirmed IHC 3+ tumours against 22.0% overall (Oh 2026)."],"target":"her2","measurement":"ihc-score","scoringRule":{"text":"3+: circumferential membrane staining that is complete, intense and in more than 10 percent of tumour cells. 2+: weak to moderate complete staining in more than 10 percent, or intense complete staining in 10 percent or less (equivocal, reflex to ISH). 1+: incomplete faint staining in more than 10 percent. 0: no staining or incomplete faint staining in 10 percent or less.","quote":"HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","sourceLabel":"ENHERTU prescribing information; scoring bands from the ASCO/CAP 2018 guideline"},"thresholds":[{"value":"IHC 3+ or ISH+","drugId":"trastuzumab-deruxtecan","cancerId":"breast-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"ENHERTU, in combination with pertuzumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test","status":"current"},{"value":"IHC 3+","drugId":"trastuzumab-deruxtecan","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens","status":"current","note":"The label adds: An FDA-authorized test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with ENHERTU is not currently available."},{"value":"IHC 3+ or IHC 2+/ISH+","drugId":"trastuzumab-deruxtecan","cancerId":"gastric-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"Select patients with locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH+).","status":"current"},{"value":"HER2 overexpression or amplification","drugId":"trastuzumab","cancerId":"breast-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=492dbdb2-077e-4064-bff3-372d6af0a7a2","quote":"Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens","status":"current"},{"value":"HER2 overexpression (gastric scoring)","drugId":"trastuzumab","cancerId":"gastric-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=492dbdb2-077e-4064-bff3-372d6af0a7a2","quote":"Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-authorized tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.","status":"current"},{"value":"IHC 3+","drugId":"zanidatamab","cancerId":"biliary-tract-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae5d9425-fae5-4541-a158-150998343348","quote":"Select patients for treatment of unresectable or metastatic biliary tract cancer based on HER2-positive (IHC 3+) tumor specimens, as detected by an FDA-authorized test","status":"current"},{"value":"IHC 3+ (with chemotherapy) or IHC 3+ or IHC 2+/ISH+ (with chemotherapy and tislelizumab)","drugId":"zanidatamab","cancerId":"gastric-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae5d9425-fae5-4541-a158-150998343348","quote":"in combination with fluoropyrimidine- and platinum-containing chemotherapy, and tislelizumab-jsgr, as first-line treatment of adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test.","status":"current"},{"value":"HER2-positive","drugId":"trastuzumab-emtansine","cancerId":"breast-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=23f3c1f4-0fc8-4804-a9e3-04cf25dd302e","quote":"Assessment of HER2 protein overexpression and/or HER2 gene amplification should be performed using FDA-authorized tests specific for breast cancers by laboratories with demonstrated proficiency.","status":"current"}],"tests":["caris-mi-profile"],"assays":["her2-herceptest","her2-pathway-4b5"],"companionDiagnostics":[{"device":"HercepTest","maker":"Dako Denmark A/S (Agilent)","companyId":"agilent","drugs":["trastuzumab"],"indication":"Breast Cancer - Tissue","pma":"P980018 (09/25/1998)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"HercepTest","maker":"Dako Denmark A/S (Agilent)","companyId":"agilent","drugs":["trastuzumab"],"indication":"Gastric and Gastroesophageal Cancer - Tissue","pma":"P980018/S010 (10/20/2010)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab"],"indication":"Breast Cancer - Tissue","pma":"P990081 (11/28/2000)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["zanidatamab"],"indication":"Biliary Tract Cancer (gallbladder adenocarcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma) - Tissue","pma":"P990081/S054 (11/20/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan","pertuzumab"],"indication":"Breast Cancer - Tissue","pma":"P990081/S059 (12/15/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Bond Oracle HER2 IHC System","maker":"Leica Biosystems","drugs":["trastuzumab"],"indication":"Breast Cancer - Tissue","pma":"P090015 (04/18/2012)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A 3+ result means your cancer makes a lot of HER2 and is HER2-positive; no further gene test is needed. In breast and stomach cancer it opens trastuzumab-based treatment; since 2024 trastuzumab deruxtecan can be used for a 3+ tumour of almost any type once other treatments have been tried. A 2+ result is not an answer on its own and should be followed by an ISH test."},{"id":"her2-ish-amplified","kind":"biomarker","name":"HER2 ISH amplified (ERBB2 gene amplification)","aka":["HER2 ISH+","HER2 FISH positive","ERBB2 amplification","HER2 amplified","HER2/CEP17 ratio >= 2.0","HER2 gene amplification","HER2 Dual ISH"],"tldr":"ISH counts copies of the HER2 gene in each tumour cell. A ratio of 2 or more against the chromosome 17 control, or 6 or more copies per cell, is amplified and HER2-positive whatever the protein stain showed.","summary":"In situ hybridisation (fluorescent FISH or chromogenic dual ISH) measures ERBB2 gene copies. Under ASCO/CAP 2018, a HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0 per cell is positive (group 1); a ratio < 2.0 with copy number >= 6.0 is positive (group 3); ratio >= 2.0 with copy number < 4.0 (group 2) and ratio < 2.0 with copy number 4.0 to < 6.0 (group 4) need concurrent IHC and are positive only if the IHC is 3+ (or 2+ on recount for group 4 in some readings). Labels for trastuzumab, pertuzumab, trastuzumab emtansine and trastuzumab deruxtecan accept ISH+ as HER2-positive; the FDA list carries the HER2 FISH pharmDx, PathVysion, INFORM HER-2/neu, SPOT-LIGHT CISH and Ventana Dual ISH kits as companion diagnostics.","asOf":"2026-09-23","links":[{"label":"ASCO/CAP HER2 testing in breast cancer guideline, 2018 focused update (Wolff et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.2018.77.8738"},{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"tags":["biomarker","her2"],"related":["her2-ihc-3-plus","her2-ihc-2-plus"],"cancers":["breast-her2-positive","gastric-her2-positive","her2-positive-early-breast-cancer","colorectal","gallbladder","biliary-tract-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab","pertuzumab","trastuzumab-emtansine","trastuzumab-deruxtecan","her2-testing-assays"],"companies":[],"institutions":[],"pathways":[],"terms":["fish","gene-amplification","her2-positive","her2-testing-in-biliary-cancer"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-valtorta-her2-scoring-colorectal-heracles-mod-pathol-2015","paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","paper-richman-her2-amplification-quasar-focus-piccolo-j-pathol-2016","paper-nakamura-triumph-ctdna-pertuzumab-trastuzumab-her2-colorectal-nat-med-2021","paper-harding-lancet-oncol","paper-angerilli-her2-ihc-cish-biliary-hum-pathol-2026","paper-mondaca-erbb2-gallbladder-us-chile-jco-go-2024"],"journals":[],"dependsOn":[],"notes":["Colorectal cancer: the HERACLES diagnostic criteria, not the breast or gastric ones, define positivity. A tumour is HER2-positive when intense membranous HER2 staining is present in more than 50% of cells (immunohistochemistry 3+), or immunohistochemistry 2+ with in situ hybridisation confirmation in more than 50% of cells; in the validation, no immunohistochemistry 0 or 1+ case was amplified and silver and fluorescence in situ hybridisation agreed completely (Valtorta 2015). That threshold selects about 5% of RAS wild-type patients (48 of 914 screened for HERACLES) and 2 to 3% of all colorectal cancers. Plasma HER2 copy number, adjusted for tumour fraction, selected patients as well as tissue in TRIUMPH (Nakamura 2021).","Gallbladder and biliary cancer: ERBB2 amplification confirmed by central ISH was the entry criterion of HERIZON-BTC-01 (Harding 2023). By sequencing, amplification was present in 8% of 260 gallbladder cancer patients alone and 1.5% with a mutation (Mondaca 2024) and in 10.2% of 244 samples in cBioPortal gbc_mskcc_2022. Chromogenic dual ISH found amplification in all IHC 3+ and some 2+ and 1+ tumours (Angerilli 2026)."],"target":"her2","measurement":"fish-ratio","scoringRule":{"text":"HER2/CEP17 ratio >= 2.0 with mean HER2 copy number >= 4.0 signals per cell is amplified; ratio < 2.0 with copy number >= 6.0 is also amplified; other combinations are resolved with concurrent immunohistochemistry.","quote":"HER-2/neu (ERBB2) gene amplification (ISH amplified)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"ISH+ (IHC 3+ or ISH+)","drugId":"trastuzumab-deruxtecan","cancerId":"breast-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"based on confirmed HER2-positive status or HER2 gene amplification (IHC 3+ or ISH+)","status":"current"},{"value":"HER2 gene amplification","drugId":"trastuzumab","cancerId":"breast-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=492dbdb2-077e-4064-bff3-372d6af0a7a2","quote":"Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens","status":"current"},{"value":"HER2 gene amplification","drugId":"pertuzumab","cancerId":"breast-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=17f85d17-ab71-4f5b-9fe3-0b8c822f69ff","quote":"Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency.","status":"current"}],"tests":[],"assays":["her2-ish"],"companionDiagnostics":[{"device":"HER2 FISH pharmDx Kit","maker":"Dako Denmark A/S (Agilent)","companyId":"agilent","drugs":["trastuzumab"],"indication":"Breast Cancer - Tissue","pma":"P040005 (05/03/2005)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"HER2 FISH pharmDx Kit","maker":"Dako Denmark A/S (Agilent)","companyId":"agilent","drugs":["trastuzumab"],"indication":"Gastric and Gastroesophageal Cancer - Tissue","pma":"P040005/S005 (10/20/2010)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PathVysion HER-2 DNA Probe Kit","maker":"Abbott Molecular","companyId":"abbott","drugs":["trastuzumab"],"indication":"Breast Cancer - Tissue","pma":"P980024 (12/11/1998)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana HER2 Dual ISH DNA Probe Cocktail","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab"],"indication":"Breast Cancer - Tissue","pma":"P190031 (07/28/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana HER2 Dual ISH DNA Probe Cocktail","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan","pertuzumab"],"indication":"Breast Cancer - Tissue","pma":"P190031/S014 (12/15/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"An amplified ISH result means your cancer has extra copies of the HER2 gene and is HER2-positive, so trastuzumab-based treatment applies even if the protein stain was only 2+. A non-amplified result after a 2+ stain means HER2-low. The ratio and copy number on the report are what the pathologist used; ask for them if the report only says positive or negative."},{"id":"her2-low-ihc","kind":"biomarker","name":"HER2-low (IHC 1+ or IHC 2+/ISH-negative)","aka":["HER2-low breast cancer","HER2-low readout","IHC 1+ or 2+/ISH-","HER2 low expression","HER2-low (IHC 1+ or IHC 2+/ISH-)"],"tldr":"HER2-low is not a new stain but a new reading of the old one: 1+ or 2+ without gene amplification. It covers about half of breast cancers and makes them eligible for trastuzumab deruxtecan.","summary":"HER2-low is defined in the trastuzumab deruxtecan label as IHC 1+ or IHC 2+ with a negative in situ hybridisation result, determined by an FDA-authorised test. DESTINY-Breast04 (2022) established the category in metastatic breast cancer after one or two lines of chemotherapy, and DESTINY-Breast06 (2025) extended it, with HER2-ultralow, to HR-positive disease after endocrine therapy. The FDA companion diagnostic list carries the PATHWAY 4B5 antibody with the detail 'HER2-low expression (IHC 1+ or IHC 2+/ISH non-amplified)'. Outside breast cancer HER2-low is a trial category, not a label one.","asOf":"2026-09-23","links":[{"label":"ENHERTU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6"}],"tags":["biomarker","her2"],"related":["her2-ihc-1-plus","her2-ihc-2-plus","her2-ultralow"],"cancers":["her2-low-metastatic-breast-cancer","breast-hr-positive","tnbc-metastatic","breast-cancer","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","her2-testing-assays"],"companies":[],"institutions":[],"pathways":[],"terms":["her2-low","ihc","fish"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-destiny-breast04-nejm-2022","paper-schettini-her2-low-features-npj-breast-cancer-2021","paper-denkert-her2-low-pooled-neoadjuvant-lancet-oncol-2021","paper-boissiere-michot-her2-ultralow-tnbc-virchows-arch-2026"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: DESTINY-Breast04 defined HER2-low as IHC 1+ or IHC 2+ with negative in situ hybridisation and enrolled 63 hormone receptor-negative patients among 557 (Modi 2022); the label covers them after one line of chemotherapy for metastatic disease. HER2-low is 36.6% of TNBC (Schettini 2021), 34.0% of hormone receptor-negative trial patients (Denkert 2021) and 24.0% of untreated TNBCs (Boissiere-Michot 2026). Reproducibility at the 0 versus 1+ boundary is poor, so a second read of a HER2 0 slide is worthwhile before ruling trastuzumab deruxtecan out."],"target":"her2","measurement":"ihc-score","scoringRule":{"text":"IHC 1+, or IHC 2+ with a non-amplified in situ hybridisation result, by an FDA-authorised HER2 assay.","quote":"HER2-low expression (IHC 1+ or IHC 2+/ISH non-amplified)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"IHC 1+ or IHC 2+/ISH-","drugId":"trastuzumab-deruxtecan","cancerId":"her2-low-metastatic-breast-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy","status":"current"}],"tests":[],"assays":["her2-herceptest","her2-pathway-4b5","her2-ish"],"companionDiagnostics":[{"device":"PATHWAY anti-Her2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan"],"indication":"Breast Cancer - Tissue","pma":"P990081/S047 (09/30/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"VENTANA HER2 Dual ISH DNA Probe Cocktail","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan"],"indication":"Breast Cancer - Tissue","pma":"P190031/S015 (05/15/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your breast cancer report says 1+, or 2+ with a negative ISH, it is HER2-low. That does not change first treatment, but once the cancer has spread and chemotherapy (or, for hormone-receptor-positive cancers, hormone therapy) has stopped working, trastuzumab deruxtecan is an on-label option. A report written before 2022 may only say 'HER2-negative'; the underlying score can be looked up."},{"id":"her2-ultralow","kind":"biomarker","name":"HER2-ultralow (IHC 0 with membrane staining)","aka":["HER2-ultralow","HER2 ultralow","ultralow","IHC 0 with faint staining","IHC >0 <1+"],"tldr":"HER2-ultralow is an IHC 0 result with a trace of membrane staining in a few cells. Since 2025, in hormone-receptor-positive breast cancer that has stopped responding to hormone therapy, it is enough for trastuzumab deruxtecan.","summary":"Ultralow is faint, incomplete membrane staining in 10 percent or fewer of tumour cells, a sub-band of the ASCO/CAP 0 score. DESTINY-Breast06 enrolled HER2-low and ultralow HR-positive metastatic breast cancer after endocrine therapy and showed a progression-free survival benefit over chemotherapy; the US label was amended in January 2025 and the FDA companion diagnostic list carries the PATHWAY 4B5 antibody with the detail 'HER2 ultralow expression (IHC 0 with membrane staining)'. Reproducibility between pathologists at this end of the scale is low, which is why re-review of 0 slides is often requested.","asOf":"2026-09-23","links":[{"label":"ENHERTU prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6"}],"tags":["biomarker","her2"],"related":["her2-ihc-0","her2-low-ihc"],"cancers":["her2-low-metastatic-breast-cancer","breast-hr-positive","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","her2-testing-assays"],"companies":[],"institutions":[],"pathways":[],"terms":["her2-low","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-boissiere-michot-her2-ultralow-tnbc-virchows-arch-2026"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: ultralow (IHC 0 with faint incomplete membrane staining in 10% or fewer cells) was 37.6% of 367 untreated TNBCs, with 38.4% null (Boissiere-Michot 2026). DESTINY-Breast06 enrolled hormone receptor-positive disease only, so the ultralow label does not extend to TNBC; ultralow status carried no prognostic weight in TNBC."],"target":"her2","measurement":"ihc-score","scoringRule":{"text":"IHC 0 with faint, incomplete membrane staining in 10 percent or fewer of tumour cells; distinguished from IHC 0 with no staining.","quote":"HER2 ultralow expression (IHC 0 with membrane staining)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"IHC 0 with membrane staining, HR-positive, after endocrine therapy","drugId":"trastuzumab-deruxtecan","cancerId":"her2-low-metastatic-breast-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6","quote":"Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression","status":"current"}],"tests":[],"assays":["her2-herceptest","her2-pathway-4b5"],"companionDiagnostics":[{"device":"PATHWAY anti-Her2/neu (4B5) Rabbit Monoclonal Primary Antibody","maker":"Ventana Medical Systems (Roche)","drugs":["trastuzumab-deruxtecan"],"indication":"Breast Cancer - Tissue","pma":"P990081/S055 (01/27/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your hormone-receptor-positive breast cancer was scored HER2 0, ask the pathologist whether any membrane staining was seen. If so it is ultralow, and trastuzumab deruxtecan is on label after hormone therapy stops working; if there was none, it is not."},{"id":"her3-expression","kind":"biomarker","name":"HER3 expression","aka":["HER3","ERBB3 expression","HER3-positive","HER3 IHC"],"tldr":"HER3 is a signalling partner of EGFR and HER2 present on most lung and breast cancers. Patritumab deruxtecan was studied in EGFR-mutant lung cancer without a HER3 threshold, and no approval exists.","summary":"Patritumab deruxtecan showed activity in EGFR-mutant NSCLC after osimertinib (HERTHENA-Lung01, HERTHENA-Lung02, NCT05338970) irrespective of HER3 membrane H-score; the US application received a complete response letter in 2024 on manufacturing grounds and no approval has followed. NRG1 fusions, which signal through HER3, are the selection marker for zenocutuzumab, a separate readout.","asOf":"2026-09-23","links":[{"label":"ClinicalTrials.gov NCT05338970 (HERTHENA-Lung02)","url":"https://clinicaltrials.gov/study/NCT05338970"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["egfr-exon-19-deletion","her2-ihc-3-plus"],"cancers":["nsclc","breast-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["patritumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"her3","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"HERTHENA-Lung02: patritumab deruxtecan versus platinum-based chemotherapy in EGFR-mutated NSCLC after EGFR TKI","source":"https://clinicaltrials.gov/study/NCT05338970","sourceLabel":"ClinicalTrials.gov NCT05338970 (HERTHENA-Lung02)"},"thresholds":[],"definedBy":{"label":"HERTHENA-Lung02 (NCT05338970)","url":"https://clinicaltrials.gov/study/NCT05338970"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"There is no approved HER3-directed drug and no HER3 test you would routinely have. Patritumab deruxtecan is available only in trials, which enrol on the EGFR mutation rather than on HER3 staining."},{"id":"hla-a-02-01","kind":"biomarker","name":"HLA-A*02:01 (HLA typing for TCR therapies)","aka":["HLA-A*02:01","HLA-A2","HLA-A*02:01-positive","HLA-A0201","HLA typing","HLA-A*02"],"tldr":"HLA-A*02:01 is the commonest tissue-type molecule in people of European descent and the one the first T-cell receptor therapies were built for. Tebentafusp and afamitresgene autoleucel work only in patients who carry it, so a blood HLA test comes before the tumour test.","summary":"HLA typing by sequencing (the SeCore CDx HLA Sequencing System is the FDA-listed companion diagnostic for both drugs) reports the patient's HLA-A alleles. Tebentafusp (Kimmtrak) is labelled for HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma; afamitresgene autoleucel (Tecelra) for synovial sarcoma in patients who are HLA-A*02:01P, -A*02:02P, -A*02:03P or -A*02:06P positive and whose tumour expresses MAGE-A4 by the MAGE-A4 IHC 1F9 pharmDx, with HLA-A*02:05P as an exclusion allele. About 45 percent of Europeans and fewer people of African or East Asian ancestry carry A*02:01, which limits access and drives development of TCR therapies for other alleles.","asOf":"2026-09-23","links":[{"label":"KIMMTRAK prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24a49f57-d2fc-4ffe-9eb1-fe0460c6b067"},{"label":"TECELRA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab24631f-3364-46e1-8074-7244863bcbab"}],"tags":["biomarker","hla"],"related":["pd-l1-cps"],"cancers":["uveal-melanoma","synovial-sarcoma","melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["tebentafusp","afamitresgene-autoleucel"],"companies":[],"institutions":[],"pathways":[],"terms":["hla-a02-restriction","uveal-melanoma-prognostic-markers"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"hla-a","measurement":"hla-typing","scoringRule":{"text":"Presence of the HLA-A*02:01 allele (for tebentafusp) or of HLA-A*02:01P, A*02:02P, A*02:03P or A*02:06P without A*02:05P (for afamitresgene autoleucel) by HLA sequencing of blood.","quote":"Eligible alleles: HLA-A*02:01, HLA-A*02:02, HLA-A*02:03 or HLA-A*02:06 and their P-group alleles. Exclusion alleles: HLA-A*02:05 and its P-group alleles.","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"HLA-A*02:01-positive","drugId":"tebentafusp","cancerId":"uveal-melanoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24a49f57-d2fc-4ffe-9eb1-fe0460c6b067","quote":"KIMMTRAK is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.","status":"current"},{"value":"HLA-A*02:01P, -A*02:02P, -A*02:03P or -A*02:06P positive and MAGE-A4-expressing","drugId":"afamitresgene-autoleucel","cancerId":"synovial-sarcoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab24631f-3364-46e1-8074-7244863bcbab","quote":"TECELRA is indicated for the treatment of adults and pediatric patients 12 years of age and older with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices.","status":"current"}],"tests":[],"assays":[],"companionDiagnostics":[{"device":"SeCore CDx HLA Sequencing System","maker":"One Lambda (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["tebentafusp"],"indication":"Uveal Melanoma - Whole Blood","pma":"BR220737 (11/28/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"SeCore CDx HLA Sequencing System","maker":"One Lambda (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["afamitresgene-autoleucel"],"indication":"Synovial sarcoma - Whole blood","pma":"BK241074 (08/01/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"MAGE-A4 IHC 1F9 pharmDx","maker":"Agilent Technologies","companyId":"agilent","drugs":["afamitresgene-autoleucel"],"indication":"Synovial sarcoma - Tissue","pma":"P230016 (08/01/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"Your HLA type is inherited and tested from a blood sample. If you carry HLA-A*02:01, tebentafusp is on label for advanced uveal melanoma, the only drug shown to extend survival in that disease, and afamitresgene autoleucel is an option for synovial sarcoma if the tumour also expresses MAGE-A4. If you do not carry the allele these particular treatments cannot work, and trials for other HLA types are the route to ask about."},{"id":"hrr-gene-mutation","kind":"biomarker","name":"Homologous recombination repair gene mutation in prostate cancer","aka":["HRR gene mutation","HRRm","HRR-mutated","homologous recombination repair mutation","DNA repair gene mutation","BRCA2 prostate","ATM prostate","CDK12 prostate"],"tldr":"A fault in one of the genes a cell uses to mend broken DNA. It decides whether a PARP inhibitor can be prescribed, but the list of genes that counts is different for each of the four approved routes, and the evidence behind them is mostly evidence about BRCA2.","summary":"Between a fifth and a quarter of metastatic prostate cancers carry an alteration in this gene set: BRCA2, BRCA1 and ATM aberrations alone were 19.3% of 150 castration-resistant tumours (Robinson 2015). About half of that is inherited: germline mutations in 20 DNA repair genes were present in 82 of 692 men with metastatic disease, 11.8%, led by BRCA2 at 5.3%, ATM at 1.6%, CHEK2 at 1.9% and BRCA1 at 0.9%, with no difference by family history or age at diagnosis (Pritchard 2016). The four approved routes ask for four different gene lists. Olaparib alone names 14 genes; olaparib with abiraterone names BRCA1 and BRCA2 only; rucaparib names BRCA1 and BRCA2 only; niraparib with abiraterone names BRCA2 alone in castration-sensitive disease and BRCA1 or BRCA2 in castration-resistant disease; talazoparib with enzalutamide names 12 genes, six of which are not on olaparib's list, including MLH1, a mismatch repair gene, and the label states that no FDA-approved test for detecting them with talazoparib is currently available. The response data do not spread evenly across those lists: in PROfound, confirmed objective response among men with a single-gene alteration and measurable disease was 24 of 43 with BRCA2 (56%), 3 of 30 with ATM (10%) and 2 of 34 with CDK12 (6%).","asOf":"2026-09-25","links":[{"label":"LYNPARZA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa"},{"label":"TALZENNA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fd147f-a77e-4a0b-9280-e82ecc41b4be"},{"label":"AKEEGA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8245a990-3268-4613-b5c5-9537858a1eb9"},{"label":"RUBRACA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0295d202-1cfe-7659-e063-6294a90a476e"},{"label":"Pritchard et al., N Engl J Med 2016: inherited DNA-repair gene mutations in 692 men with metastatic prostate cancer unselected for family history","url":"https://doi.org/10.1056/NEJMoa1603144"}],"tags":["biomarker","prostate"],"related":["brca-germline","brca-somatic","hrd-positive"],"cancers":["prostate","prostate-mcrpc","prostate-mhspc"],"sections":[],"technologies":["cgp","germline-testing","liquid-biopsy","parp-inhibitor"],"targets":["brca","atm","cdk12","palb2","chek2","rad51c","rad51d","bard1","brip1","parp"],"drugs":["olaparib","rucaparib","niraparib","talazoparib"],"companies":[],"institutions":[],"pathways":["homologous-recombination-repair","base-excision-repair-parp","synthetic-lethality-map","ddr"],"terms":["germline-vs-somatic","gbrca-mutation","hrd","brca-reversion-mutations","synthetic-lethality","vus","castration-resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-abida-triton2-rucaparib-brca-jco-2020","paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017","paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"target":"brca","measurement":"sequencing-variant","scoringRule":{"text":"A deleterious or suspected deleterious alteration in a homologous recombination repair gene on tumour tissue or, where the label allows it, on blood or plasma, reported gene by gene and with germline status stated separately, because the eligible gene list differs by medicine and by disease state.","quote":"Select patients for the treatment of HRR gene-mutated mCRPC with TALZENNA based on the presence of alterations in genes directly or indirectly involved in HRR (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C).","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fd147f-a77e-4a0b-9280-e82ecc41b4be","sourceLabel":"TALZENNA prescribing information, patient selection 2.1"},"thresholds":[{"value":"Deleterious or suspected deleterious germline or somatic mutation in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L","drugId":"olaparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.","status":"current"},{"value":"Deleterious or suspected deleterious BRCA1 or BRCA2 mutation, with abiraterone and prednisone or prednisolone","drugId":"olaparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).","status":"current"},{"value":"Deleterious BRCA1 or BRCA2 mutation, germline and/or somatic","drugId":"rucaparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0295d202-1cfe-7659-e063-6294a90a476e","quote":"for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy.","status":"current"},{"value":"Deleterious or suspected deleterious BRCA2 mutation, with abiraterone acetate and prednisone","drugId":"niraparib","cancerId":"prostate-mhspc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8245a990-3268-4613-b5c5-9537858a1eb9","quote":"AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA2-mutated (BRCA2m) metastatic castration-sensitive prostate cancer (mCSPC).","status":"current"},{"value":"Deleterious or suspected deleterious BRCA1 or BRCA2 mutation, with abiraterone acetate and prednisone","drugId":"niraparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8245a990-3268-4613-b5c5-9537858a1eb9","quote":"AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).","status":"current"},{"value":"Mutation in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 or RAD51C, with enzalutamide","drugId":"talazoparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fd147f-a77e-4a0b-9280-e82ecc41b4be","quote":"TALZENNA is indicated in combination with enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).","status":"current","note":"The label states that an FDA-approved test for the detection of HRR gene mutations for use with TALZENNA is not currently available."}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result decides whether a PARP inhibitor tablet is an option. Two things are worth asking about. First, which gene it is: the evidence is strongest for BRCA2 and much weaker for the others, so it is reasonable to ask what the chance of benefit is for your particular gene. Second, whether it is inherited: a tumour test cannot tell you, and a separate blood or saliva test is needed, which also matters for your children and your brothers and sisters."},{"id":"hrd-positive","kind":"biomarker","name":"HRD-positive (genomic instability score)","aka":["HRD","HRD-positive","HRD positive","homologous recombination deficiency","genomic instability score","GIS","GIS >= 42","myChoice HRD","HRD score","genomic scar"],"tldr":"HRD-positive means the tumour's genome carries the scars of failed double-strand break repair (or a BRCA mutation), measured as a genomic instability score. In ovarian cancer it selects niraparib, and olaparib with bevacizumab, as first-line maintenance.","summary":"The Myriad myChoice CDx combines tumour BRCA1/2 status with a genomic instability score built from loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions; the assay calls HRD-positive at a GIS of 42 or more (the PRIMA and PAOLA-1 trials' cut-off) or any deleterious BRCA mutation. Niraparib's US label defines HRD-positive status as 'a deleterious or suspected deleterious BRCA mutation, and/or genomic instability' and the olaparib plus bevacizumab first-line maintenance indication is for HRD-positive advanced ovarian cancer. Because the scar accumulates over time, HRD status is read on tumour tissue and does not capture reversion, which is why HRD-positive tumours can still be PARP-resistant.","asOf":"2026-09-23","links":[{"label":"ZEJULA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7f675e2-159c-490c-b6f4-3f16d9492b7d"},{"label":"Lynparza prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa"}],"tags":["biomarker","brca","genome-wide"],"related":["brca-somatic","brca-germline"],"cancers":["ovarian","high-grade-serous-ovarian-cancer","tnbc","tnbc-early","pancreatic","brca-palb2-pdac"],"sections":[],"technologies":[],"targets":[],"drugs":["niraparib","olaparib","bevacizumab","mychoice-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["hrd","platinum-sensitivity"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-telli-hrd-score-platinum-tnbc-ccr-2016","paper-loibl-geparsixto-survival-hrd-ann-oncol-2018","paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019","paper-davies-nat-med","paper-tutt-nat-med","paper-park-hrd-pancreatic-platinum-ccr-2020","paper-waddell-whole-genomes-pancreatic-nature-2015","paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: the HRD score threshold of 42 was set in three neoadjuvant TNBC platinum trials, where HR deficiency (score 42 or more or BRCA1/2 mutation) predicted RCB 0/I and pCR (Telli 2016); HR deficiency was present in 70.5% of 193 GeparSixto TNBCs and predicted pCR but not carboplatin benefit (Loibl 2018); HRDetect-high was 58.6% of 237 population-based genomes and prognostic on chemotherapy (Staaf 2019). In advanced disease the Myriad HRD score did not predict carboplatin benefit in TNT (Tutt 2018). No breast label uses an HRD score; the ovarian thresholds do not transfer.","Pancreatic ductal adenocarcinoma: no genomic instability score has a pancreatic threshold or label. Homologous recombination deficiency is defined in the literature by core or biallelic gene mutation, by the unstable structural subtype or by signature 3: 19% of 262 advanced patients by gene mutation (Park 2020), and 45% of signature-defined double-strand break repair cases had no BRCA1, BRCA2 or PALB2 event at all (Connor 2017). First-line platinum benefit tracks the deficiency (hazard ratio 0.44) while non-platinum does not (Park 2020); 4 of 5 platinum-treated patients with defective DNA maintenance responded in the first whole-genome series (Waddell 2015)."],"target":"brca","measurement":"genomic-instability-score","scoringRule":{"text":"HRD-positive: a deleterious or suspected deleterious tumour BRCA1/2 mutation, or a genomic instability score at or above the assay's cut-off (42 on the myChoice CDx), computed from loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions.","quote":"Deleterious or suspected deleterious germline or somatic mutations in BRCA1 and BRCA2 genes and/or positive Genomic Instability Score","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"HRD-positive (BRCA mutation and/or genomic instability)","drugId":"niraparib","cancerId":"ovarian","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7f675e2-159c-490c-b6f4-3f16d9492b7d","quote":"for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: o a deleterious or suspected deleterious BRCA mutation, and/or o genomic instability","status":"current"},{"value":"HRD-positive","drugId":"olaparib","cancerId":"ovarian","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy","status":"current"}],"tests":["mychoice-cdx","caris-mi-profile","tempus-xt"],"assays":["mychoice-cdx"],"companionDiagnostics":[{"device":"Myriad myChoice CDx","maker":"Myriad Genetic Laboratories","companyId":"myriad-genetics","drugs":["olaparib"],"indication":"Ovarian Cancer - Tissue","pma":"P190014/S003 (05/08/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Myriad myChoice CDx","maker":"Myriad Genetic Laboratories","companyId":"myriad-genetics","drugs":["niraparib"],"indication":"Ovarian Cancer - Tissue","pma":"P190014/S011 (03/10/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"HRD-positive on a myChoice report (a BRCA mutation or a genomic instability score of 42 or more) means your ovarian cancer is likely to respond to PARP inhibitors: niraparib alone, or olaparib with bevacizumab, are on label as maintenance after first chemotherapy. An HRD-negative result does not rule out niraparib, whose first-line label covers all comers, but the expected benefit is smaller."},{"id":"idh1-r132","kind":"biomarker","name":"IDH1 R132 mutation","aka":["IDH1 R132H","IDH1 R132C","IDH1 mutation","IDH1-mutant","IDH1 R132","mIDH1","susceptible IDH1 mutation"],"tldr":"IDH1 R132 mutations turn a metabolic enzyme into a producer of the oncometabolite 2-HG. They define lower-grade gliomas and occur in acute myeloid leukaemia and bile duct cancer, each with an approved IDH1 inhibitor.","summary":"Codon 132 substitutions (R132H in over 90 percent of gliomas; R132C, G, S and L more often in AML and cholangiocarcinoma) are detected by IHC for R132H in glioma and by PCR or sequencing elsewhere. Ivosidenib (Tibsovo) is labelled for AML (newly diagnosed unfit, and relapsed or refractory), MDS and previously treated cholangiocarcinoma with a susceptible IDH1 mutation as detected by an FDA-approved test; olutasidenib (Rezlidhia) for relapsed or refractory AML with a susceptible IDH1 mutation; vorasidenib (Voranigo, 2024) for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation after surgery. The Abbott RealTime IDH1 and Oncomine Dx Target Test are the listed companion diagnostics.","asOf":"2026-09-23","links":[{"label":"TIBSOVO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d"},{"label":"VORANIGO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31405fee-55b7-4857-987e-2724ee76be84"}],"tags":["biomarker","idh"],"related":["idh2-mutation","1p19q-codeletion-readout","mgmt-promoter-methylation"],"cancers":["aml","aml-idh","cholangiocarcinoma","glioblastoma","idh-mutant-astrocytoma","oligodendroglioma","mds"],"sections":[],"technologies":[],"targets":[],"drugs":["ivosidenib","olutasidenib","vorasidenib","oncomine-dx-target-test"],"companies":[],"institutions":[],"pathways":[],"terms":["ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"idh","measurement":"sequencing-variant","scoringRule":{"text":"A susceptible IDH1 codon 132 substitution (R132C, R132H, R132G, R132S, R132L) by PCR or sequencing of blood, marrow or tumour tissue; R132H can be screened by immunohistochemistry in glioma.","quote":"R132 mutations (R132C, R132H, R132G, R132S, and R132L)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"Susceptible IDH1 mutation","drugId":"ivosidenib","cancerId":"aml-idh","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d","quote":"TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible IDH1 mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction","status":"current"},{"value":"Susceptible IDH1 mutation","drugId":"olutasidenib","cancerId":"aml-idh","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4a0c7c8b-b95f-455d-9600-b7351e4397fe","quote":"REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test","status":"current"},{"value":"Susceptible IDH1 or IDH2 mutation, grade 2 glioma after surgery","drugId":"vorasidenib","cancerId":"idh-mutant-astrocytoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31405fee-55b7-4857-987e-2724ee76be84","quote":"VORANIGO is an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection.","status":"current"}],"tests":["foundationone-cdx","foundationone-heme","tempus-xt","trusight-oncology-comprehensive","neotype-profiles"],"assays":["idh1-abbott","oncomine-dx"],"companionDiagnostics":[{"device":"Abbott RealTime IDH1","maker":"Abbott Molecular","companyId":"abbott","drugs":["ivosidenib"],"indication":"Acute Myeloid Leukemia - Peripheral Blood or Bone Marrow","pma":"P170041 (07/20/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Abbott RealTime IDH1","maker":"Abbott Molecular","companyId":"abbott","drugs":["olutasidenib"],"indication":"Acute Myeloid Leukemia - Peripheral Blood or Bone Marrow","pma":"P170041/S006 (12/01/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["ivosidenib"],"indication":"Cholangiocarcinoma - Tissue","pma":"P160045/S028 (08/25/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["vorasidenib"],"indication":"Astrocytoma and Oligodendroglioma - Tissue","pma":"P160045/S046 (09/18/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"An IDH1 mutation opens a targeted tablet in three settings: ivosidenib or olutasidenib in acute myeloid leukaemia, ivosidenib in bile duct cancer after chemotherapy, and vorasidenib in a grade 2 glioma after surgery, where it can delay the need for radiotherapy and chemotherapy. In glioma the mutation also carries a better outlook than the same tumour without it."},{"id":"idh2-mutation","kind":"biomarker","name":"IDH2 mutation (R140 and R172)","aka":["IDH2 R140Q","IDH2 R172K","IDH2 mutation","IDH2-mutant","mIDH2"],"tldr":"IDH2 mutations at codons 140 and 172 do the same job as IDH1 R132, producing 2-HG. Enasidenib is approved for relapsed AML with them, and vorasidenib for grade 2 gliomas with either IDH gene mutated.","summary":"R140Q is the commonest IDH2 mutation in AML; R172K predominates in glioma and angioimmunoblastic T-cell lymphoma. Enasidenib (Idhifa, 2017) is labelled for relapsed or refractory AML with an IDH2 mutation as detected by an FDA-approved test, the Abbott RealTime IDH2 assay listing R140Q, R140L, R140G, R140W, R172K, R172M, R172G, R172S and R172W; vorasidenib covers IDH2 R172 mutations in grade 2 glioma with the Oncomine Dx Target Test. IDH2-mutant AML has a lower rate of differentiation syndrome recognition problems only because the drug is older; the risk is the same class effect.","asOf":"2026-09-23","links":[{"label":"Idhifa prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a5b4cdf0-3fa8-4c6c-80f6-8d8a00e3a5b6"}],"tags":["biomarker","idh"],"related":["idh1-r132"],"cancers":["aml","aml-idh","idh-mutant-astrocytoma","oligodendroglioma"],"sections":[],"technologies":[],"targets":[],"drugs":["enasidenib","vorasidenib"],"companies":[],"institutions":[],"pathways":[],"terms":["ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"idh","measurement":"sequencing-variant","scoringRule":{"text":"An IDH2 codon 140 or 172 substitution (R140Q, R140L, R140G, R140W, R172K, R172M, R172G, R172S, R172W) by PCR or sequencing.","quote":"R140Q, R140L, R140G, R140W, R172K, R172M, R172G, R172S, and R172W","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"IDH2 mutation","drugId":"enasidenib","cancerId":"aml-idh","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a5b4cdf0-3fa8-4c6c-80f6-8d8a00e3a5b6","quote":"IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test","status":"current"},{"value":"Susceptible IDH1 or IDH2 mutation, grade 2 glioma","drugId":"vorasidenib","cancerId":"oligodendroglioma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31405fee-55b7-4857-987e-2724ee76be84","quote":"Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, as detected by an FDA-approved test","status":"current"}],"tests":["foundationone-heme","tempus-xt","neotype-profiles"],"assays":["idh2-abbott","oncomine-dx"],"companionDiagnostics":[{"device":"Abbott RealTime IDH2","maker":"Abbott Molecular","companyId":"abbott","drugs":["enasidenib"],"indication":"Acute Myeloid Leukemia - Peripheral Blood or Bone Marrow","pma":"P170005 (08/01/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"An IDH2 mutation in acute myeloid leukaemia that has come back opens enasidenib tablets; in a grade 2 glioma after surgery it opens vorasidenib. Both drugs can cause differentiation syndrome in leukaemia, a reaction your team will watch for in the first weeks."},{"id":"ig-tcr-clonality","kind":"biomarker","name":"Immunoglobulin and T-cell receptor clonality","aka":["IGH clonality","TCR clonality","clonal rearrangement","gene rearrangement study","B-cell clonality","T-cell clonality","BIOMED-2"],"tldr":"A test that asks whether a group of lymphocytes all descend from one cell. Cancer is one family; a normal immune response is a crowd. It is used when the appearance under the microscope does not settle the question.","summary":"Every lymphocyte rearranges its antigen receptor genes into a sequence unique to itself, so a lymphoma made of one clone gives amplicons of one length and sequence while a reactive population gives a smooth spread.\n\nThe European BIOMED-2 collaboration standardised the assay into 107 primers in 18 multiplex tubes covering IGH in two configurations, IGK, IGL, TCRB, TCRG and TCRD plus the BCL1-IGH and BCL2-IGH translocations, with products read by heteroduplex analysis or fragment sizing. The complementarity of the tubes is what makes the detection rate high: combined IGH and IGK tubes detect virtually all clonal B-cell proliferations even where somatic hypermutation is heavy, and combined TCRB and TCRG tubes detect virtually all clonal T-cell populations (van Dongen 2003). The EuroClonality-NGS successor sequences the amplicons rather than sizing them and produces a patient-specific sequence that can be followed afterwards as a residual disease marker.\n\nThe result is a pattern, not a diagnosis, and the commonest harm this test does is being read as one.","asOf":"2026-09-30","links":[{"label":"van Dongen et al., Leukemia 2003: BIOMED-2 multiplex PCR for clonal immunoglobulin and T-cell receptor rearrangements","url":"https://doi.org/10.1038/sj.leu.2403202"}],"tags":["biomarker","lymphoma"],"related":[],"cancers":["non-hodgkin-lymphoma","cutaneous-t-cell-lymphoma","sezary-syndrome","malt-lymphoma","peripheral-t-cell-lymphoma","follicular-lymphoma"],"sections":[],"technologies":["clonality-testing","ngs-mrd-clonoseq","flow-cytometry-mrd"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["clonal-evolution"],"terms":["ngs","mrd","lymphoma-bio-germinal-centre"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"noParentReason":"The readout is a pattern across the immunoglobulin and T-cell receptor loci rather than a result for one gene or protein: the question is whether the population is monoclonal, and no single parent gene answers it.","measurement":"sequencing-variant","scoringRule":{"text":"Multiplex PCR, or targeted sequencing, across the V, D and J segments, reported as clonal, polyclonal or oligoclonal, with the loci tested named. A clonal result should be read with the morphology and immunophenotype and never alone: clonal populations occur in reactive, autoimmune and age-related conditions, and a polyclonal result does not exclude a lymphoma in which the malignant cells are a small minority.","quote":"In particular, combined application of IGH (VH-JH and DH-JH) and IGK tubes can detect virtually all clonal B-cell proliferations, even in B-cell malignancies with high levels of somatic mutations.","source":"https://doi.org/10.1038/sj.leu.2403202","sourceLabel":"van Dongen et al., Leukemia 2003"},"thresholds":[],"definedBy":{"label":"van Dongen et al., Leukemia 2003: BIOMED-2 multiplex PCR for clonal immunoglobulin and T-cell receptor rearrangements","url":"https://doi.org/10.1038/sj.leu.2403202"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A clonal result is a piece of evidence, not a verdict. It is most useful when a biopsy is small or the appearance is borderline, and it is read together with everything else. A report that says clonal does not by itself mean cancer."},{"id":"ki-67-index","kind":"biomarker","name":"Ki-67 index (proliferation by IHC)","aka":["Ki-67","Ki67","Ki-67 index","Ki-67 labelling index","Ki-67 score","MIB-1 index","Ki-67 >= 20%","Ki-67 ≥20%","proliferation index"],"tldr":"Ki-67 is the percentage of tumour cells that are dividing. In neuroendocrine tumours it sets the grade; in breast cancer a 20 percent cut-off was briefly a condition of adjuvant abemaciclib, then dropped from the label in 2023.","summary":"The Ki-67 labelling index is the percentage of tumour cell nuclei staining with the MIB-1 antibody. In gastroenteropancreatic neuroendocrine tumours the WHO classification grades G1 (< 3 percent), G2 (3 to 20 percent) and G3 (> 20 percent). In breast cancer the October 2021 FDA approval of adjuvant abemaciclib (monarchE cohort 1) required node-positive, high-risk, HR-positive HER2-negative disease with Ki-67 >= 20 percent by the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) companion diagnostic; the March 2023 label expansion removed the Ki-67 requirement, and the current label describes the assay only in the trial narrative. The International Ki-67 in Breast Cancer Working Group considers scores of 5 percent or less and 30 percent or more reproducible and the range between them not.","asOf":"2026-09-23","links":[{"label":"Verzenio prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=be4bc0de-0fdc-4d46-8d25-be43c79e6a06"}],"tags":["biomarker","proliferation"],"related":["er-status","pr-status"],"cancers":["breast-hr-positive","hr-positive-early-high-risk","neuroendocrine","pancreatic-net","lung-net"],"sections":[],"technologies":[],"targets":[],"drugs":["abemaciclib"],"companies":[],"institutions":[],"pathways":[],"terms":["net-grade-ki67","proliferation","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"mki67","measurement":"ihc-score","scoringRule":{"text":"Percentage of tumour cell nuclei staining for Ki-67 (MIB-1), counted in the invasive tumour; in monarchE cohort 2 a score of 20 percent or more was required, measured centrally with the Ki-67 IHC MIB-1 pharmDx.","quote":"Breast tumor samples were tested at central sites using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to establish if the Ki-67 score was ≥20%.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=be4bc0de-0fdc-4d46-8d25-be43c79e6a06","sourceLabel":"Verzenio prescribing information (clinical studies section)"},"thresholds":[{"value":"Ki-67 >= 20% (2021 adjuvant approval, requirement removed March 2023)","drugId":"abemaciclib","cancerId":"hr-positive-early-high-risk","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=be4bc0de-0fdc-4d46-8d25-be43c79e6a06","quote":"To be enrolled in cohort 2, patients had to have 1-3 pALN and Ki-67 score ≥20%.","status":"historic","note":"The current label no longer restricts adjuvant abemaciclib by Ki-67; the threshold is kept as the historic 2021 approval condition."}],"definedBy":{"label":"WHO Classification of Tumours, Digestive System Tumours, 5th edition (neuroendocrine grading by Ki-67)","url":"https://tumourclassification.iarc.who.int/"},"tests":[],"assays":["ki67-mib1"],"companionDiagnostics":[],"forPatient":"Ki-67 tells you how fast the cancer is growing. In a neuroendocrine tumour it sets the grade, which steers treatment. In early breast cancer a high Ki-67 (20 percent or more) was once required for adjuvant abemaciclib; it no longer is, but the number still helps your team judge how much benefit chemotherapy or a CDK4/6 inhibitor is likely to add."},{"id":"kit-d816v","kind":"biomarker","name":"KIT D816V","aka":["KIT D816V","D816V","c-KIT D816V","KIT exon 17 mutation","KIT D816V mastocytosis"],"tldr":"KIT D816V is the mutation behind almost every case of systemic mastocytosis. It makes the disease resistant to imatinib, and it is detected by a highly sensitive blood PCR; avapritinib treats the disease whether or not the mutation is confirmed.","summary":"The exon 17 D816V substitution locks KIT in the active conformation and is present in over 90 percent of systemic mastocytosis, often at low allele burden requiring sensitive allele-specific PCR of blood or marrow. The FDA companion diagnostic list carries the ARUP KIT D816V Assay for imatinib in aggressive systemic mastocytosis (a humanitarian device exemption, H140006, 2015): imatinib is labelled for aggressive systemic mastocytosis without the D816V mutation or with unknown status, so the test selects patients by excluding D816V. Avapritinib's labels for advanced and indolent systemic mastocytosis do not require D816V testing; the mutation is also found in core-binding-factor AML and some GISTs where it confers imatinib resistance.","asOf":"2026-09-23","links":[{"label":"AYVAKIT prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9"},{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"tags":["biomarker","kit"],"related":["pdgfra-exon-18-d842v"],"cancers":["systemic-mastocytosis","aml","gist"],"sections":[],"technologies":[],"targets":[],"drugs":["imatinib","avapritinib"],"companies":[],"institutions":[],"pathways":[],"terms":["gatekeeper-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"kit","measurement":"sequencing-variant","scoringRule":{"text":"The KIT c.2447A>T (p.D816V) substitution by allele-specific quantitative PCR or sequencing of blood or marrow; for imatinib the selecting result is its absence.","quote":"KIT D816V Assay (ARUP Laboratories, Inc.): KIT D816V","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"D816V absent or unknown (negative selector for imatinib)","drugId":"imatinib","cancerId":"systemic-mastocytosis","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"KIT D816V Assay (ARUP Laboratories, Inc.) Aggressive Systemic Mastocytosis - Bone Marrow Gleevec (imatinib mesylate) NDA 021588 H140006 (12/18/2015)","status":"current","note":"Imatinib's label covers aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown mutational status."}],"tests":["foundationone-heme","neotype-profiles"],"assays":[],"companionDiagnostics":[{"device":"KIT D816V Assay","maker":"ARUP Laboratories","drugs":["imatinib"],"indication":"Aggressive Systemic Mastocytosis - Bone Marrow","pma":"H140006 (12/18/2015)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"In systemic mastocytosis a KIT D816V result confirms the diagnosis and tells your team that imatinib will not work; avapritinib is the on-label targeted treatment and does not require the mutation to be shown. The mutation is often present in tiny amounts, so a negative result from an insensitive test should be repeated with a sensitive blood PCR."},{"id":"kras-g12c","kind":"biomarker","name":"KRAS G12C","aka":["KRAS G12C","G12C","KRAS p.G12C","KRAS c.34G>T","KRAS G12C-mutated"],"tldr":"KRAS G12C swaps glycine 12 for cysteine and was the first KRAS mutation a drug could grip. Sotorasib and adagrasib are approved for it in lung cancer, and with an EGFR antibody in bowel cancer.","summary":"The c.34G>T (G12C) substitution is found in about 13 percent of lung adenocarcinomas and 3 to 4 percent of colorectal cancers. Sotorasib and adagrasib are labelled as single agents for KRAS G12C-mutated locally advanced or metastatic NSCLC after at least one prior systemic therapy, and in colorectal cancer sotorasib with panitumumab and adagrasib with cetuximab after prior chemotherapy, each 'as determined by an FDA-approved test'. The therascreen KRAS RGQ PCR Kit, Guardant360 CDx, Agilent Resolution ctDx FIRST and FoundationOne CDx carry the claims. G12C is the only KRAS mutation with an approved drug; the other codon 12 and 13 mutations are used as negative selectors for EGFR antibodies in colorectal cancer.","asOf":"2026-09-23","links":[{"label":"LUMAKRAS prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1"},{"label":"KRAZATI prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01"}],"tags":["biomarker","kras"],"related":["kras-g12d","braf-v600e"],"cancers":["nsclc","colorectal","pancreatic","kras-g12c-pdac","metastatic-pdac"],"sections":[],"technologies":[],"targets":[],"drugs":["sotorasib","adagrasib","divarasib","olomorasib","panitumumab","cetuximab","therascreen-cdx","guardant360-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["kras-mutation-subtypes","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","paper-schirripa-kras-g12c-metastatic-colorectal-clin-colorectal-cancer-2020","paper-codebreak-300-nejm-2023","paper-krystal-1-crc-yaeger-nejm-2023","paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016","paper-kris-lung-cancer-mutation-consortium-jama-2014","paper-arbour-kras-co-mutation-outcomes-ccr-2018"],"journals":[],"dependsOn":[],"notes":["Pancreatic ductal adenocarcinoma: G12C is 1 to 2% of cases, about 1.2% of KRAS-mutant MSK-IMPACT samples (cBioPortal). CodeBreaK 100 treated 38 previously treated patients with sotorasib for 8 confirmed responses (21%), progression-free survival 4.0 months and overall survival 6.9 months (Strickler 2023); KRYSTAL-1 gave 7 responses in 21 pancreatic patients (33.3%) with adagrasib (Bekaii-Saab 2023). Neither drug has a pancreatic approval, and the threshold is simply the presence of the allele on a tumour panel or plasma test.","Colorectal cancer: G12C is about 7% of KRAS mutation records and about 3% of all colorectal cancers (cBioPortal), or 145 of 839 KRAS-mutant patients (17%) in an Italian series where it carried shorter overall survival than other KRAS alleles (hazard ratio 1.32) and more lung and liver metastases (Schirripa 2020). The threshold is the presence of the allele on a tumour panel or plasma test. Unlike in lung cancer the inhibitor must be paired with an EGFR antibody, because blocking G12C alone triggers adaptive EGFR reactivation: that is the design of CodeBreaK 300 (sotorasib plus panitumumab) and of the adagrasib plus cetuximab arm of KRYSTAL-1.","Lung cancer: 41 to 51% of KRAS mutation records and about 13% of all adenocarcinomas, the highest share of any common cancer, because the G to T transversion that produces it is the tobacco carcinogen signature (Alexandrov 2016; cBioPortal). Unlike in colorectal cancer, a G12C inhibitor has single-agent activity in lung cancer without an EGFR antibody alongside it. What modifies the outcome is the co-mutation: STK11 and KEAP1 loss, present in about a fifth of these tumours each, predict poor benefit from checkpoint blockade in this KRAS-mutant population specifically (Ricciuti 2022)."],"target":"kras","measurement":"sequencing-variant","scoringRule":{"text":"The KRAS c.34G>T (p.G12C) substitution detected in tumour tissue or plasma by PCR or sequencing.","quote":"KRAS: KRAS G12C (therascreen KRAS RGQ PCR Kit, Guardant360 CDx, Agilent Resolution ctDx FIRST)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"KRAS G12C","drugId":"sotorasib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","quote":"As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy.","status":"current"},{"value":"KRAS G12C","drugId":"sotorasib","cancerId":"colorectal","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","quote":"LUMAKRAS, in combination with panitumumab, is indicated for the treatment of adult patients with KRAS G12C -mutated metastatic colorectal cancer (mCRC), as determined by an FDA-approved test","status":"current"},{"value":"KRAS G12C","drugId":"adagrasib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","quote":"As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy.","status":"current"},{"value":"KRAS G12C","drugId":"adagrasib","cancerId":"colorectal","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","quote":"KRAZATI in combination with cetuximab is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive","caris-mi-cancer-seek"],"assays":["kras-therascreen","guardant360-cdx","resolution-ctdx-first"],"companionDiagnostics":[{"device":"therascreen KRAS RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["sotorasib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P110027/S012 (05/28/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen KRAS RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["adagrasib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P110027/S013 (12/02/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen KRAS RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["adagrasib","cetuximab"],"indication":"Colorectal Cancer - Tissue","pma":"P110027/S017 (06/21/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen KRAS RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["sotorasib","panitumumab"],"indication":"Colorectal Cancer - Tissue","pma":"P110027/S018 (01/16/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Guardant360 CDx","maker":"Guardant Health","companyId":"guardant-health","drugs":["sotorasib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P200010/S002 (05/28/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Agilent Resolution ctDx FIRST assay","maker":"Resolution Bioscience (Agilent)","companyId":"agilent","drugs":["adagrasib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P210040 (12/12/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"KRAS G12C is the one KRAS change with approved tablets. In lung cancer sotorasib or adagrasib are on label after a first treatment; in bowel cancer they are given with an EGFR antibody after chemotherapy. Other KRAS mutations (G12D, G12V) do not qualify for these drugs yet, so the exact letter on your report matters."},{"id":"kras-g12d","kind":"biomarker","name":"KRAS G12D (and other non-G12C KRAS mutations)","aka":["KRAS G12D","G12D","KRAS G12V","KRAS G13D","KRAS mutant","KRAS codon 12 mutation"],"tldr":"G12D is the commonest KRAS mutation, especially in pancreatic cancer, and has no approved drug yet. In bowel cancer any KRAS or NRAS mutation is a reason not to give EGFR antibodies, which is where the approvals sit.","summary":"KRAS G12D (c.35G>A) drives about 40 percent of pancreatic and 12 percent of colorectal cancers; G12V and G13D follow. No G12D-selective drug is approved: zoldonrasib (RMC-9805) and the pan-RAS(ON) inhibitor daraxonrasib are in trials (RASolute 302, NCT06625320, is the phase 3 in pancreatic cancer). The approvals that turn on non-G12C KRAS status are negative ones: cetuximab and panitumumab are labelled for KRAS wild-type (and RAS wild-type) metastatic colorectal cancer, with the therascreen KRAS RGQ PCR Kit, cobas KRAS test, FoundationOne CDx and Tempus xT CDx listed as companion diagnostics for detecting the absence of codon 12 and 13 mutations.","asOf":"2026-09-23","links":[{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"tags":["biomarker","kras"],"related":["kras-g12c"],"cancers":["pancreatic","colorectal","nsclc","metastatic-pdac"],"sections":[],"technologies":[],"targets":[],"drugs":["cetuximab","panitumumab","therascreen-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["kras-mutation-subtypes","wild-type"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bournet-kras-g12d-prognosis-pancreatic-ctg-2016","paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018","paper-daraxonrasib-pancreatic-n-engl-j-med-2026","paper-karapetis-kras-cetuximab-colorectal-nejm-2008","paper-douillard-prime-panitumumab-ras-nejm-2013","paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016"],"journals":[],"dependsOn":[],"notes":["Pancreatic ductal adenocarcinoma: G12D is the commonest allele, about 40% of KRAS mutations, and carries the worst prognosis, 6 months against 9 for other alleles (hazard ratio 1.47) in 219 advanced patients (Bournet 2016) and 15.3 months after resection (Qian 2018). RASolute 302 randomised on RAS G12, G13 or Q61 mutation or none identified rather than on a single allele, with daraxonrasib giving overall survival 13.2 against 6.6 months (hazard ratio 0.40) in the G12 population (O'Reilly 2026); G12D-selective inhibitors such as zoldonrasib and MRTX1133 are in trials.","Colorectal cancer: G12D is the commonest KRAS allele here, about 29% of KRAS mutation records (cBioPortal), and the one with no approved inhibitor, which is why it appears on the cancer record's open problems. Like every RAS mutation it predicts no benefit from cetuximab or panitumumab (Karapetis 2008, Douillard 2013). G13D, almost unique to colorectal cancer among the common RAS-driven tumours at about 18% of records, is treated the same way: the retrospective suggestion that G13D tumours might still respond to cetuximab has never been confirmed prospectively.","Lung cancer: G12D is 12.2% of KRAS mutation records and G12V 14.9%, so the non-G12C alleles together are more than half of KRAS-mutant lung adenocarcinoma and none of them has an approved inhibitor (cBioPortal). G12D is relatively enriched in never smokers, where it leads the short list of KRAS alleles, which is the inverse of the smoking-driven G12C pattern (Alexandrov 2016)."],"target":"kras","measurement":"sequencing-variant","scoringRule":{"text":"Presence of a KRAS codon 12 or 13 (or exon 3 and 4) mutation other than G12C by PCR or sequencing; for EGFR antibodies the selecting result is the absence of KRAS and NRAS mutations in exons 2, 3 and 4.","quote":"KRAS wild-type (absence of mutations in codons 12 and 13)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"KRAS wild-type (negative selector)","drugId":"cetuximab","cancerId":"colorectal","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"KRAS wild-type (absence of mutations in codons 12 and 13)","status":"current","note":"FDA companion diagnostic row for the therascreen KRAS RGQ PCR Kit with Erbitux, P110030 (06 July 2012)."},{"value":"KRAS and NRAS wild-type (negative selector)","drugId":"panitumumab","cancerId":"colorectal","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"KRAS wild-type (absence of mutations in exons 2, 3, or 4) and NRAS wild-type (absence of mutations in exons 2, 3, or 4)","status":"current","note":"FDA companion diagnostic rows for FoundationOne CDx and xT CDx with Vectibix."}],"definedBy":{"label":"RASolute 302: daraxonrasib versus chemotherapy in previously treated metastatic pancreatic cancer (ClinicalTrials.gov NCT06625320)","url":"https://clinicaltrials.gov/study/NCT06625320"},"tests":["foundationone-cdx","tempus-xt","guardant360-cdx","caris-mi-cancer-seek"],"assays":["kras-therascreen","foundationone-cdx-panel"],"companionDiagnostics":[{"device":"therascreen KRAS RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["cetuximab"],"indication":"Colorectal Cancer - Tissue","pma":"P110030 (07/06/2012)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen KRAS RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["panitumumab"],"indication":"Colorectal Cancer - Tissue","pma":"P110027 (05/23/2014)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["panitumumab"],"indication":"Colorectal Cancer - Tissue (KRAS and NRAS wild-type)","pma":"P170019 (11/30/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A KRAS G12D, G12V or G13D result does not yet open a targeted tablet outside a trial, and in bowel cancer it means the EGFR antibodies cetuximab and panitumumab should not be used. In pancreatic cancer, trials of RAS inhibitors are recruiting and are worth asking about. Only a KRAS G12C result qualifies for the approved KRAS drugs."},{"id":"met-amplification-readout","kind":"biomarker","name":"MET amplification (gene copy number)","aka":["MET amplification","MET amp","MET copy number gain","MET/CEP7 ratio","high-level MET amplification","MET GCN >= 10"],"tldr":"MET amplification means extra copies of the MET gene, either as a primary driver in a few lung cancers or as the escape route after EGFR inhibitors. No label yet selects on it; trials define it by FISH ratio or copy number.","summary":"MET amplification is scored by FISH as MET/CEP7 ratio (high-level at 5 or more in the Camidge classification, or 2 or more with mean copies of 10 or more) or by sequencing as gene copy number (GCN 10 or more is the common trial threshold). It occurs de novo in 1 to 4 percent of NSCLC and arises in 5 to 20 percent of EGFR-mutant cancers progressing on osimertinib, the setting of the MARIPOSA-2 and the SAVANNAH trial of osimertinib plus savolitinib (NCT03778229). No approval names MET amplification as the selection criterion; amivantamab is approved on EGFR status rather than MET, and capmatinib's label covers exon 14 skipping only.","asOf":"2026-09-23","links":[{"label":"SAVANNAH (NCT03778229)","url":"https://clinicaltrials.gov/study/NCT03778229"}],"tags":["biomarker","met","no-approval"],"related":["met-ex14","met-overexpression","egfr-t790m"],"cancers":["nsclc","gastric"],"sections":[],"technologies":[],"targets":[],"drugs":["capmatinib","tepotinib","amivantamab","telisotuzumab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":["met-amplification","gene-amplification","fish"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-engelman-met-amplification-gefitinib-resistance-science-2007","paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013","paper-awad-met-exon-14-mutations-lung-jco-2016"],"journals":[],"dependsOn":[],"notes":["Lung cancer: 2 to 3% at diagnosis (cBioPortal) and commoner as acquired resistance, in 4 of 18 specimens resistant to a first-generation EGFR inhibitor (Engelman 2007) and 4 of 75 in the larger rebiopsy series (Yu 2013). There is no agreed copy-number threshold, which is the practical problem: low-level gain accompanies the aneuploidy of a third of lung tumours, and the ratio to chromosome 7 rather than the absolute copy number is what separates focal amplification from polysomy. When it is the resistance mechanism, the EGFR inhibitor should be continued and a MET inhibitor added rather than substituted."],"target":"met","measurement":"copy-number","scoringRule":{"text":"MET/CEP7 ratio by FISH (high-level 5 or more) or MET gene copy number by sequencing (trial thresholds of 6 or 10 copies); no label defines a threshold.","quote":"MET amplification (bypass resistance)","source":"https://clinicaltrials.gov/study/NCT03778229","sourceLabel":"SAVANNAH trial (NCT03778229): MET overexpression and/or amplification defined by IHC 90 percent 3+ or FISH 10 or more copies"},"thresholds":[],"definedBy":{"label":"SAVANNAH: osimertinib plus savolitinib in MET-amplified or overexpressed EGFR-mutant NSCLC after osimertinib (ClinicalTrials.gov NCT03778229)","url":"https://clinicaltrials.gov/study/NCT03778229"},"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","caris-mi-profile"],"assays":[],"companionDiagnostics":[],"forPatient":"MET amplification on your report does not yet open an approved treatment on its own. If your lung cancer is EGFR-mutant and grew on osimertinib, it is the reason trials combine a MET inhibitor with the EGFR drug, and your team may discuss those trials or amivantamab, which is approved on EGFR status."},{"id":"met-ex14","kind":"biomarker","name":"MET exon 14 skipping mutation","aka":["METex14","MET exon 14 skipping","MET ex14","METΔex14","MET exon 14 alteration","MET splice site mutation"],"tldr":"MET exon 14 skipping is a splice-site change that lets the MET receptor escape degradation and keep signalling. It is found in 3 to 4 percent of lung cancers and is treated with capmatinib or tepotinib.","summary":"Mutations at the exon 14 splice acceptor or donor sites, or in the Y1003 juxtamembrane region, cause the exon to be skipped, removing the CBL binding site. They are detected by DNA sequencing (with splice-site coverage) or, more sensitively, RNA sequencing of tissue or plasma. Capmatinib (Tabrecta, 2020) is labelled for metastatic NSCLC with a mutation that leads to MET exon 14 skipping as detected by an FDA-approved test, and tepotinib (Tepmetko, 2021) for NSCLC harbouring MET exon 14 skipping alterations; FoundationOne CDx and Liquid CDx are the companion diagnostics for both.","asOf":"2026-09-23","links":[{"label":"TABRECTA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=455892c3-d144-4ba8-9ab4-79cabff9876d"},{"label":"TEPMETKO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=80a0f1b9-071a-47f5-9e67-32d638a669dc"}],"tags":["biomarker","met"],"related":["met-amplification-readout","met-overexpression"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["capmatinib","tepotinib","capmatinib-tepotinib","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["met-exon-14-skipping","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-awad-met-exon-14-mutations-lung-jco-2016","paper-frampton-met-exon-14-cancer-discov-2015","paper-tcga-lung-adenocarcinoma-nature-2014","paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Lung cancer: 2 to 4% of adenocarcinomas, 3.0% of 933 non-squamous cancers in the founding clinical series and 4% read directly in messenger RNA in the TCGA cohort (Awad 2016, Cancer Genome Atlas Research Network 2014). The variants are splice-site and juxtamembrane alterations in the introns flanking exon 14, so a coding-exon panel returns a wild-type result; detection needs intron baiting or RNA. The patients are older (median 72.5 years), 68% women and 36% never smokers, and stage IV cases carry concurrent MET amplification and strong c-Met staining far more often than early-stage ones (Awad 2016)."],"target":"met","measurement":"sequencing-variant","scoringRule":{"text":"A single nucleotide variant or indel at the MET exon 14 splice sites or within exon 14 that leads to exon 14 skipping, by DNA or RNA sequencing of tissue or plasma.","quote":"MET single nucleotide variants and indels that lead to MET exon 14 skipping","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"MET exon 14 skipping","drugId":"capmatinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=455892c3-d144-4ba8-9ab4-79cabff9876d","quote":"TABRECTA is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.","status":"current"},{"value":"MET exon 14 skipping","drugId":"tepotinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=80a0f1b9-071a-47f5-9e67-32d638a669dc","quote":"TEPMETKO is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations.","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive","caris-mi-profile"],"assays":["foundationone-cdx-panel","foundationone-liquid-cdx"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["capmatinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P170019/S011 (05/06/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne Liquid CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["capmatinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P190032/S001 (07/15/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["tepotinib"],"indication":"Non-small cell lung cancer (NSCLC) - Tissue","pma":"P170019/S067 (05/12/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A MET exon 14 skipping result means capmatinib or tepotinib, both tablets, are on label for advanced lung cancer. These tumours are common in older patients and respond less well to immunotherapy alone, so the MET tablet is usually chosen first or after one line of chemotherapy."},{"id":"mgmt-promoter-methylation","kind":"biomarker","name":"MGMT promoter methylation","aka":["MGMT methylation","MGMT methylated","MGMT promoter methylated","MGMT unmethylated","methylated MGMT","MGMT status"],"tldr":"Methylation of the MGMT promoter switches off the repair enzyme that undoes temozolomide's damage. Methylated glioblastomas live longer on temozolomide; unmethylated ones gain little, and trials now use the result to spare or intensify chemotherapy.","summary":"Methylation-specific PCR, pyrosequencing or methylation arrays report the promoter as methylated or unmethylated, with laboratory-specific cut-offs (pyrosequencing commonly 10 percent). The temozolomide (Temodar) label for newly diagnosed glioblastoma does not require MGMT testing; the EORTC/NCIC trial that established the regimen showed the survival benefit concentrated in methylated tumours (Hegi et al., NEJM 2005), and EANO and NCCN guidelines recommend testing, with omission of temozolomide an option for elderly patients with unmethylated tumours. The CeTeG/NOA-09 trial (NCT01149109) tested lomustine plus temozolomide only in methylated glioblastoma.","asOf":"2026-09-23","links":[{"label":"Hegi et al. 2005","url":"https://doi.org/10.1056/NEJMoa043331"},{"label":"TEMODAR prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=046a9011-3911-4d3f-a15f-fbb56d5aad56"}],"tags":["biomarker","methylation","no-approval"],"related":["idh1-r132","1p19q-codeletion-readout","h3-k27m"],"cancers":["glioblastoma","idh-mutant-astrocytoma"],"sections":[],"technologies":[],"targets":[],"drugs":["temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":["mgmt","alkylating-agent"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"mgmt-protein","measurement":"methylation","scoringRule":{"text":"Promoter methylation of MGMT by methylation-specific PCR (methylated versus unmethylated) or pyrosequencing (laboratory cut-off, often around 10 percent mean methylation across CpG sites); no label defines a threshold.","quote":"MGMT promoter methylation status was associated with benefit from temozolomide in the EORTC 26981/22981 NCIC CE.3 trial","source":"https://doi.org/10.1056/NEJMoa043331","sourceLabel":"Hegi et al., MGMT gene silencing and benefit from temozolomide in glioblastoma, N Engl J Med 2005"},"thresholds":[],"definedBy":{"label":"Hegi et al., N Engl J Med 2005 (EORTC 26981/22981 NCIC CE.3 correlative study)","url":"https://doi.org/10.1056/NEJMoa043331"},"tests":["caris-mi-profile","tempus-xt"],"assays":[],"companionDiagnostics":[],"forPatient":"A methylated MGMT result means temozolomide is more likely to help and is a reason to give it in full; an unmethylated result means the benefit is small, and for older patients radiotherapy alone or a trial may be discussed. The result does not change surgery or radiotherapy and is not a drug approval criterion."},{"id":"msi-high","kind":"biomarker","name":"MSI-high (microsatellite instability by PCR or sequencing)","aka":["MSI-H","MSI-high","MSI high","microsatellite instability-high","microsatellite unstable","MSI status","MSI-H/dMMR","MSS","microsatellite stable"],"tldr":"MSI-high means the tumour's DNA has unstable repeat sequences, the footprint of failed mismatch repair. It is measured by PCR or sequencing, gives the same answer as dMMR in most tumours, and unlocks the same immunotherapies.","summary":"Microsatellite instability is scored by PCR across a panel of mononucleotide repeats (MSI-H when a set fraction of markers is unstable, typically 2 of 5 Bethesda or Promega markers, or 30 percent or more of a larger panel) or by next-generation sequencing algorithms that count unstable loci across hundreds of sites; MSS is stable and MSI-L is intermediate and grouped with MSS. Labels write 'MSI-H or dMMR' and accept either route; FoundationOne CDx and Caris MI Cancer Seek carry MSI-H companion claims for pembrolizumab and dostarlimab, the Biocartis Idylla MSI test for nivolumab in colorectal cancer, and, in the other direction, the Promega OncoMate MSI and Caris assays report 'not MSI-H' to select pembrolizumab with lenvatinib in endometrial cancer.","asOf":"2026-09-23","links":[{"label":"KEYTRUDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287"},{"label":"OPDIVO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394"}],"tags":["biomarker","mmr"],"related":["dmmr-ihc","tmb-high"],"cancers":["colorectal","endometrial","endometrial-mmr-deficient","gastric-msi-high","metastatic-cancer","tnbc","pancreatic","msi-high-pdac","gallbladder","cholangiocarcinoma","prostate","prostate-mcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","nivolumab","ipilimumab","dostarlimab","lenvatinib","foundationone-cdx","caris-mi-cancer-seek"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","mss-pmmr","ngs","tumour-agnostic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ren-tnbc-mmr-msi-440-front-oncol-2021","paper-kurata-japanese-tnbc-msi-breast-cancer-2020","paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021","paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020","paper-le-mmr-deficiency-pd1-nejm-2015","paper-le-mmr-deficiency-science-2017","paper-keynote-177-nejm-2020","paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014","paper-moreira-lynch-syndrome-identification-jama-2012","paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019","paper-giraldo-gallbladder-msk-impact-ccr-2022","paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019","paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014","paper-guedes-msh2-loss-primary-prostate-ccr-2017"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: MSI-high in 0 of 195 by PCR (Ren 2021) and 2 of 228, 0.9% (Kurata 2020); the rare positive qualifies for tumour-agnostic pembrolizumab and is best caught on a comprehensive panel rather than by dedicated testing.","Pancreatic ductal adenocarcinoma: MSI-high or mismatch repair deficient in about 1 to 2% and 0.8% of 833 MSK patients, every one of whom had Lynch syndrome (Hu 2018; Luchini 2021). It is the threshold for tumour-agnostic pembrolizumab, whose pancreatic cohort in KEYNOTE-158 gave 4 responses among 22 patients (Marabelle 2020), and the only approved immunotherapy route in this disease. Test medullary and colloid tumours specifically.","Colorectal cancer: MSI-high or mismatch repair deficient in 10 to 15% of resected disease but only about 5% of first-line metastatic disease (153 of 3,063; Venderbosch 2014). The threshold is binary and is the entry criterion for every colorectal immunotherapy trial: first-line pembrolizumab gave progression-free survival of 16.5 against 8.2 months (hazard ratio 0.60) in KEYNOTE-177, nivolumab gave 23 responses in 74 previously treated patients (Overman 2017), and four weeks of neoadjuvant nivolumab plus ipilimumab produced pathological complete response in 68% of locally advanced dMMR colon cancers (NICHE-2). Every colorectal cancer should be tested, because the same result identifies Lynch syndrome (Moreira 2012).","Gallbladder cancer: MSI-high in 6 of 244 samples (2.5%) by MSIsensor in cBioPortal gbc_mskcc_2022, 0.6% (2 of 170 tested) in Indian patients (Suryavanshi 2025) and 1.3% (4 of 308) in Western cholangiocarcinoma by a three-marker panel (Goeppert 2019). The tumour-agnostic pembrolizumab indication applies; the first-line biliary immunotherapy approvals were unselected.","Prostate cancer: microsatellite instability-high or mismatch repair deficient in 32 of 1,033 men with an assessable tumour, 3.1%, of whom 7, 21.9%, carried a pathogenic germline Lynch syndrome variant, and 2 of 6 men with serial tumours acquired the phenotype during their disease course. Eleven men received a PD-1 or PD-L1 antibody and 6, 54.5%, had a PSA fall of more than half, with 5 of the 6 responders still on treatment at up to 89 weeks (Abida 2019).","The mechanism differs from bowel cancer: among 60 advanced prostate cancers, 7 were hypermutated and all had mismatch repair gene mutations with microsatellite instability, frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 promoter methylation, so an assay designed around the colorectal mechanism can miss it (Pritchard 2014)."],"target":"mmr","measurement":"msi-status","scoringRule":{"text":"MSI-H: instability at the required fraction of tested microsatellite loci (for example 2 or more of 5 mononucleotide markers by PCR, or the sequencing panel's validated cut-off across many loci); otherwise microsatellite stable.","quote":"Microsatellite instability – High (MSI-H)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"MSI-H or dMMR, tumour-agnostic","drugId":"pembrolizumab","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.","status":"current"},{"value":"MSI-H or dMMR","drugId":"pembrolizumab","cancerId":"colorectal","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-authorized test.","status":"current"},{"value":"MSI-H or dMMR (single agent after chemotherapy)","drugId":"nivolumab","cancerId":"colorectal","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394","quote":"OPDIVO, as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.","status":"current"},{"value":"Not MSI-H / pMMR (selects the lenvatinib combination)","drugId":"lenvatinib","cancerId":"endometrial","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H as determined by an FDA-authorized test","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","caris-mi-cancer-seek","tempus-xt","trusight-oncology-500","stratangs","omniseq-insight","altera","oncoextra","bostongene-tumor-portrait"],"assays":["msi-pcr","foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["pembrolizumab"],"indication":"Solid Tumors - Tissue","pma":"P170019/S029 (02/18/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"MI Cancer Seek (MCS)","maker":"Caris Life Sciences","companyId":"caris","drugs":["pembrolizumab"],"indication":"Solid Tumors - Tissue","pma":"P240010 (11/05/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"MI Cancer Seek (MCS)","maker":"Caris Life Sciences","companyId":"caris","drugs":["dostarlimab"],"indication":"Solid Tumors - Tissue","pma":"P240010 (11/05/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Idylla CDx MSI Test","maker":"Biocartis","drugs":["nivolumab","ipilimumab"],"indication":"Colorectal Cancer (CRC) - Tissue","pma":"P250005 (08/15/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"OncoMate MSI Dx Analysis System","maker":"Promega","drugs":["pembrolizumab","lenvatinib"],"indication":"Endometrial Carcinoma (EC) - Tissue","pma":"P240026 (11/05/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"MSI-high on a PCR or sequencing report means the same for treatment as dMMR on a stain: checkpoint immunotherapy is on label across many cancers once other treatment has been tried, and first line in bowel cancer. A stable (MSS) result in endometrial cancer selects a different combination, pembrolizumab with lenvatinib. Either result should prompt a conversation about inherited risk."},{"id":"mycn-amp","kind":"biomarker","name":"MYCN amplification","aka":["MYCN amplification","MYCN-amplified","MYCN amp","N-myc amplification","MYCN-amplified neuroblastoma","MYCN FISH"],"tldr":"MYCN amplification, more than four times the normal copy number of the gene on FISH, marks the most aggressive fifth of neuroblastomas and puts a child in the high-risk group whatever their age or stage. No drug targets it; it decides how much treatment is given.","summary":"The INRG and COG definitions call MYCN amplified when the signal count is more than four times that of the chromosome 2 reference (or more than 10 copies), by FISH on tumour or bone marrow. Amplification is present in about 20 percent of neuroblastomas and assigns high risk in the INRG classification irrespective of other features (except some stage L1 tumours), triggering induction chemotherapy, surgery, tandem transplant, radiotherapy and anti-GD2 immunotherapy with dinutuximab. Dinutuximab's label describes high-risk neuroblastoma without naming MYCN. Amplification also defines a spinal ependymoma subtype and is found in some medulloblastomas.","asOf":"2026-09-23","links":[{"label":"INRG classification (Cohn et al. 2009)","url":"https://doi.org/10.1200/JCO.2008.16.6785"},{"label":"Unituxin prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d66bdf0d-9d65-45de-ae5b-a58617c27492"}],"tags":["biomarker","paediatric","no-approval"],"related":["tp53-del17p"],"cancers":["neuroblastoma","neuroblastoma-high-risk","neuroblastoma-intermediate-risk"],"sections":[],"technologies":[],"targets":[],"drugs":["dinutuximab"],"companies":[],"institutions":[],"pathways":[],"terms":["mycn-amplification","gene-amplification","fish","segmental-chromosomal-aberrations"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"mycn","measurement":"copy-number","scoringRule":{"text":"MYCN signal count more than four times the reference (chromosome 2 centromere or a control probe) by FISH, or more than 10 copies by molecular methods; gain below that is not amplification.","quote":"MYCN status: amplified versus not amplified is a criterion of the International Neuroblastoma Risk Group (INRG) classification","source":"https://doi.org/10.1200/JCO.2008.16.6785","sourceLabel":"Cohn et al., The International Neuroblastoma Risk Group (INRG) classification system, J Clin Oncol 2009"},"thresholds":[],"definedBy":{"label":"INRG classification system (Cohn et al., J Clin Oncol 2009)","url":"https://doi.org/10.1200/JCO.2008.16.6785"},"tests":["foundationone-cdx","caris-mi-profile"],"assays":[],"companionDiagnostics":[],"forPatient":"If your child's neuroblastoma is MYCN-amplified it is treated as high risk with the full programme of chemotherapy, surgery, stem cell rescue, radiotherapy and immunotherapy, even when the tumour is small or the child is young. There is no drug aimed at MYCN itself yet, though trials of indirect approaches are open."},{"id":"nectin-4-expression","kind":"biomarker","name":"Nectin-4 expression","aka":["Nectin-4","NECTIN4 expression","Nectin-4 positive","Nectin-4 H-score"],"tldr":"Nectin-4 is expressed by almost every urothelial cancer, so enfortumab vedotin is given without a test. Nectin-4 amplification is being studied as a marker of especially strong response.","summary":"Enfortumab vedotin (Padcev) is labelled alone and with pembrolizumab for locally advanced or metastatic urothelial cancer with no Nectin-4 requirement; the pivotal EV-201 and EV-301 trials enrolled without testing after screening showed near-universal expression. Retrospective work links NECTIN4 amplification to higher response rates; a Nectin-4 PET tracer is in early trials. No approval or guideline sets a threshold.","asOf":"2026-09-23","links":[{"label":"PADCEV prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5631d3e-4604-4363-8f20-11dfc5a4a8ed"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["trop2-expression","fgfr3-alteration"],"cancers":["urothelial"],"sections":[],"technologies":[],"targets":[],"drugs":["enfortumab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc","gene-amplification"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"nectin4","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"PADCEV is a Nectin-4-directed antibody and microtubule inhibitor conjugate","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5631d3e-4604-4363-8f20-11dfc5a4a8ed","sourceLabel":"PADCEV prescribing information (DailyMed)"},"thresholds":[],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"Enfortumab vedotin does not need a Nectin-4 test; the antigen is present in nearly all bladder cancers. Research is looking at whether tumours with extra copies of the Nectin-4 gene respond even better, but that is not part of routine care."},{"id":"npm1-mutation","kind":"biomarker","name":"NPM1 mutation","aka":["NPM1 mutation","NPM1-mutated AML","NPM1c","mutated NPM1","NPM1 type A","NPM1mut"],"tldr":"NPM1 mutations, found in about a third of adult acute myeloid leukaemias, misplace the nucleophosmin protein into the cytoplasm. They mean a better outlook without FLT3-ITD, a sensitive MRD marker, and since 2025 a targeted menin inhibitor.","summary":"Frameshift insertions in NPM1 exon 12 (type A, TCTG, in about 80 percent) are detected by PCR or sequencing and the transcript is tracked as measurable residual disease. Ziftomenib (Komzifti, 2025) is labelled for relapsed or refractory AML with a susceptible NPM1 mutation and no satisfactory alternative; revumenib (Revuforj) gained an NPM1-mutated relapsed or refractory indication in 2025 alongside its KMT2A-rearranged one. NPM1-mutated AML without FLT3-ITD is favourable-risk in ELN 2022 and is often spared transplant in first remission if MRD clears.","asOf":"2026-09-23","links":[{"label":"Komzifti prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b650f696-3391-4274-8b55-a5f5e9d04769"},{"label":"Revuforj prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6eb3cdbc-0e74-477d-82d6-3bb172d3f63f"}],"tags":["biomarker","aml"],"related":["flt3-itd","idh1-r132"],"cancers":["aml","aml-npm1-kmt2a"],"sections":[],"technologies":[],"targets":[],"drugs":["ziftomenib","revumenib"],"companies":[],"institutions":[],"pathways":[],"terms":["mrd","molecular-response"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"npm1","measurement":"sequencing-variant","scoringRule":{"text":"An NPM1 exon 12 frameshift insertion (type A, B, D or other) by PCR or sequencing of blood or marrow; quantitative PCR of the mutant transcript is used for residual disease.","quote":"KOMZIFTI is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation who have no satisfactory alternative treatment options","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b650f696-3391-4274-8b55-a5f5e9d04769","sourceLabel":"Komzifti prescribing information"},"thresholds":[{"value":"Susceptible NPM1 mutation, relapsed or refractory","drugId":"ziftomenib","cancerId":"aml-npm1-kmt2a","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b650f696-3391-4274-8b55-a5f5e9d04769","quote":"KOMZIFTI is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation who have no satisfactory alternative treatment options","status":"current"},{"value":"NPM1 mutation, relapsed or refractory","drugId":"revumenib","cancerId":"aml-npm1-kmt2a","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6eb3cdbc-0e74-477d-82d6-3bb172d3f63f","quote":"REVUFORJ is indicated for the treatment of relapsed or refractory acute myeloid leukemia with a susceptible nucleophosmin 1 ( NPM1 ) mutation in adult and pediatric patients 1 year and older who have no satisfactory alternative treatment options.","status":"current"}],"tests":["foundationone-heme","neotype-profiles"],"assays":[],"companionDiagnostics":[],"forPatient":"An NPM1 mutation at diagnosis is, on its own, good news: these leukaemias respond well to chemotherapy, and the mutation can be tracked in your blood to catch relapse early. If the leukaemia does come back, ziftomenib or revumenib tablets are on label. Whether you also have a FLT3-ITD changes the plan, so both results are read together."},{"id":"nrg1-fusion","kind":"biomarker","name":"NRG1 gene fusion","aka":["NRG1 fusion","neuregulin 1 fusion","NRG1 gene rearrangement","CD74-NRG1","CD74::NRG1","SLC3A2-NRG1","NRG1-rearranged","NRG1+"],"tldr":"A rare fusion that joins the neuregulin 1 gene to a partner, leaving the HER3 ligand stuck on the cell surface where it switches HER3 on continuously. It is found in a small percentage of lung adenocarcinomas, particularly invasive mucinous adenocarcinoma in people who have never smoked, and in pancreatic and biliary cancers, and zenocutuzumab is approved for it.","summary":"NRG1 encodes neuregulin 1, the ligand of HER3. A fusion (CD74::NRG1 and SLC3A2::NRG1 are the commonest partners) keeps the EGF-like domain of neuregulin tethered to the membrane, where it drives HER2-HER3 dimerisation and downstream signalling; the readout is filed under HER3 for that reason, and it is why a HER2 by HER3 bispecific antibody treats it. The fusions are rare, enriched in invasive mucinous adenocarcinoma of the lung and in people who have never smoked, and they are missed by DNA-only panels often enough that RNA sequencing is the recommended way to look for them. Zenocutuzumab (Bizengri) was approved by the FDA under accelerated approval on the basis of overall response rate and duration of response, for advanced unresectable or metastatic NRG1 fusion-positive non-small cell lung cancer and pancreatic adenocarcinoma after progression on prior systemic therapy, with cholangiocarcinoma added to the label in May 2026. No companion diagnostic is listed on the FDA device list for it; the label asks only that patients be selected on the presence of an NRG1 gene fusion in tumour specimens.","asOf":"2026-09-23","links":[{"label":"BIZENGRI (zenocutuzumab) prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=203daea4-fc87-40a4-a92f-ba2351b16de1"},{"label":"Jonna et al., Clin Cancer Res 2019: NRG1 fusions in 41 of 21,858 solid tumours profiled by RNA sequencing","url":"https://doi.org/10.1158/1078-0432.CCR-19-0160"},{"label":"Fernandez-Cuesta et al., Cancer Discov 2014: CD74-NRG1 fusions in invasive mucinous lung adenocarcinoma","url":"https://doi.org/10.1158/2159-8290.CD-13-0633"},{"label":"cBioPortal study luad_mskcc_2023_met_organotropism (MSK, Cancer Cell 2023; 2,653 MSK-IMPACT lung adenocarcinoma samples, 2,422 with copy number and structural variants)","url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism"}],"tags":["biomarker","fusion"],"related":["ntrk-fusion","ret-fusion","ros1-fusion","her2-mutation"],"cancers":["nsclc","pancreatic","cholangiocarcinoma","invasive-mucinous-adenocarcinoma-lung","lung-cancer"],"sections":[],"technologies":["rna-seq","cgp"],"targets":["nrg1","her2"],"drugs":["zenocutuzumab"],"companies":[],"institutions":[],"pathways":["rtk-activation","pi3k-akt-mtor"],"terms":["gene-fusion","tumour-agnostic","never-smoker-lung-cancer"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-jonna-nrg1-fusions-solid-tumours-ccr-2019","paper-fernandez-cuesta-cd74-nrg1-fusion-lung-cancer-discov-2014"],"journals":[],"dependsOn":[],"notes":["Lung cancer: an NRG1 rearrangement is a ligand event rather than a kinase event. The fusion keeps the EGF-like domain of neuregulin 1 anchored at the cell surface, where it supplies the ligand for HER2 and HER3 dimers and switches on PI3K and AKT, which is why the treatment is an antibody aimed at the receptor pair and not a kinase inhibitor. It was found by transcriptome sequencing of 25 never-smoker lung adenocarcinomas and confirmed in 4 of 102 driver-negative tumours, every one of them the invasive mucinous subtype (Fernandez-Cuesta 2014). Across 21,858 tumours profiled by anchored multiplex RNA sequencing, 41 carried an NRG1 fusion, 0.2 percent; the 25 lung cases were the largest group and 0.3 percent of the lung cancers tested, with heterogeneous partner genes, so an assay that reports only named fusions misses most of them (Jonna 2019). cBioPortal structural variants record 7 of 2,422 in luad_mskcc_2023_met_organotropism and 2 of 232 never-smoker genomes."],"target":"her3","measurement":"sequencing-variant","scoringRule":{"text":"An in-frame fusion involving NRG1 detected in a tumour specimen, best by RNA sequencing because DNA-only panels miss many of these rearrangements.","quote":"Select patients for treatment with BIZENGRI based on the presence of an NRG1 gene fusion in tumor specimens","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=203daea4-fc87-40a4-a92f-ba2351b16de1","sourceLabel":"BIZENGRI (zenocutuzumab) prescribing information, section 2.1 Patient Selection (DailyMed, revised May 2026)"},"thresholds":[{"value":"NRG1 gene fusion in a tumour specimen","drugId":"zenocutuzumab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=203daea4-fc87-40a4-a92f-ba2351b16de1","quote":"BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.","status":"current"},{"value":"NRG1 gene fusion in a tumour specimen","drugId":"zenocutuzumab","cancerId":"pancreatic","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=203daea4-fc87-40a4-a92f-ba2351b16de1","quote":"BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.","status":"current"},{"value":"NRG1 gene fusion in a tumour specimen","drugId":"zenocutuzumab","cancerId":"cholangiocarcinoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=203daea4-fc87-40a4-a92f-ba2351b16de1","quote":"BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic cholangiocarcinoma harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.","status":"current"}],"tests":["foundationone-cdx","tempus-xt","caris-mi-profile","oncoextra"],"assays":[],"companionDiagnostics":[],"forPatient":"An NRG1 fusion is rare and easy to miss, and it opens a treatment that nothing else does: zenocutuzumab is approved for advanced lung, pancreatic and bile duct cancers that carry one, after other treatment has stopped working. Ask whether the panel your tumour was tested on included RNA sequencing, because DNA-only panels miss many NRG1 fusions."},{"id":"ntrk-fusion","kind":"biomarker","name":"NTRK1/2/3 gene fusion","aka":["NTRK fusion","NTRK gene fusion","TRK fusion","NTRK1 fusion","NTRK2 fusion","NTRK3 fusion","ETV6-NTRK3","ETV6::NTRK3","TRK fusion cancer","NTRK"],"tldr":"An NTRK fusion joins one of three TRK kinase genes to a partner and drives cancers from infant fibrosarcoma to salivary and thyroid tumours, rare in common cancers but near-universal in a few rare ones. Larotrectinib, entrectinib and repotrectinib are approved for it regardless of tumour type.","summary":"NTRK1, NTRK2 and NTRK3 fusions (ETV6::NTRK3 in secretory carcinomas and infantile fibrosarcoma, LMNA::NTRK1 and TPM3::NTRK1 elsewhere) are best detected by RNA sequencing; DNA panels miss some NTRK2 and NTRK3 events because of long introns, and pan-TRK immunohistochemistry is a screen that needs molecular confirmation. Larotrectinib (2018) and entrectinib (2019) are labelled tumour-agnostically for solid tumours with an NTRK gene fusion without a known acquired resistance mutation, metastatic or where surgery would cause severe morbidity, with no satisfactory alternative or after progression; repotrectinib (2024) for NTRK fusion-positive solid tumours. FoundationOne CDx and Liquid CDx and TruSight Oncology Comprehensive are the listed companion diagnostics.","asOf":"2026-09-23","links":[{"label":"VITRAKVI prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd"},{"label":"Rozlytrek prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908"}],"tags":["biomarker","fusion"],"related":["ret-fusion","ros1-fusion","alk-fusion"],"cancers":["metastatic-cancer","sarcoma","thyroid","salivary-gland","colorectal","nsclc","pancreatic","kras-wild-type-pdac","gallbladder","biliary-tract-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["larotrectinib","entrectinib","repotrectinib","foundationone-cdx","trusight-oncology-comprehensive"],"companies":[],"institutions":[],"pathways":[],"terms":["gene-fusion","tumour-agnostic","tki-term"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-oreilly-hechtman-ntrk-fusion-pancreatic-larotrectinib-ann-oncol-2019","paper-philip-kras-wild-type-pancreatic-ccr-2022","paper-giraldo-gallbladder-msk-impact-ccr-2022","paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026"],"journals":[],"dependsOn":[],"notes":["Pancreatic ductal adenocarcinoma: NTRK fusions in about 0.4%, enriched in KRAS wild-type disease; the published pancreatic case responded to larotrectinib for six months under the tumour-agnostic approval before acquiring resistance (O'Reilly and Hechtman 2019).","Colorectal cancer: NTRK1 and NTRK3 fusions in about 0.2 to 0.3% of tumours (cBioPortal), enriched in RAS and BRAF wild-type, mismatch repair deficient, right-sided disease. The threshold is the presence of a fusion on an RNA-based or fusion-capable DNA assay, and the approvals (larotrectinib, entrectinib) are tumour-agnostic.","Gallbladder cancer: one LMNA::NTRK1 fusion patient among 233 (about 0.4%) in cBioPortal gbc_mskcc_2022; NTRK1 fusions were among the actionable findings (Giraldo 2022) and NTRK-driven biliary tumours retained the driver at progression (Cowzer 2026). RNA-based testing is needed because DNA panels miss some NTRK2 and NTRK3 events.","Lung cancer: about 0.2% of adenocarcinomas by structural-variant calling (cBioPortal), covered by tumour-agnostic approvals rather than a lung indication. NTRK point mutations are common on exome panels and are passengers, so only a fusion assay gives an actionable result."],"target":"ntrk","measurement":"sequencing-variant","scoringRule":{"text":"An in-frame fusion involving the kinase domain of NTRK1, NTRK2 or NTRK3 detected by RNA or DNA sequencing (pan-TRK IHC as a screen only), without a known acquired resistance mutation.","quote":"NTRK1, NTRK2 and NTRK3 fusions","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"NTRK gene fusion without a known acquired resistance mutation","drugId":"larotrectinib","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd","quote":"VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.","status":"current"},{"value":"NTRK gene fusion in tumour or plasma","drugId":"entrectinib","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908","quote":"Select patients for treatment of locally advanced or metastatic solid tumors with ROZLYTREK based on the presence of a NTRK gene fusion in tumor or plasma specimens","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","trusight-oncology-comprehensive","tempus-xt","caris-mi-profile","oncoextra"],"assays":["foundationone-cdx-panel","foundationone-liquid-cdx"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["larotrectinib"],"indication":"Solid Tumors - Tissue","pma":"P170019/S017 (10/23/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["entrectinib"],"indication":"Solid Tumors - Tissue","pma":"P170019/S014 (06/07/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne Liquid CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["entrectinib"],"indication":"Solid Tumors - Plasma","pma":"P190032/S004 (12/22/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"TruSight Oncology Comprehensive","maker":"Illumina","companyId":"illumina","drugs":["larotrectinib"],"indication":"Solid Tumors - Tissue","pma":"P230011 (08/21/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your tumour carries an NTRK fusion, a TRK tablet (larotrectinib, entrectinib or repotrectinib) is on label whatever the type of cancer, once it has spread or cannot be removed without serious harm, and responses are frequent and often long. Ask whether the test included RNA sequencing, because DNA-only panels can miss these fusions."},{"id":"pd-l1-cps","kind":"biomarker","name":"PD-L1 CPS (combined positive score)","aka":["PD-L1 CPS","CPS","combined positive score","PD-L1 combined positive score","CPS >= 1","CPS >= 10","PD-L1 CPS 1","PD-L1 CPS 10","CPS≥1","CPS≥10"],"tldr":"CPS counts every PD-L1-stained cell in the tumour, immune cells included, and divides by the number of tumour cells. Pembrolizumab labels use CPS 1 or CPS 10 as the gate in head and neck, stomach, oesophageal, cervical, ovarian and triple-negative breast cancer.","summary":"The combined positive score is the 22C3 pharmDx read used outside lung cancer: the number of PD-L1-staining cells (tumour cells, lymphocytes and macrophages) divided by the total number of viable tumour cells, multiplied by 100, so it can exceed 100 in principle and is reported as a whole number. Pembrolizumab's US label gates first-line head and neck cancer, HER2-negative and HER2-positive gastric or GEJ adenocarcinoma, first-line oesophageal cancer with chemotherapy, cervical cancer and platinum-resistant ovarian cancer at CPS >= 1, and triple-negative breast cancer and second-line oesophageal squamous cancer at CPS >= 10. Nivolumab's label now restricts its gastric, GEJ and oesophageal indications to tumours expressing PD-L1 (>= 1), measured with the 28-8 pharmDx. Because the denominator is tumour cells only, CPS is not interchangeable with TPS or with the SP142 immune-cell score.","asOf":"2026-09-23","links":[{"label":"KEYTRUDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287"},{"label":"OPDIVO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394"},{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"tags":["biomarker","pd-l1"],"related":["pd-l1-tps","pd-l1-ic-score","pd-l1-tc-score"],"cancers":["head-and-neck","gastric","gastric-her2-positive","gastric-pdl1-high","esophageal","oesophageal-squamous-cell-carcinoma","cervical","tnbc","tnbc-metastatic","ovarian","platinum-resistant-ovarian-cancer","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","nivolumab","sacituzumab-govitecan","dako-pd-l1-22c3-pharmdx"],"companies":[],"institutions":[],"pathways":[],"terms":["cps","pd-l1-testing","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-355-nejm-2022","paper-keynote-355-lancet-2020","paper-sigurjonsdottir-sp142-22c3-tnbc-bcr-2023","paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","paper-albrecht-pdl1-western-gallbladder-cancers-2021"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: the pembrolizumab threshold is 22C3 CPS 10 or more, the KEYNOTE-355 subgroup whose overall survival was 23.0 versus 16.1 months (hazard ratio 0.73); CPS 1 or more did not reach significance (Cortes 2022). CPS 10 or more was 27.2% of 232 unselected early TNBCs and CPS 1 or more 53.9% (Sigurjonsdottir 2023); 80.9% of IMpassion130 samples were CPS 1 or more (Rugo 2021). The same threshold now gates sacituzumab govitecan plus pembrolizumab (ASCENT-04). CPS 10 and SP142 IC 1% agree weakly (kappa 0.48) and are not interchangeable.","Gallbladder cancer: combined positive score was reported alongside TPS in 131 Western cases (Albrecht 2021); TOPAZ-1 and KEYNOTE-966 enrolled biliary patients regardless of PD-L1, so no CPS threshold applies to durvalumab or pembrolizumab in this cancer."],"target":"pdl1","measurement":"combined-positive-score","scoringRule":{"text":"Count PD-L1-positive tumour cells, lymphocytes and macrophages; divide by the number of viable tumour cells; multiply by 100. A specimen must hold at least 100 viable tumour cells to be scored.","quote":"PD-L1 protein expression [Combined Positive Score (CPS) ≥ 1]","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"CPS >= 1","drugId":"pembrolizumab","cancerId":"head-and-neck","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test.","status":"current"},{"value":"CPS >= 1","drugId":"pembrolizumab","cancerId":"gastric","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test.","status":"current"},{"value":"CPS >= 1","drugId":"pembrolizumab","cancerId":"gastric-her2-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1)","status":"current"},{"value":"CPS >= 1 (with chemotherapy); CPS >= 10 (single agent, squamous, after prior therapy)","drugId":"pembrolizumab","cancerId":"esophageal","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"in combination with platinum- and fluoropyrimidine-based chemotherapy for patients whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10)","status":"current"},{"value":"CPS >= 1","drugId":"pembrolizumab","cancerId":"cervical","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test.","status":"current"},{"value":"CPS >= 10","drugId":"pembrolizumab","cancerId":"tnbc-metastatic","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test","status":"current"},{"value":"CPS >= 10","drugId":"sacituzumab-govitecan","cancerId":"tnbc-metastatic","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"in combination with sacituzumab govitecan-hziy, for the first-line treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test.","status":"current"},{"value":"CPS >= 1","drugId":"pembrolizumab","cancerId":"platinum-resistant-ovarian-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"in combination with paclitaxel, with or without bevacizumab, for the treatment of adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test","status":"current"},{"value":"PD-L1 >= 1 (28-8 pharmDx)","drugId":"nivolumab","cancerId":"gastric","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394","quote":"OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1)","status":"current"},{"value":"PD-L1 >= 1 (28-8 pharmDx)","drugId":"nivolumab","cancerId":"oesophageal-squamous-cell-carcinoma","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394","quote":"OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1)","status":"current"}],"tests":["omniseq-insight","caris-mi-profile"],"assays":["pdl1-22c3","pdl1-28-8"],"companionDiagnostics":[{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["pembrolizumab"],"indication":"Head and Neck Squamous Cell Carcinoma (HNSCC) - Tissue","pma":"P150013/S014 (06/10/2019)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["pembrolizumab"],"indication":"Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma - Tissue","pma":"P150013/S027 (11/07/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["pembrolizumab"],"indication":"Esophageal or Gastroesophageal Junction (GEJ) Carcinoma - Tissue","pma":"P150013/S032 (02/11/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["pembrolizumab"],"indication":"Cervical Cancer - Tissue","pma":"P150013/S009 (06/12/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["pembrolizumab"],"indication":"Triple-Negative Breast Cancer (TNBC) - Tissue","pma":"P150013/S020 (11/13/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["pembrolizumab"],"indication":"Epithelial Ovarian, Fallopian Tube Cancer, or Primary Peritoneal Carcinoma (EOC) - Tissue","pma":"P150013/S033 (02/10/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 28-8 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["nivolumab"],"indication":"Esophageal squamous cell carcinoma (ESCC), and gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma - Tissue","pma":"P150025/S018 (07/01/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"Your report gives a CPS number. Whether it counts as positive depends on the cancer: the pembrolizumab label asks for 1 or more in head and neck, stomach, oesophageal, cervical and platinum-resistant ovarian cancer, and 10 or more in triple-negative breast cancer. The same number can open a treatment in one cancer and not in another, and a score below the cut-off does not mean immunotherapy can never be used, only that this particular indication does not apply."},{"id":"pd-l1-ic-score","kind":"biomarker","name":"PD-L1 IC score (immune-cell score, SP142)","aka":["PD-L1 IC","IC score","immune cell score","tumor-infiltrating immune cell score","SP142 IC","IC >= 1%","IC >= 5%","IC >= 10%","IC≥1%","IC2/3"],"tldr":"The IC score measures how much of the tumour area is covered by PD-L1-stained immune cells rather than tumour cells. It belongs to the SP142 assay used with atezolizumab and is read differently from every other PD-L1 score.","summary":"The VENTANA SP142 assay scores PD-L1 on tumour-infiltrating immune cells as the proportion of tumour area they occupy: IC0 (< 1 percent), IC1 (1 to < 5 percent), IC2 (5 to < 10 percent), IC3 (>= 10 percent). Atezolizumab's current US label uses IC >= 10 percent as one arm of the first-line NSCLC single-agent gate (the other being TC >= 50 percent). Earlier atezolizumab indications that used IC scores, IC >= 5 percent in cisplatin-ineligible urothelial cancer and IC >= 1 percent in triple-negative breast cancer (IMpassion130), were withdrawn in the United States in 2022 and 2021; the FDA companion diagnostic list still carries the urothelial SP142 approval of 2016. Blueprint comparison studies found SP142 stains fewer tumour cells than 22C3, 28-8 or SP263, so an SP142 result cannot be swapped for a TPS or CPS.","asOf":"2026-09-23","links":[{"label":"TECENTRIQ prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee"}],"tags":["biomarker","pd-l1"],"related":["pd-l1-cps","pd-l1-tps","pd-l1-tc-score"],"cancers":["nsclc","urothelial","tnbc-metastatic","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","ventana-pd-l1-sp142"],"companies":[],"institutions":[],"pathways":[],"terms":["pd-l1-testing","ihc","tils"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","paper-sigurjonsdottir-sp142-22c3-tnbc-bcr-2023","paper-impassion130-n-engl-j-med-2018","paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020","paper-blueprint-phase-2-pd-l1-assays-jto-2018","paper-rimm-pd-l1-assay-comparison-jama-oncol-2017"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: IMpassion130 defined PD-L1-positive as SP142 tumour-infiltrating immune cells covering 1% or more of the tumour area, 46.4% of 614 centrally scored samples (Rugo 2021) and 50.9% of 232 early tumours (Sigurjonsdottir 2023). SP263 and 22C3 call IC 1% in about 74% of the same samples, but the atezolizumab benefit was confined to SP142-positive cases, so a positive on another clone does not qualify (Rugo 2021). The US indication was withdrawn in 2021; the threshold remains in the European authorisation.","Lung cancer: the immune-cell score is an area fraction, the percentage of the tumour area occupied by PD-L1-staining immune cells, and it is the least reproducible measurement in lung pathology. Agreement between pathologists on it is 0.18 to 0.19 against 0.86 to 0.93 for tumour cells (Tsao 2018) and interassay concordance is 0.277 against 0.813 (Rimm 2017). It nevertheless carries a threshold, since IMpower110 selected on tumour-cell 1% or more or immune-cell 1% or more, with the survival benefit confined to the highest expressers (Herbst 2020)."],"target":"pdl1","measurement":"immune-cell-score","scoringRule":{"text":"Proportion of the tumour area occupied by PD-L1-staining tumour-infiltrating immune cells of any intensity, in bands IC0 to IC3; read on the SP142 assay only.","quote":"PD-L1 protein expression (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"IC >= 10% (or TC >= 50%)","drugId":"atezolizumab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee","quote":"TECENTRIQ, as a single agent, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations","status":"current"},{"value":"IC >= 5% (cisplatin-ineligible)","drugId":"atezolizumab","cancerId":"urothelial","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"PD-L1 protein expression (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area)","status":"withdrawn","note":"The first-line urothelial indication was withdrawn in the United States in November 2022; the SP142 companion diagnostic approval (P160002, 18 May 2016) remains on the FDA list."},{"value":"IC >= 1%","drugId":"atezolizumab","cancerId":"tnbc-metastatic","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee","status":"withdrawn","note":"Accelerated approval with nab-paclitaxel (IMpassion130, 2019) was withdrawn in the United States in August 2021; the indication remains authorised in the European Union."}],"tests":[],"assays":["pdl1-sp142"],"companionDiagnostics":[{"device":"Ventana PD-L1 (SP142) Assay","maker":"Ventana Medical Systems (Roche)","drugs":["atezolizumab"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160002/S006 (07/02/2018)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana PD-L1 (SP142) Assay","maker":"Ventana Medical Systems (Roche)","drugs":["atezolizumab"],"indication":"Urothelial Carcinoma - Tissue","pma":"P160002 (05/18/2016)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your report says SP142 and gives an IC percentage, it is measuring immune cells around the tumour, not the tumour itself. In lung cancer an IC of 10 percent or more (or tumour cells at 50 percent or more) allows atezolizumab alone as first treatment. The older uses of this score in bladder and triple-negative breast cancer were withdrawn in the United States, so ask which label your country follows."},{"id":"pd-l1-tc-score","kind":"biomarker","name":"PD-L1 TC score (tumour-cell score, SP263 and 28-8)","aka":["PD-L1 TC","TC score","tumor cell score","tumour cell score","TC >= 1%","TC >= 50%","PD-L1 >= 1% tumor cells","SP263 TC","28-8 TC","TC≥1%","TC≥50%"],"tldr":"The TC score is the percentage of tumour cells staining for PD-L1 on the SP263 or 28-8 assays. Atezolizumab uses 1 percent after lung surgery and 50 percent for first-line treatment alone; nivolumab with ipilimumab uses 1 percent in first-line lung cancer.","summary":"Tumour-cell scoring on the VENTANA SP263 and Dako 28-8 assays is arithmetically the same as TPS (percentage of tumour cells with membrane staining) but is tied to different drugs and assays, so labels write it as TC or as 'PD-L1 expression on >= 1% of tumor cells'. Atezolizumab's adjuvant NSCLC indication after resection and platinum chemotherapy requires PD-L1 on >= 1 percent of tumour cells (IMpower010, SP263), and its first-line single-agent indication uses TC >= 50 percent (or IC >= 10 percent). Nivolumab with ipilimumab in first-line metastatic NSCLC is approved for tumours expressing PD-L1 >= 1 percent on the 28-8 pharmDx (CheckMate 227). Blueprint phase 2 found SP263, 22C3 and 28-8 closely concordant for tumour-cell scoring, which is why the FDA has accepted each as a companion for several antibodies.","asOf":"2026-09-23","links":[{"label":"TECENTRIQ prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee"},{"label":"OPDIVO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394"}],"tags":["biomarker","pd-l1"],"related":["pd-l1-cps","pd-l1-tps","pd-l1-ic-score"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","nivolumab","ipilimumab","ventana-pd-l1-sp263"],"companies":[],"institutions":[],"pathways":[],"terms":["pd-l1-testing","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020","paper-checkmate-026-first-line-nivolumab-nejm-2017","paper-blueprint-phase-2-pd-l1-assays-jto-2018"],"journals":[],"dependsOn":[],"notes":["Lung cancer: the tumour-cell score is what the 28-8 and SP263 assays report, and what SP142 reports alongside its immune-cell score. Thresholds in use are 1%, 5%, 10%, 25% and 50%, each belonging to the trial that drew it: CheckMate 026 randomised at 5% or more and failed (progression-free survival 4.2 against 5.9 months), while IMpower110 used the SP142 combination of tumour-cell 50% or more or immune-cell 10% or more and found overall survival of 20.2 against 13.1 months (Carbone 2017, Herbst 2020). Between-pathologist agreement on the tumour-cell read is excellent (intraclass correlation 0.86 to 0.93) (Tsao 2018)."],"target":"pdl1","measurement":"tumour-cell-score","scoringRule":{"text":"Percentage of tumour cells with membrane staining of any intensity on the SP263 or 28-8 assay; immune cells are not counted.","quote":"PD-L1 protein expression (PD-L1 stained ≥ 1% of tumor cells [TC ≥ 1%])","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"PD-L1 on >= 1% of tumour cells (adjuvant)","drugId":"atezolizumab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee","quote":"as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-authorized test.","status":"current"},{"value":"TC >= 50% (or IC >= 10%)","drugId":"atezolizumab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee","quote":"whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%])","status":"current"},{"value":"PD-L1 >= 1% tumour cells (28-8 pharmDx)","drugId":"nivolumab","cancerId":"nsclc","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"PD-L1 protein expression (tumor cell staining ≥1%)","status":"current","note":"FDA companion diagnostic row P150025/S013 (15 May 2020) for Opdivo in combination with Yervoy in NSCLC."}],"tests":[],"assays":["pdl1-sp263","pdl1-28-8"],"companionDiagnostics":[{"device":"Ventana PD-L1 (SP263) Assay","maker":"Ventana Medical Systems (Roche)","drugs":["atezolizumab"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160046/S010 (10/15/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 28-8 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["nivolumab","ipilimumab"],"indication":"Non-small cell lung cancer (NSCLC) - Tissue","pma":"P150025/S013 (05/15/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A TC percentage is the share of tumour cells that stain. After lung cancer surgery, 1 percent or more is the label threshold for a year of atezolizumab; in metastatic lung cancer 50 percent or more allows atezolizumab on its own, and 1 percent or more allows nivolumab with ipilimumab. Ask which assay was used, because the drug the result applies to follows the assay."},{"id":"pd-l1-tps","kind":"biomarker","name":"PD-L1 TPS (tumour proportion score)","aka":["PD-L1 TPS","TPS","tumor proportion score","tumour proportion score","TPS >= 1%","TPS >= 50%","PD-L1 TPS 50","PD-L1 high","PD-L1 ≥50%","TPS≥50%","TPS≥1%"],"tldr":"TPS is the share of tumour cells whose membrane stains for PD-L1, ignoring immune cells. In lung cancer it decides whether pembrolizumab or cemiplimab can be given alone: 1 percent opens the door, 50 percent is where single-agent treatment is strongest.","summary":"The tumour proportion score is the percentage of viable tumour cells showing partial or complete membrane staining at any intensity, read on the 22C3 pharmDx (and, for cemiplimab, also the SP263 assay). Pembrolizumab's US label uses TPS >= 1 percent for first-line single-agent treatment of stage III or metastatic NSCLC without EGFR or ALK alterations and for second-line treatment after platinum chemotherapy; cemiplimab's single-agent first-line indication requires TPS >= 50 percent. The KEYNOTE-024 trial that set the 50 percent bar and KEYNOTE-042 that lowered the gate to 1 percent are the sources of the two numbers. TPS is a lung-specific read; the same slide scored as CPS would include immune cells and give a different number.","asOf":"2026-09-23","links":[{"label":"KEYTRUDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287"},{"label":"LIBTAYO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4347ae1f-d397-4f18-8b70-03897e1c054a"}],"tags":["biomarker","pd-l1"],"related":["pd-l1-cps","pd-l1-ic-score","pd-l1-tc-score"],"cancers":["nsclc","lung-cancer","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","cemiplimab","dako-pd-l1-22c3-pharmdx","ventana-pd-l1-sp263"],"companies":[],"institutions":[],"pathways":[],"terms":["tps","pd-l1-testing","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-neyaz-pdl1-gallbladder-histopathology-2018","paper-albrecht-pdl1-western-gallbladder-cancers-2021","paper-patil-gallbladder-immune-microenvironment-aimm-2021","paper-keynote-024-nejm-2016","paper-keynote-010-lancet-2016","paper-blueprint-phase-2-pd-l1-assays-jto-2018","paper-rimm-pd-l1-assay-comparison-jama-oncol-2017","paper-hirsch-j-thorac-oncol"],"journals":[],"dependsOn":[],"notes":["Gallbladder cancer: tumour proportion score 1% or more in 14.7% of 131 Western cases, above 10% in 4.7% and above 25% in 3.1% (Albrecht 2021); 23.0% at 1%, 14.9% at 10% and 7.5% at 50% with the SP263 clone in 174 Indian cases (Neyaz 2018). TPS above 10% was an independent negative prognostic factor in the Western series. No biliary approval uses a PD-L1 threshold.","Lung cancer: the tumour proportion score is the 22C3 read, the percentage of viable tumour cells with any membrane staining over at least 100 tumour cells, with immune cells excluded. Two thresholds carry approvals: 50% or more for first-line pembrolizumab monotherapy, where progression-free survival was 10.3 against 6.0 months with chemotherapy (Reck 2016), and 1% or more for pembrolizumab after platinum (Herbst 2016). The score can be reported from a 22C3, 28-8 or SP263 stain, since the three are comparable on tumour cells across both Blueprint phases, but not from SP142, which stains fewer tumour cells (mean score 1.99 against 2.96 for 22C3) and would move tumours across the 50% line (Tsao 2018, Rimm 2017). Cytology cell blocks are acceptable and digital reading agrees with glass (Tsao 2018)."],"target":"pdl1","measurement":"tumour-proportion-score","scoringRule":{"text":"Percentage of viable tumour cells with partial or complete membrane staining of any intensity; at least 100 viable tumour cells must be present.","quote":"PD-L1 protein expression [Tumor Proportion Score (TPS) ≥ 50%]","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"TPS >= 1%","drugId":"pembrolizumab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.","status":"current"},{"value":"TPS >= 1% (after platinum chemotherapy)","drugId":"pembrolizumab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-authorized test, with disease progression on or after platinum-containing chemotherapy.","status":"current"},{"value":"TPS >= 50%","drugId":"cemiplimab","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4347ae1f-d397-4f18-8b70-03897e1c054a","quote":"LIBTAYO as a single agent is indicated for the first-line treatment of adult patients with NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations","status":"current"}],"tests":["omniseq-insight"],"assays":["pdl1-22c3","pdl1-sp263"],"companionDiagnostics":[{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["pembrolizumab"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P150013 (10/02/2015); updated P150013/S012 (04/16/2019)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"PD-L1 IHC 22C3 pharmDx","maker":"Agilent Technologies (Dako)","companyId":"agilent","drugs":["cemiplimab"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P150013/S021 (02/22/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana PD-L1 (SP263) Assay","maker":"Ventana Medical Systems (Roche)","drugs":["cemiplimab"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160046/S013 (03/01/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"In lung cancer the report gives a percentage of tumour cells. At 50 percent or more the labels allow pembrolizumab or cemiplimab on their own as first treatment; between 1 and 49 percent pembrolizumab alone is still on label but chemotherapy combinations are usually chosen; below 1 percent immunotherapy is given with chemotherapy rather than alone. The score does not apply if the tumour has an EGFR or ALK alteration, which take priority."},{"id":"pdgfra-exon-18-d842v","kind":"biomarker","name":"PDGFRA exon 18 mutation (D842V)","aka":["PDGFRA D842V","D842V","PDGFRA exon 18","PDGFRA exon 18 mutation","PDGFRA-mutant GIST"],"tldr":"PDGFRA D842V drives about 5 percent of gastrointestinal stromal tumours and is resistant to imatinib. Avapritinib is the approved drug for GISTs with PDGFRA exon 18 mutations including D842V.","summary":"Exon 18 mutations sit in the activation loop; D842V, the commonest, stabilises the active kinase and blocks imatinib, sunitinib and regorafenib binding. Avapritinib (Ayvakit, 2020) is labelled for unresectable or metastatic GIST harbouring a PDGFRA exon 18 mutation, including D842V, and the therascreen PDGFRA RGQ PCR Kit is its companion diagnostic (P210002, 2023). Non-D842V exon 18 mutations remain partly imatinib-sensitive, so the exact variant is reported.","asOf":"2026-09-23","links":[{"label":"AYVAKIT prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9"}],"tags":["biomarker","gist"],"related":["kit-d816v"],"cancers":["gist","gist-pdgfra-d842v"],"sections":[],"technologies":[],"targets":[],"drugs":["avapritinib","imatinib","therascreen-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["gist-risk-stratification"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"pdgfra","measurement":"sequencing-variant","scoringRule":{"text":"A PDGFRA exon 18 mutation, including D842V, by the therascreen PDGFRA RGQ PCR Kit or sequencing of tumour tissue.","quote":"PDGFRA: D842V","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"PDGFRA exon 18 mutation including D842V","drugId":"avapritinib","cancerId":"gist-pdgfra-d842v","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9","quote":"1.1 PDGFRA Exon 18 Mutation-Positive Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) AYVAKIT ® is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.","status":"current"}],"tests":["foundationone-cdx","tempus-xt","caris-mi-profile"],"assays":[],"companionDiagnostics":[{"device":"therascreen PDGFRA RGQ PCR Kit","maker":"QIAGEN","companyId":"qiagen","drugs":["avapritinib"],"indication":"Gastrointestinal Stromal Tumors (GIST) - Tissue","pma":"P210002 (06/29/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your GIST carries a PDGFRA D842V mutation, imatinib is unlikely to work and avapritinib tablets are the on-label treatment for advanced disease. Every GIST should have KIT and PDGFRA sequenced before treatment, because the mutation decides the drug and the dose."},{"id":"pik3ca-hotspot-mutation","kind":"biomarker","name":"PIK3CA mutation","aka":["PIK3CA mutation","PIK3CA-mutated","PIK3CA H1047R","PIK3CA E545K","PIK3CA E542K","PIK3CA hotspot","PI3K mutation breast cancer"],"tldr":"PIK3CA mutations in the helical and kinase domains are found in about 40 percent of hormone-receptor-positive breast cancers. Alpelisib, inavolisib and capivasertib are approved for tumours that carry them.","summary":"Hotspots E542K and E545K (helical domain, exon 9) and H1047R (kinase domain, exon 20) are detected in tissue or plasma; the therascreen PIK3CA RGQ PCR Kit covers 11 mutations and FoundationOne CDx and Liquid CDx report the gene. Alpelisib (Piqray) is labelled with fulvestrant for HR-positive HER2-negative PIK3CA-mutated advanced breast cancer after endocrine therapy; inavolisib (Itovebi) with palbociclib and fulvestrant for endocrine-resistant PIK3CA-mutated disease recurring during or after adjuvant endocrine therapy; capivasertib (Truqap) with fulvestrant for tumours with PIK3CA, AKT1 or PTEN alterations. All three name an FDA-approved test. Hyperglycaemia and rash are the class effects that the PIK3CA result buys into.","asOf":"2026-09-23","links":[{"label":"PIQRAY prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b20b4e18-7a4b-4500-a08f-06c6dab0ee5b"},{"label":"Itovebi prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5de59f5b-e5db-410f-b692-658686ef4107"},{"label":"TRUQAP prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf"}],"tags":["biomarker","pi3k"],"related":["akt1-e17k","pten-alteration","esr1-mutation-ctdna"],"cancers":["breast-hr-positive","hr-positive-metastatic-post-cdk46","endometrial","tnbc","colorectal","nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["alpelisib","inavolisib","capivasertib","therascreen-cdx","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["hyperglycaemia","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018","paper-schmid-pakt-capivasertib-tnbc-jco-2020"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: PIK3CA mutation in 10 to 18% by cohort and 55% of the LAR subtype (Bareche 2018); part of the PIK3CA/AKT1/PTEN-altered group (20%) that gained most from capivasertib in PAKT (Schmid 2020). The alpelisib and capivasertib labels are hormone receptor-positive only.","Colorectal cancer: E545K, H1047R and E542K are the commonest of the 20 to 28% of tumours with a PIK3CA mutation (331, 232 and 216 samples of 1,486 in crc_msk_2026; cBioPortal), enriched on the right and in mismatch repair deficient disease. No approved colorectal therapy depends on the result; the readout is used for trial eligibility and in the aspirin literature.","Lung cancer: 5 to 7% of adenocarcinomas, where it is usually a passenger, and 11 to 16% of squamous tumours with amplification in a further 37.8% (cBioPortal). E545K and E542K lead and H1047R trails, the reverse of the breast cancer pattern, and no lung approval turns on the result."],"target":"pik3ca","measurement":"sequencing-variant","scoringRule":{"text":"A PIK3CA hotspot mutation (C420R, E542K, E545A/D/G/K, Q546E/R, H1047L/R/Y on the therascreen kit; wider sets on sequencing panels) in tumour tissue or plasma; a negative plasma result should be followed by tissue testing.","quote":"C420R, E542K, E545A, E545D [1635G>T only], E545G, E545K, Q546E, Q546R, H1047L, H1047R, and H1047Y","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"PIK3CA-mutated","drugId":"alpelisib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b20b4e18-7a4b-4500-a08f-06c6dab0ee5b","quote":"PIQRAY is indicated in combination with fulvestrant for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.","status":"current"},{"value":"PIK3CA-mutated, endocrine-resistant","drugId":"inavolisib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5de59f5b-e5db-410f-b692-658686ef4107","quote":"ITOVEBI, in combination with palbociclib and fulvestrant, is indicated for the treatment of adults with endocrine-resistant, PIK3CA -mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy","status":"current"},{"value":"PIK3CA, AKT1 or PTEN alteration","drugId":"capivasertib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf","quote":"in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN -alterations as detected by an FDA-approved test","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","caris-mi-cancer-seek"],"assays":["pik3ca-therascreen","foundationone-cdx-panel","foundationone-liquid-cdx"],"companionDiagnostics":[{"device":"therascreen PIK3CA RGQ PCR Kit","maker":"QIAGEN","companyId":"qiagen","drugs":["alpelisib"],"indication":"Breast Cancer - Tissue or Plasma","pma":"P190001 (05/24/2019) P190004 (05/24/2019)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["alpelisib"],"indication":"Breast Cancer - Tissue","pma":"P170019/S006 (12/03/2019)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne Liquid CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["inavolisib"],"indication":"Breast Cancer - Plasma","pma":"P190032/S023 (10/10/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["capivasertib","fulvestrant"],"indication":"Breast Cancer - Tissue","pma":"P170019/S048 (11/16/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A PIK3CA mutation in hormone-receptor-positive breast cancer opens three targeted tablets given with fulvestrant: inavolisib (with palbociclib) if the cancer came back during or soon after adjuvant hormone therapy, and alpelisib or capivasertib after hormone therapy for advanced disease. All raise blood sugar, so your team will check glucose before and during treatment."},{"id":"pr-status","kind":"biomarker","name":"PR status (progesterone receptor by IHC)","aka":["PR status","PR-positive","PR positive","PR+","PgR","progesterone receptor status","PR-negative","PR >= 1%"],"tldr":"PR status is read the same way as ER: 1 percent or more of nuclei staining is positive. It is measured alongside ER, adds to prognosis, and a tumour positive for either receptor counts as hormone-receptor-positive.","summary":"The ASCO/CAP 2020 guideline applies the same 1 percent nuclear staining threshold to the progesterone receptor as to ER; PR is a downstream target of ER signalling, so PR-negativity in an ER-positive tumour flags a less endocrine-responsive cancer with a worse outlook. Labels use the phrase 'hormone receptor (HR)-positive', which by convention means ER-positive or PR-positive or both, so PR alone can qualify a patient for endocrine therapy and CDK4/6 inhibitors. In endometrial cancer PR expression is used to select progestin therapy under guidelines rather than labels.","asOf":"2026-09-23","links":[{"label":"ASCO/CAP estrogen and progesterone receptor testing guideline, 2020 update (Allison et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.19.02309"}],"tags":["biomarker","hormone-receptor"],"related":["er-status","ki-67-index"],"cancers":["breast-hr-positive","breast-cancer","endometrial"],"sections":[],"technologies":[],"targets":[],"drugs":["tamoxifen","letrozole","fulvestrant","palbociclib"],"companies":[],"institutions":[],"pathways":[],"terms":["hormone-receptor-status","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"pgr","measurement":"ihc-score","scoringRule":{"text":"PR-positive: at least 1 percent of tumour cell nuclei stain positive by IHC; PR-negative below 1 percent.","quote":"PgR-positive... if ≥ 1% of tumor cell nuclei are immunoreactive","source":"https://doi.org/10.1200/JCO.19.02309","sourceLabel":"ASCO/CAP estrogen and progesterone receptor testing guideline, 2020 update (Allison et al., J Clin Oncol)"},"thresholds":[{"value":"Hormone receptor-positive (ER or PR >= 1%)","drugId":"palbociclib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=89a142d5-7e61-48bf-9e77-e2cd124c4792","quote":"hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer","status":"current","note":"Palbociclib label wording; the 1 percent rule is the ASCO/CAP guideline's, not the label's."}],"definedBy":{"label":"ASCO/CAP estrogen and progesterone receptor testing guideline, 2020 update (Allison et al., J Clin Oncol)","url":"https://doi.org/10.1200/JCO.19.02309"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A PR-positive result adds to the case for hormone-blocking treatment and generally means a better outlook; a PR-negative result in an ER-positive cancer is a sign the cancer may respond less well to hormone therapy alone. Either receptor at 1 percent or more makes the cancer hormone-receptor-positive for treatment purposes."},{"id":"psma-pet-expression","kind":"biomarker","name":"PSMA expression by PET (PSMA-positive)","aka":["PSMA PET positive","PSMA-positive","PSMA expression","PSMA PET","Ga-68 PSMA-11 uptake","piflufolastat PET","PSMA-avid","PSMA uptake greater than liver"],"tldr":"PSMA-positive means prostate cancer deposits light up on a PSMA PET scan more than the liver does. It is the entry ticket for lutetium-177 PSMA therapy and the basis of the imaging that now stages most advanced prostate cancer.","summary":"Gallium-68 gozetotide (Locametz, Illuccix), piflufolastat F-18 (Pylarify) and flotufolastat F-18 (Posluma) image PSMA. The Pluvicto label requires selection with Locametz or another approved PSMA PET product based on PSMA expression in tumours; the VISION and PSMAfore trials defined positivity as at least one metastatic lesion with uptake greater than liver parenchyma and no PSMA-negative lesions above size limits (short axis 1 cm in soft tissue, 2.5 cm in nodes, or any measurable bone lesion with soft tissue component), and the label's clinical studies section repeats this. Pluvicto is now labelled for both PSMA-positive metastatic castration-resistant disease after an ARPI and, since 2026, PSMA-positive metastatic androgen pathway modulation-naive or -sensitive disease with an ARPI.","asOf":"2026-09-23","links":[{"label":"PLUVICTO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14908037-2892-4d98-a053-253ce35afb1a"}],"tags":["biomarker","pet"],"related":["sstr-pet-expression","ar-v7-splice-variant"],"cancers":["prostate","prostate-mcrpc","prostate-mhspc","prostate-bcr"],"sections":[],"technologies":[],"targets":[],"drugs":["pluvicto","ga68-psma-11","locametz","illuccix","pylarify","flotufolastat","lu177-psma-it","ac225-psma"],"companies":[],"institutions":[],"pathways":[],"terms":["theranostics","prrt-term"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-silver-psma-expression-normal-malignant-tissues-ccr-1997","paper-propsma-hofman-lancet-2020","paper-fendler-psma-pet-biochemical-recurrence-jama-oncol-2019","paper-therap-lancet-2021"],"journals":[],"dependsOn":[],"notes":["Where PSMA sits in the body, from the tissue survey the imaging rests on: detectable in prostatic epithelium, duodenal mucosa, a subset of proximal renal tubules and colonic neuroendocrine cells, and undetectable in every other normal tissue including cerebral cortex and cerebellum; present in 33 of 35 primary prostate adenocarcinomas and 7 of 8 nodal metastases but only 8 of 18 bone metastases, with expression falling as tumours dedifferentiate (Silver 1997).","What the scan changes at staging: in 302 men randomised before curative-intent treatment, PSMA PET-CT was 27% more accurate than CT with bone scan, 92% against 65%, with sensitivity 85% against 38%, management change in 28% against 15%, fewer equivocal findings, 7% against 23%, and less radiation, 8.4 against 19.2 mSv (Hofman 2020).","What it changes at biochemical recurrence: recurrence was localised in 475 of 635 men, 75%, with detection rising from 38% below PSA 0.5 ng/mL to 97% at 5.0 or above, and positive predictive value 0.84 by histopathology (Fendler 2019).","How many men it excludes from radioligand therapy: of 291 men screened for TheraP with PSMA and FDG PET, 200, 69%, were eligible, the rest excluded for PSMA-low disease or FDG-positive PSMA-negative sites (Hofman 2021)."],"target":"psma","measurement":"pet-tracer-expression","scoringRule":{"text":"At least one metastatic lesion with PSMA PET uptake greater than normal liver, and no PSMA-negative measurable lesions (the VISION criteria) on an approved PSMA PET tracer.","quote":"Select patients for treatment using LOCAMETZ ® or another approved PSMA positron emission tomography (PET) product based on PSMA expression in tumors.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14908037-2892-4d98-a053-253ce35afb1a","sourceLabel":"PLUVICTO prescribing information"},"thresholds":[{"value":"PSMA-positive by PSMA PET","drugId":"pluvicto","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14908037-2892-4d98-a053-253ce35afb1a","quote":"for the treatment of adult patients with PSMA-positive metastatic androgen pathway modulation-resistant (mAPMR) prostate cancer who have been treated with ARPI therapy, and are considered appropriate to delay taxane-based chemotherapy, or have received prior taxane-based chemotherapy.","status":"current"},{"value":"PSMA-positive by PSMA PET","drugId":"pluvicto","cancerId":"prostate-mhspc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14908037-2892-4d98-a053-253ce35afb1a","quote":"in combination with androgen receptor pathway inhibitor (ARPI) therapy for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer.","status":"current"}],"tests":[],"assays":["psma-pet-selection"],"companionDiagnostics":[],"forPatient":"A PSMA PET scan that shows your cancer taking up the tracer more strongly than your liver makes you PSMA-positive, which is required for lutetium-177 PSMA treatment. The same scan is used to find where the cancer is. If some deposits do not take up the tracer, the treatment may not reach them, which is why the scan is read lesion by lesion."},{"id":"pten-alteration","kind":"biomarker","name":"PTEN alteration (sequencing) and PTEN loss (IHC)","aka":["PTEN loss","PTEN deficiency","PTEN-deficient","PTEN alteration","PTEN deletion","PTEN mutation","PTEN IHC loss","PTEN null"],"tldr":"PTEN can be lost by mutation or deletion (read by sequencing) or as absent protein on a stain. Both readouts select capivasertib: alterations in breast cancer, and protein deficiency in metastatic hormone-sensitive prostate cancer.","summary":"PTEN loss removes the brake on PI3K signalling. In breast cancer capivasertib with fulvestrant is labelled for tumours with PIK3CA, AKT1 or PTEN alterations by FoundationOne CDx (CAPItello-291); in prostate cancer, following CAPItello-281, the 2026 label adds capivasertib with abiraterone for metastatic androgen pathway modulation-naive or -sensitive prostate cancer selected on PTEN deficiency in tumour tissue by the VENTANA PTEN (SP218) RxDx Assay (P250031, 12 June 2026). The IHC rule is loss of PTEN staining in tumour cells with retained stromal staining; the sequencing rule is a deleterious mutation or homozygous deletion.","asOf":"2026-09-23","links":[{"label":"TRUQAP prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf"}],"tags":["biomarker","pi3k"],"related":["pik3ca-hotspot-mutation","akt1-e17k"],"cancers":["breast-hr-positive","prostate-mhspc","prostate","endometrial","glioblastoma","tnbc","tnbc-metastatic","prostate-mcrpc"],"sections":[],"technologies":[],"targets":[],"drugs":["capivasertib","abiraterone","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["pten-loss","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-barroso-sousa-tmb-pten-ici-mtnbc-ccr-2020","paper-kim-lotus-ipatasertib-tnbc-lancet-oncol-2017","paper-tcga-breast-molecular-portraits-nature-2012","paper-ferraldeschi-pten-protein-loss-abiraterone-eur-urol-2015","paper-ipatential150-ipatasertib-abiraterone-pten-lancet-2021","paper-carver-pi3k-ar-reciprocal-feedback-prostate-cancer-cell-2011"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: PTEN mutation or loss in up to 35% of basal-like tumours (Cancer Genome Atlas 2012) and 29% of 62 metastatic TNBC patients on immunotherapy, where it marked non-response (6% versus 48%) and shorter survival (Barroso-Sousa 2020); PTEN-low by immunohistochemistry was the co-primary population of LOTUS (Kim 2017). No approval in TNBC uses it.","Prostate cancer: deep deletion in 12 to 41% depending on disease state, 17.4% of 489 TCGA primaries and 25.7 to 41.0% in the metastatic castration-resistant cohorts (cBioPortal), with inactivating mutation adding 3 to 11% on top.","Protein loss is the measurement that matters and it is read by immunohistochemistry: loss in 40% of 144 men treated with abiraterone, associated with shorter overall survival, 14 against 21 months, hazard ratio 1.75, and concordant between hormone-sensitive and castration-resistant biopsies in 86% of 41 paired cases, so the diagnostic block usually answers the question (Ferraldeschi 2015).","It selects a treatment. IPATential150 prospectively stratified 1,101 men by PTEN loss on a single validated assay, found 521, 47%, PTEN-loss, and showed radiographic progression-free survival of 18.5 against 16.5 months with ipatasertib added to abiraterone in that group, hazard ratio 0.77, with grade 3 or higher adverse events in 70% against 39% (Sweeney 2021). The rationale is the reciprocal feedback between the PI3K and androgen receptor pathways (Carver 2011)."],"target":"pten","measurement":"sequencing-variant","scoringRule":{"text":"Sequencing: a deleterious PTEN mutation or deletion in tumour tissue or plasma. Immunohistochemistry: absence of PTEN staining in tumour cells with retained staining in adjacent stroma, on the VENTANA PTEN (SP218) RxDx Assay for prostate cancer.","quote":"PTEN protein Loss/Deficient","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"PTEN alteration (with PIK3CA and AKT1 as the qualifying set)","drugId":"capivasertib","cancerId":"breast-hr-positive","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf","quote":"with one or more PIK3CA/AKT1/PTEN -alterations as detected by an FDA-approved test","status":"current"},{"value":"PTEN deficiency in tumour tissue (IHC)","drugId":"capivasertib","cancerId":"prostate-mhspc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d698c106-2322-401e-b738-cbd83c843ecf","quote":"Select patients for the treatment of metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer with TRUQAP based on PTEN deficiency in tumor tissue","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","tempus-xt","caris-mi-profile"],"assays":["foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["capivasertib","fulvestrant"],"indication":"Breast Cancer - Tissue","pma":"P170019/S048 (11/16/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"VENTANA PTEN (SP218) RxDx Assay","maker":"Ventana Medical Systems (Roche Tissue Diagnostics)","drugs":["capivasertib"],"indication":"Metastatic hormone-sensitive prostate cancer (mHSPC) - Tissue","pma":"P250031 (06/12/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"PTEN loss means the PI3K growth pathway is running without its brake. In hormone-receptor-positive breast cancer it qualifies you for capivasertib with fulvestrant after hormone therapy; in newly metastatic hormone-sensitive prostate cancer a PTEN-deficient stain qualifies you for capivasertib added to abiraterone. Ask which test was used, because the breast indication uses sequencing and the prostate one a stain."},{"id":"ras-wild-type","kind":"biomarker","name":"RAS wild-type (extended KRAS and NRAS testing)","aka":["RAS wild-type","RAS wild type","KRAS wild-type","KRAS wild type","wild-type RAS","extended RAS","extended RAS testing","RAS/BRAF wild-type","pan-RAS wild-type","RAS-WT"],"tldr":"RAS wild-type is the absence of a mutation, and it is the result that decides whether the EGFR antibodies cetuximab and panitumumab can be given in bowel cancer. Extended testing means KRAS and NRAS exons 2, 3 and 4, not just codons 12 and 13.","summary":"This is a negative selector: the drug is given when nothing is found. Cetuximab and panitumumab only work in metastatic colorectal cancer whose RAS genes are unmutated, because a mutation downstream of the receptor makes blocking the receptor pointless. The definition widened once. The 2012 and 2014 companion diagnostic claims asked only for KRAS codons 12 and 13 (exon 2); the PRIME extended analysis (Douillard, New England Journal of Medicine 2013) then showed that patients with RAS mutations outside exon 2, in KRAS or NRAS exons 3 and 4, did worse when panitumumab was added, so the wild-type definition was extended to KRAS and NRAS exons 2, 3 and 4 and the panitumumab label and its companion diagnostics were rewritten around it. The FDA list now carries both definitions side by side: FoundationOne CDx, xT CDx, the CRCDx RAS Mutation Detection Assay and MI Cancer Seek report KRAS and NRAS wild-type across exons 2, 3 and 4 for panitumumab, while the cetuximab rows on the same devices, on the therascreen KRAS RGQ PCR Kit and on ONCO/Reveal Dx still read codons 12 and 13. An assay that reads codons 12 and 13 alone misses about one KRAS mutation in six and nearly every NRAS mutation, so a codon 12 and 13 wild-type result is not the same claim as an extended RAS wild-type result. Sidedness is read alongside it: in RAS wild-type disease an EGFR antibody improves survival in left-sided tumours and not in right-sided ones. RAS wild-type is also the setting for the HER2-directed colorectal combinations and, with a BRAF V600E mutation, for encorafenib with cetuximab.","asOf":"2026-09-23","links":[{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"label":"Douillard et al., PRIME extended RAS analysis (NEJM 2013)","url":"https://doi.org/10.1056/NEJMoa1305275"}],"tags":["biomarker","kras","negative-selector"],"related":["kras-g12d","kras-g12c","braf-v600e"],"cancers":["colorectal","rectal-cancer","colon-cancer","her2-amplified-colorectal","braf-v600e-colorectal"],"sections":[],"technologies":["companion-diagnostic"],"targets":[],"drugs":["cetuximab","panitumumab","encorafenib","tucatinib","trastuzumab","sotorasib","adagrasib","therascreen-cdx","tempus-xt-cdx","foundationone-cdx","caris-mi-cancer-seek"],"companies":[],"institutions":[],"pathways":[],"terms":["wild-type","extended-ras-testing","sidedness","ngs"],"trials":["prime","paradigm","crystal-fire3","calgb-80405","opus","codebreak-300","mountaineer"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"kras","measurement":"sequencing-variant","scoringRule":{"text":"No activating mutation detected in KRAS or NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61) or exon 4 (codons 117 and 146) by PCR or sequencing of tumour tissue. Older cetuximab claims test KRAS codons 12 and 13 only; the label wording differs between the two antibodies and the report should say which was done.","quote":"KRAS wild-type (absence of mutations in exons 2, 3, and 4) and NRAS wild type (absence of mutations in exons 2, 3, and 4)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"KRAS and NRAS wild-type across exons 2, 3 and 4","drugId":"panitumumab","cancerId":"colorectal","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"KRAS wild-type (absence of mutations in exons 2, 3, and 4) and NRAS wild type (absence of mutations in exons 2, 3, and 4)","status":"current","note":"FDA companion diagnostic row for FoundationOne CDx with Vectibix, P170019 (30 November 2017); xT CDx (P210011), the CRCDx RAS Mutation Detection Assay Kit (P220005) and MI Cancer Seek (P240010) carry the same wording."},{"value":"KRAS wild-type at codons 12 and 13","drugId":"cetuximab","cancerId":"colorectal","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"KRAS wild-type (absence of mutations in codons 12 and 13)","status":"current","note":"FDA companion diagnostic row for FoundationOne CDx with Erbitux, P170019 (30 November 2017); the therascreen KRAS RGQ PCR Kit (P110027/S013, 2 December 2022), ONCO/Reveal Dx (P200011) and xT CDx (P210011) carry the same exon 2 wording. Guidelines ask for extended RAS testing before either antibody."}],"definedBy":{"label":"Douillard et al., New England Journal of Medicine 2013: panitumumab with FOLFOX4 in the PRIME trial, the extended RAS analysis that widened the wild-type definition to KRAS and NRAS exons 2, 3 and 4","url":"https://doi.org/10.1056/NEJMoa1305275"},"tests":["foundationone-cdx","tempus-xt","caris-mi-cancer-seek","guardant360-cdx"],"assays":["kras-therascreen","foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["panitumumab"],"indication":"Colorectal Cancer - Tissue (KRAS and NRAS wild-type, exons 2, 3 and 4)","pma":"P170019 (11/30/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["cetuximab"],"indication":"Colorectal Cancer - Tissue (KRAS wild-type, codons 12 and 13)","pma":"P170019 (11/30/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"xT CDx","maker":"Tempus Labs","companyId":"tempus","drugs":["panitumumab"],"indication":"Colorectal Cancer (CRC) - Tissue (matching blood or saliva), KRAS and NRAS wild-type","pma":"P210011 (04/28/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"xT CDx","maker":"Tempus Labs","companyId":"tempus","drugs":["cetuximab"],"indication":"Colorectal Cancer (CRC) - Tissue (matching blood or saliva), KRAS wild-type at codons 12 or 13","pma":"P210011 (04/28/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"CRCDx RAS Mutation Detection Assay Kit","maker":"EntroGen","drugs":["panitumumab"],"indication":"Colorectal Cancer (CRC) - Tissue","pma":"P220005 (09/29/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"MI Cancer Seek (MCS)","maker":"Caris Life Sciences","companyId":"caris","drugs":["panitumumab"],"indication":"Colorectal Cancer - Tissue","pma":"P240010 (11/05/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"therascreen KRAS RGQ PCR Kit","maker":"QIAGEN Manchester","companyId":"qiagen","drugs":["cetuximab"],"indication":"Colorectal Cancer - Tissue (KRAS wild-type, codons 12 and 13)","pma":"P110027/S013 (12/02/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"ONCO/Reveal Dx Lung and Colon Cancer Assay","maker":"Pillar Biosciences","drugs":["cetuximab","panitumumab"],"indication":"Colorectal Cancer - Tissue","pma":"P200011 (07/30/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"RAS wild-type is good news in metastatic bowel cancer: it means the EGFR antibodies cetuximab and panitumumab are options, usually alongside chemotherapy. Ask whether the test was extended RAS, covering KRAS and NRAS exons 2, 3 and 4, because the older tests looked only at two spots in KRAS and can call a tumour wild-type when it is not. Which side of the bowel the tumour started on is read alongside the result, because the antibodies work better in left-sided tumours. RAS wild-type is also needed for the HER2-directed combinations and for encorafenib with cetuximab when BRAF V600E is present."},{"id":"ret-fusion","kind":"biomarker","name":"RET fusion and RET mutation","aka":["RET fusion","RET rearrangement","RET fusion-positive","KIF5B-RET","KIF5B::RET","CCDC6-RET","RET mutation","RET M918T","RET-mutant medullary thyroid cancer","RET-altered"],"tldr":"RET fusions drive 1 to 2 percent of lung cancers and some thyroid cancers; RET point mutations drive medullary thyroid cancer. Selpercatinib is approved for RET fusions in any solid tumour and for RET-mutant medullary thyroid cancer; pralsetinib for RET fusion lung cancer.","summary":"RET fusions (KIF5B::RET, CCDC6::RET, NCOA4::RET) are detected by RNA or DNA sequencing and FISH; RET point mutations (M918T, codon 634 and others, germline in MEN2) by sequencing. Selpercatinib (Retevmo) is labelled for RET fusion-positive NSCLC, RET fusion-positive thyroid cancer, RET-mutant medullary thyroid cancer and, since 2022, RET fusion-positive solid tumours after prior therapy, each as detected by an FDA-approved test; pralsetinib (Gavreto) for RET fusion-positive NSCLC. The Oncomine Dx Target Test, FoundationOne CDx and TruSight Oncology Comprehensive are the listed companion diagnostics.","asOf":"2026-09-23","links":[{"label":"Retevmo prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7fa848ba-a59c-4144-9f52-64d090f4d828"},{"label":"Gavreto prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16edd46e-28b8-f06d-e063-6394a90ae31b"}],"tags":["biomarker","fusion"],"related":["alk-fusion","ntrk-fusion","ros1-fusion"],"cancers":["nsclc","thyroid","medullary-thyroid-cancer","papillary-thyroid-cancer","metastatic-cancer","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["selpercatinib","pralsetinib","oncomine-dx-target-test","foundationone-cdx","trusight-oncology-comprehensive"],"companies":[],"institutions":[],"pathways":[],"terms":["gene-fusion","tumour-agnostic","tki-term"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Colorectal cancer: RET fusions in about 0.1% of tumours (NCOA4-RET the commonest; cBioPortal), in the same wild-type, mismatch repair deficient, right-sided corner as the NTRK fusions. Selpercatinib's tumour-agnostic approval is the route; there is no colorectal-specific trial.","Lung cancer: 1 to 2% of adenocarcinomas, with KIF5B the dominant partner and CCDC6 second, the reverse of the thyroid pattern (cBioPortal). RET was added to the recommended panel content for laboratories performing next-generation sequencing in the 2018 guideline (Lindeman 2018)."],"target":"ret","measurement":"sequencing-variant","scoringRule":{"text":"A RET gene fusion by RNA or DNA sequencing (or FISH), or an activating RET point mutation, small deletion or insertion by sequencing.","quote":"RET fusions; RET mutations (SNVs, MNVs, and deletions)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"RET fusion-positive","drugId":"pralsetinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16edd46e-28b8-f06d-e063-6394a90ae31b","quote":"Adult patients with metastatic rearranged during transfection (RET ) fusion-positive non-small cell lung cancer as detected by an FDA approved test (NSCLC).","status":"current"},{"value":"RET fusion-positive (NSCLC, thyroid, solid tumours) and RET-mutant medullary thyroid cancer","drugId":"selpercatinib","cancerId":"medullary-thyroid-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7fa848ba-a59c-4144-9f52-64d090f4d828","status":"current","note":"Retevmo label indications 1.1 to 1.4 (DailyMed set id 7fa848ba): RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer, RET fusion-positive thyroid cancer, and RET fusion-positive solid tumours after prior systemic treatment, each as detected by an FDA-approved test."},{"value":"RET fusion-positive","drugId":"selpercatinib","cancerId":"nsclc","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"RET fusions","status":"current","note":"FDA companion diagnostic rows for the Oncomine Dx Target Test (P160045/S031) and TruSight Oncology Comprehensive (P230011) with Retevmo in NSCLC."}],"tests":["foundationone-cdx","trusight-oncology-comprehensive","tempus-xt","guardant360-cdx","caris-mi-cancer-seek"],"assays":["oncomine-dx","foundationone-cdx-panel"],"companionDiagnostics":[{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["pralsetinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160045/S019 (09/04/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["selpercatinib"],"indication":"Medullary Thyroid Cancer (MTC) - Tissue","pma":"P160045/S031 (09/21/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["selpercatinib"],"indication":"Solid Tumors - Tissue","pma":"P170019/S043 (10/06/2023)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"TruSight Oncology Comprehensive","maker":"Illumina","companyId":"illumina","drugs":["selpercatinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P230011 (08/21/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A RET fusion means selpercatinib (or, in lung cancer, pralsetinib) is an on-label tablet whatever the cancer type once other treatment has been tried, and first line in lung cancer. In medullary thyroid cancer a RET point mutation qualifies for selpercatinib too, and if the mutation is inherited (MEN2) relatives should be tested."},{"id":"rhoa-g17v","kind":"biomarker","name":"RHOA G17V","aka":["RHOA G17V","RHOA Gly17Val","RHOA mutation","T-follicular-helper lymphoma mutation"],"tldr":"A single change in a small signalling protein, found in about two thirds of one kind of T-cell lymphoma. It is useful because it is specific to the tumour cells, while the other mutations in the same disease are also present in normal blood cells.","summary":"RHOA is a small GTPase. The G17V substitution produces a protein that does not bind GTP and that also blocks the function of the normal copy, so it acts against the wild-type protein rather than simply being inactive.\n\nIt was reported in 68% of angioimmunoblastic T-cell lymphoma samples, and remarkably every case carrying it also carried a TET2 mutation; the RHOA mutation was found only in the tumour cells, while TET2 mutations were found in tumour and non-tumour haematopoietic cells alike, which places the TET2 lesion earlier, in the stem cell (Sakata-Yanagimoto 2014). An independent series found it in 22 of 35 angioimmunoblastic cases, 67%, and in 8 of 44 cases of peripheral T-cell lymphoma not otherwise specified, 18%, alongside recurrent TET2, DNMT3A and IDH2 mutations and less frequent FYN, ATM, B2M and CD58 lesions (Palomero 2014).\n\nThe ordering matters clinically as well as biologically: this is a lymphoma that grows out of clonal haematopoiesis, which is part of why it occurs in older people and why hypomethylating agents have activity in it.","asOf":"2026-09-30","links":[{"label":"Sakata-Yanagimoto et al., Nat Genet 2014: somatic RHOA G17V in angioimmunoblastic T-cell lymphoma","url":"https://doi.org/10.1038/ng.2872"},{"label":"Palomero et al., Nat Genet 2014: recurrent mutations in epigenetic regulators, RHOA and FYN in peripheral T-cell lymphoma","url":"https://doi.org/10.1038/ng.2873"}],"tags":["biomarker","lymphoma"],"related":[],"cancers":["angioimmunoblastic-t-cell-lymphoma","peripheral-t-cell-lymphoma","non-hodgkin-lymphoma"],"sections":[],"technologies":["cgp"],"targets":["rhoa","tet2","dnmt3a","fyn"],"drugs":["azacitidine","romidepsin"],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","clonal-haematopoiesis"],"terms":["ngs","driver-mutation","clonal-evolution-theory"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"rhoa","measurement":"sequencing-variant","scoringRule":{"text":"Targeted sequencing of RHOA codon 17 on tissue, reported as mutated or wild-type, usually within a T-cell lymphoma panel alongside TET2, DNMT3A and IDH2. Sensitivity matters because the tumour cells are often a minority of an angioimmunoblastic node, which is full of reactive B cells, plasma cells and vessels.","quote":"Here we report somatic RHOA mutations encoding a p.Gly17Val alteration in 68% of AITL samples.","source":"https://doi.org/10.1038/ng.2872","sourceLabel":"Sakata-Yanagimoto et al., Nature Genetics 2014"},"thresholds":[],"definedBy":{"label":"Palomero et al., Nat Genet 2014: recurrent mutations in epigenetic regulators, RHOA and FYN in peripheral T-cell lymphoma","url":"https://doi.org/10.1038/ng.2873"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result supports the diagnosis when the biopsy is difficult to read, which it often is in this lymphoma. It does not yet select a licensed drug, although the related mutations in the same disease are the reason hypomethylating treatments are used and studied in it."},{"id":"ros1-fusion","kind":"biomarker","name":"ROS1 fusion (ROS1-positive)","aka":["ROS1 fusion","ROS1 rearrangement","ROS1-positive","ROS1+","CD74-ROS1","CD74::ROS1"],"tldr":"A ROS1 fusion drives about 1 to 2 percent of lung adenocarcinomas and behaves much like ALK. Crizotinib, entrectinib, repotrectinib and taletrectinib are approved for it.","summary":"ROS1 rearrangements (partners include CD74, SLC34A2 and EZR) are detected by FISH, IHC or sequencing; the FDA list carries the Oncomine Dx Target Test for crizotinib and FoundationOne CDx and Liquid CDx for entrectinib. Crizotinib was the first drug labelled for ROS1-positive metastatic NSCLC (2016); entrectinib (2019) and repotrectinib (2023) followed, the latter with activity after prior ROS1 inhibitors and against the G2032R solvent-front mutation; taletrectinib (Ibtrozi, 2025) is labelled for locally advanced or metastatic ROS1-positive NSCLC without a named test requirement.","asOf":"2026-09-23","links":[{"label":"Rozlytrek prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908"},{"label":"IBTROZI prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51ac8e52-3269-4102-8dc8-dba22d82128c"}],"tags":["biomarker","fusion"],"related":["alk-fusion","ntrk-fusion"],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["crizotinib","entrectinib","repotrectinib","taletrectinib","oncomine-dx-target-test","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["gene-fusion","tki-term"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bergethon-ros1-rearrangements-lung-jco-2012","paper-lindeman-lung-molecular-testing-guideline-jto-2018"],"journals":[],"dependsOn":[],"notes":["Lung cancer: 1 to 3% of adenocarcinomas, CD74 the commonest partner, in younger patients who are more often never smokers, with survival no different from ROS1-negative disease (Bergethon 2012; cBioPortal). Testing is recommended for every patient with adenocarcinoma, with immunohistochemistry acceptable as a screen and confirmation required (Lindeman 2018). ROS1 missense variants on a panel are not this readout."],"target":"ros1","measurement":"sequencing-variant","scoringRule":{"text":"A ROS1 gene fusion or rearrangement by FISH, immunohistochemistry confirmed by a molecular method, or DNA or RNA sequencing of tissue or plasma.","quote":"ROS1 fusions","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"ROS1-positive","drugId":"entrectinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908","quote":"Adult patients with ROS1- positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.","status":"current"},{"value":"ROS1-positive","drugId":"repotrectinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fb526827-40ba-4462-94cf-179ae3b0cb8a","quote":"adult patients with locally advanced or metastatic ROS1- positive non-small cell lung cancer (NSCLC).","status":"current"},{"value":"ROS1-positive","drugId":"taletrectinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51ac8e52-3269-4102-8dc8-dba22d82128c","quote":"IBTROZI ® (taletrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC)","status":"current"},{"value":"ALK or ROS1-positive","drugId":"crizotinib","cancerId":"nsclc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7","quote":"whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test.","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","guardant360-cdx","tempus-xt","trusight-oncology-comprehensive"],"assays":["oncomine-dx","foundationone-cdx-panel","foundationone-liquid-cdx"],"companionDiagnostics":[{"device":"Oncomine Dx Target Test","maker":"Life Technologies (Thermo Fisher Scientific)","companyId":"thermo-fisher","drugs":["crizotinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P160045 (06/22/2017)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["entrectinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Tissue","pma":"P170019/S014 (06/07/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne Liquid CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["entrectinib"],"indication":"Non-Small Cell Lung Cancer (NSCLC) - Plasma","pma":"P190032/S004 (12/22/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A ROS1 fusion means a ROS1 tablet (repotrectinib, taletrectinib, entrectinib or crizotinib) is the first treatment for advanced lung cancer, with the newer drugs preferred where brain spread is a concern. If the tumour later grows, a second ROS1 inhibitor may still work depending on the resistance mutation found."},{"id":"sstr-pet-expression","kind":"biomarker","name":"Somatostatin receptor expression by PET (SSTR-positive)","aka":["SSTR PET positive","somatostatin receptor-positive","SSTR-positive","DOTATATE PET positive","Krenning score","SSTR2 expression","octreoscan positive"],"tldr":"Somatostatin receptor-positive means a neuroendocrine tumour takes up a DOTATATE tracer on PET. It is the requirement for lutetium-177 dotatate and the marker that predicts response to octreotide and lanreotide.","summary":"Gallium-68 or copper-64 DOTATATE PET (Netspot, Detectnet) images SSTR2; the Lutathera label covers somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, including foregut, midgut and hindgut, in adults and children 12 and over, with the NETTER-1 trial requiring uptake at least equal to liver (Krenning score 2 or higher) on every lesion. The Krenning scale (0 to 4, from no uptake to greater than spleen or kidney) is the historic scintigraphy score carried over to PET. Actinium-225 DOTATATE and other radioligands in trials use the same selection.","asOf":"2026-09-23","links":[{"label":"Lutathera prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72d1a024-00b7-418a-b36e-b2cb48f2ab55"}],"tags":["biomarker","pet"],"related":["psma-pet-expression","ki-67-index"],"cancers":["neuroendocrine","pancreatic-net","lung-net"],"sections":[],"technologies":[],"targets":[],"drugs":["lutathera","ga68-dotatate","ryz101"],"companies":[],"institutions":[],"pathways":[],"terms":["theranostics","prrt-term","net-grade-ki67"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"sstr2","measurement":"pet-tracer-expression","scoringRule":{"text":"Tumour uptake of a somatostatin receptor PET tracer at least equal to normal liver (Krenning score 2 or higher) in target lesions; the Lutathera label states 'somatostatin receptor-positive' without a numeric cut-off.","quote":"LUTATHERA is indicated for the treatment of adult and pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72d1a024-00b7-418a-b36e-b2cb48f2ab55","sourceLabel":"Lutathera prescribing information"},"thresholds":[{"value":"Somatostatin receptor-positive by SSTR imaging","drugId":"lutathera","cancerId":"neuroendocrine","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72d1a024-00b7-418a-b36e-b2cb48f2ab55","quote":"LUTATHERA is indicated for the treatment of adult and pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors.","status":"current"}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A DOTATATE PET scan that lights up your tumour at least as brightly as your liver makes it somatostatin receptor-positive, which is needed for lutetium-177 dotatate and predicts benefit from the monthly somatostatin injections. Tumours that do not take up the tracer, often the fast-growing ones, need a different plan."},{"id":"spop-mutation","kind":"biomarker","name":"SPOP mutation","aka":["SPOP","SPOP mutant","SPOP F133L","SPOP mutation","speckle-type POZ protein mutation"],"tldr":"The commonest single point mutation in prostate cancer, in about one tumour in eight. Tumours carrying it never have the usual ERG fusion, and men whose metastatic disease carries it tend to stay hormone-sensitive for longer.","summary":"Missense mutation in the substrate-binding cleft of SPOP, the adaptor of a cullin-3 ubiquitin ligase, found in 6 to 15% of tumours across multiple independent cohorts in the discovery paper and defining a molecular subtype that lacks ETS rearrangements (Barbieri 2012). Recomputed on cBioPortal: 318 of 2,260 (14.1%) in prostate_msk_2024, 260 of 2,069 (12.6%) in prad_msk_stopsack_2021, 55 of 494 (11.1%) in prad_tcga_pan_can_atlas_2018, 53 of 424 (12.5%) in prad_mcspc_mskcc_2020 and 25 of 444 (5.6%) in prad_su2c_2019. The mutations are tightly clustered: of 325 mutation records in prostate_msk_2024, F133L accounts for 66, F133V 43, F102C 33, F102V 22, W131G 20, Y87N 14 and Y87C 14. With FOXA1-mutant tumours, SPOP-mutant tumours carry the highest androgen receptor transcriptional output of the seven TCGA classes (Cancer Genome Atlas Research Network 2015). In 424 men with metastatic castration-sensitive disease, SPOP alteration was associated with a lower rate of castration resistance and longer overall survival, adjusting for disease volume and other pathways (Stopsack 2020).","asOf":"2026-09-25","links":[{"label":"Barbieri et al., Nat Genet 2012: exome sequencing of 112 prostate tumour and normal pairs identifies recurrent SPOP, FOXA1 and MED12 mutations","url":"https://doi.org/10.1038/ng.2279"},{"label":"Stopsack et al., Clin Cancer Res 2020: oncogenic alterations, phenotypes and outcomes in 424 men with metastatic castration-sensitive prostate cancer","url":"https://doi.org/10.1158/1078-0432.CCR-20-0168"},{"label":"cBioPortal study prostate_msk_2024 (MSK-IMPACT, Clin Cancer Res 2024; 2,260 prostate cancers, the largest panel cohort, primary and metastatic)","url":"https://www.cbioportal.org/study/summary?id=prostate_msk_2024"}],"tags":["biomarker","prostate"],"related":["tmprss2-erg-fusion"],"cancers":["prostate","prostate-mhspc"],"sections":[],"technologies":["cgp"],"targets":["spop","androgen-receptor"],"drugs":[],"companies":[],"institutions":[],"pathways":["ubiquitin-proteasome-system","ar-signaling","prostate-cancer-signalling"],"terms":["driver-mutation","gene-fusion","castration-resistance","mcrpc-mhspc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012","paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","paper-stopsack-mcspc-genomic-alterations-outcomes-ccr-2020"],"journals":[],"dependsOn":[],"notes":[],"target":"spop","measurement":"sequencing-variant","scoringRule":{"text":"A missense mutation in the SPOP substrate-binding cleft, most often at F133, F102, W131 or Y87, on tumour sequencing. It is mutually exclusive with ETS rearrangement, so a tumour reported as both should prompt a check.","quote":"SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6-15% of tumors across multiple independent cohorts.","source":"https://doi.org/10.1038/ng.2279","sourceLabel":"Barbieri et al., Nature Genetics 2012"},"thresholds":[],"definedBy":{"label":"Stopsack et al., Clin Cancer Res 2020: oncogenic alterations and outcomes in 424 men with metastatic castration-sensitive prostate cancer","url":"https://doi.org/10.1158/1078-0432.CCR-20-0168"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"No treatment is chosen because of this result, and on the evidence so far it is a favourable one: men whose metastatic prostate cancer carries it tend to respond to hormone treatment for longer. It is a description of the kind of prostate cancer you have rather than an instruction."},{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","aka":["STK11 mutation","LKB1 loss","KEAP1 mutation","STK11/KEAP1 co-mutation","KL subtype"],"tldr":"Two genes that, when broken in a lung cancer that also has a faulty KRAS gene, predict that immunotherapy will work much less well. In a lung cancer with a normal KRAS gene the same faults appear to make no difference.","summary":"STK11 (LKB1) and KEAP1 are among the most frequently inactivated genes in lung adenocarcinoma, at 13 to 18% and 11 to 18% by cohort, rising to 22.1% each among patients selected for PD-(L)1 blockade (cBioPortal). STK11 loss makes a tumour immune-poor, with low PD-L1 and few infiltrating lymphocytes, and was first tied to PD-1 inhibitor resistance in KRAS-mutant disease (Skoulidis 2018); KEAP1 loss frees NRF2 and switches on an antioxidant programme, and was the strongest independent predictor of short survival among 330 KRAS-mutant patients (hazard ratio 1.96, and 3.54 from the start of immunotherapy) (Arbour 2018). The dependence on KRAS status is the part most often forgotten: across 1,261 patients in two cohorts, STK11 and KEAP1 mutations predicted worse progression-free survival (hazard ratios 2.04 and 2.05) and overall survival (2.09 and 2.24) on PD-(L)1 blockade only in KRAS-mutant tumours, with no effect in KRAS wild-type disease, and the immune phenotype differences were similarly confined (Ricciuti 2022). In the randomised setting the picture is weaker still: neither gene changed the benefit of pembrolizumab monotherapy in KEYNOTE-042 nor of pembrolizumab with chemotherapy in KEYNOTE-189 and KEYNOTE-407 (Mok 2023, Garassino 2023).","asOf":"2026-09-25","links":[{"label":"Skoulidis et al., Cancer Discov 2018: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma","url":"https://doi.org/10.1158/2159-8290.CD-18-0099"},{"label":"Arbour et al., Clin Cancer Res 2018: co-occurring alterations and outcomes in 330 KRAS-mutant lung cancers","url":"https://doi.org/10.1158/1078-0432.CCR-17-1841"},{"label":"Ricciuti et al., J Thorac Oncol 2022: STK11 and KEAP1 mutations and PD-(L)1 inhibition in 1,261 lung adenocarcinomas, by KRAS status","url":"https://doi.org/10.1016/j.jtho.2021.10.013"},{"label":"cBioPortal study nsclc_pd1_msk_2018 (MSK, J Clin Oncol 2018; 240 non-small-cell lung cancers profiled before PD-(L)1 blockade)","url":"https://www.cbioportal.org/study/summary?id=nsclc_pd1_msk_2018"}],"tags":["biomarker","immunotherapy"],"related":["kras-g12c","kras-g12d","pd-l1-tps"],"cancers":["nsclc"],"sections":[],"technologies":["cgp","checkpoint-inhibitor"],"targets":["stk11","keap1","kras"],"drugs":[],"companies":[],"institutions":[],"pathways":["t-cell-exhaustion","keap1-nrf2","ras-mapk","pd1-checkpoint"],"terms":["stk11-keap1","kras-mutation-subtypes","cold-vs-hot","resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kras-nsclc-cancer-discov-2018","paper-arbour-kras-co-mutation-outcomes-ccr-2018","paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022","paper-keynote-042-tmb-mutations-ann-oncol-2023","paper-keynote-189-407-tmb-jtocrr-2023"],"journals":[],"dependsOn":[],"notes":[],"target":"stk11","measurement":"sequencing-variant","scoringRule":{"text":"A deleterious (truncating, splice-site or known damaging missense) mutation in STK11 or KEAP1 on tumour sequencing, interpreted only together with KRAS status, since the association with immunotherapy outcome is confined to KRAS-mutant tumours.","quote":"STK11 and KEAP1 mutations were associated with significantly worse progression-free and overall survival to immunotherapy uniquely among KRAS-mutant but not KRAS wild-type lung adenocarcinomas","source":"https://doi.org/10.1016/j.jtho.2021.10.013","sourceLabel":"Ricciuti et al., Journal of Thoracic Oncology 2022"},"thresholds":[],"definedBy":{"label":"Skoulidis et al., Cancer Discovery 2018: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma","url":"https://doi.org/10.1158/2159-8290.CD-18-0099"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result is a prediction about how well immunotherapy is likely to work, not a rule about what can be given. It is used alongside the PD-L1 result and the rest of the genetic report when a treatment plan is discussed, and it matters mainly when the cancer also carries a KRAS change."},{"id":"tissue-factor-expression","kind":"biomarker","name":"Tissue factor expression","aka":["tissue factor","TF expression","F3 expression","tissue factor positive"],"tldr":"Tissue factor, the clotting trigger, is overexpressed on cervical and several other cancers. Tisotumab vedotin is labelled for cervical cancer without a tissue factor test.","summary":"Tisotumab vedotin (Tivdak) is a tissue factor-directed ADC labelled for recurrent or metastatic cervical cancer after chemotherapy (innovaTV 301); the label names tissue factor only as the target and no expression threshold was used in the trials. Its ocular toxicity mirrors mirvetuximab's and requires the same eye care.","asOf":"2026-09-23","links":[{"label":"TIVDAK prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9fe3f32-4219-466e-acb9-3f609b4f4df1"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["folr1-expression","pd-l1-cps"],"cancers":["cervical","recurrent-metastatic-cervical-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["tisotumab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"tissue-factor","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"TIVDAK is a tissue factor (TF)-directed antibody and microtubule inhibitor conjugate","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9fe3f32-4219-466e-acb9-3f609b4f4df1","sourceLabel":"TIVDAK prescribing information (DailyMed)"},"thresholds":[],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"No tissue factor test is done before tisotumab vedotin; the drug is given on the basis of the cancer type. Eye drops and regular eye checks are part of the treatment."},{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","aka":["TMB-H","TMB-high","TMB high","tumor mutational burden","tumour mutational burden","TMB >= 10 mut/Mb","TMB ≥10","TMB-H solid tumors","bTMB","blood TMB"],"tldr":"TMB counts how many mutations a tumour carries per million DNA letters. Ten or more, measured by FoundationOne CDx, allows pembrolizumab for almost any solid tumour after other treatment has failed.","summary":"Tumour mutational burden is the number of somatic non-synonymous (and, on some panels, synonymous) mutations per megabase of sequenced coding DNA, estimated from a large targeted panel and calibrated to whole-exome values. Pembrolizumab's US label (June 2020, KEYNOTE-158) covers unresectable or metastatic TMB-H solid tumours defined as >= 10 mutations per megabase by an FDA-authorised test, after prior treatment and with no satisfactory alternative; FoundationOne CDx is the listed companion diagnostic. Because panels differ in gene content and algorithms, a TMB of 10 on one assay is not the same as 10 on another; the label's limitation of use notes the benefit was not established in patients with central nervous system cancers. TMB is a genome-wide readout with no parent gene, so it sits under no target here.","asOf":"2026-09-23","links":[{"label":"KEYTRUDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287"}],"tags":["biomarker","genome-wide"],"related":["msi-high","dmmr-ihc"],"cancers":["metastatic-cancer","nsclc","melanoma","urothelial","tnbc","tnbc-metastatic","pancreatic","colorectal","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["tmb","ngs","tumour-agnostic","neoantigen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-barroso-sousa-breast-tmb-prevalence-ann-oncol-2020","paper-barroso-sousa-tmb-pten-ici-mtnbc-ccr-2020","paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","paper-philip-kras-wild-type-pancreatic-ccr-2022","paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016","paper-le-mmr-deficiency-pd1-nejm-2015","paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021","paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-giraldo-gallbladder-msk-impact-ccr-2022","paper-rizvi-mutational-landscape-pd1-science-2015","paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018","paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022","paper-keynote-042-tmb-mutations-ann-oncol-2023","paper-keynote-189-407-tmb-jtocrr-2023","paper-checkmate-026-first-line-nivolumab-nejm-2017"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: 10 or more mutations per megabase in about 5% of breast cancers, more often HR-negative/HER2-negative and metastatic (8.4% versus 2.9%; Barroso-Sousa 2020), 4.1% of 123 TCGA triple-negative exomes (cBioPortal) and 18% of 62 pretreated metastatic TNBC patients on immunotherapy trials, where it went with progression-free survival of 12.5 versus 3.7 months (Barroso-Sousa 2020, Clin Cancer Res). The tumour-agnostic pembrolizumab indication applies on a FoundationOne CDx value; APOBEC rather than mismatch repair drives most hypermutated TNBC.","Pancreatic ductal adenocarcinoma: 10 or more mutations per megabase in 1 to 2% of panel-tested tumours (35 of 2,336 MSK-IMPACT samples, median 3.46; cBioPortal), and TMB-high at the stricter 20 threshold together with MSI-high in 0.5% of samples (Singhi 2019); 4.5% of KRAS wild-type against 1% of mutant tumours (Philip 2022). Exome medians are about 1 per megabase, so the panel figure is a convention rather than a biological rate.","Colorectal cancer: 10 or more mutations per megabase in 15 to 19% of panel-tested tumours (1,340 of 7,237 in crc_msk_2026, median 6.05; cBioPortal), but almost all of that group is the MSI-high group (median 56.9) plus the POLE-hotspot group (median 172.1), against 5.7 in microsatellite-stable disease. A TMB-high result in a microsatellite-stable tumour with no POLE exonuclease mutation therefore deserves scrutiny before it is used to justify a checkpoint inhibitor under the tumour-agnostic approval, for which there is no colorectal-specific evidence.","Gallbladder cancer: median 4.1 non-synonymous mutations per megabase on the 505-gene MSK-IMPACT panel with 28 of 244 samples (11.5%) at 10 or more (cBioPortal gbc_mskcc_2022), against a median of 0.82 per megabase by whole-exome sequencing (Nepal 2021) and TMB-high in 1.3% (1 of 79) of Indian patients on mixed panels (Suryavanshi 2025). The pembrolizumab threshold applies only to the FoundationOne CDx value.","Lung cancer: this is where mutational burden was discovered as a predictor and where it failed as a selector. It is a real correlate: burden tracks response, progression-free survival and overall survival for single-agent PD-(L)1 blockade within every PD-L1 stratum in 1,552 patients, with response 57% where burden and PD-L1 are both high and 8.7% where neither is (Ricciuti 2022), and tissue burden of 175 or more mutations per exome selected benefit from pembrolizumab monotherapy in KEYNOTE-042 (overall survival hazard ratio 0.62 against 1.09 below the cut) (Mok 2023). But the threshold moves with the assay and the unit, the data-derived cut in the largest cohort was more than 19 mutations per megabase rather than 10, and in the trials of pembrolizumab with chemotherapy, the regimen most patients receive, continuous burden predicted nothing in either histology (Garassino 2023). The tumour-agnostic approval at 10 or more mutations per megabase rests on a basket trial with no lung cohort."],"measurement":"tmb-threshold","scoringRule":{"text":"Somatic mutations per megabase of coding sequence counted on a validated panel; 10 or more is TMB-high for the pembrolizumab indication.","quote":"tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-authorized test","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","sourceLabel":"KEYTRUDA prescribing information"},"thresholds":[{"value":"TMB >= 10 mutations per megabase","drugId":"pembrolizumab","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","caris-mi-cancer-seek","tempus-xt","trusight-oncology-500","stratangs","omniseq-insight","altera","oncoextra","bostongene-tumor-portrait","tempus-xe"],"assays":["tmb-panel","foundationone-cdx-panel"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["pembrolizumab"],"indication":"Solid Tumors - Tissue","pma":"P170019/S016 (06/16/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If a FoundationOne CDx report gives a TMB of 10 or more mutations per megabase, pembrolizumab is on label for your cancer once other treatments have been tried, whatever the organ it started in. A TMB from a different test may use a different scale; ask whether the number was measured on an FDA-authorised assay before treating it as the same threshold."},{"id":"tmprss2-erg-fusion","kind":"biomarker","name":"TMPRSS2-ERG fusion (and the other ETS rearrangements)","aka":["TMPRSS2-ERG","TMPRSS2:ERG","ERG rearrangement","ETS fusion","ERG fusion","ERG positive","ETS-positive prostate cancer","TMPRSS2-ETV1"],"tldr":"The commonest genetic change in prostate cancer, present in roughly half of tumours. Nothing treats it and it does not make the cancer more dangerous; it is useful mainly for recognising that two samples came from the same tumour.","summary":"A fusion joining the 5' untranslated region of the androgen-responsive gene TMPRSS2 to an ETS transcription factor, usually ERG, found by looking for outlier expression and confirmed in 23 of 29 samples by fluorescence in situ hybridisation (Tomlins 2005). Frequency depends on the assay as much as on the population: cBioPortal structural variants give ERG rearrangement in 152 of 333 (45.6%) in prad_tcga_pub, matching the 46% the TCGA paper reports, and 203 of 494 (41.1%) in prad_tcga_pan_can_atlas_2018, against 24 to 26% in the MSK-IMPACT panel cohorts, where the breakpoint introns have to be baited to be seen. Counting all ETS fusions together (ERG, ETV1, ETV4, ETV5, FLI1) gives 224 of 494 (45.3%) in the TCGA PanCancer deposit and 172 of 444 (38.7%) in prad_su2c_2019. Ancestry moves it further: in 65 treatment-naive Chinese prostate cancers the fusion rate was low and CHD1 deletion high (Ren 2018), with 4 of 65 ERG rearrangements in the deposit. The prognostic answer is clear and negative: in 1,180 men followed a median of 12.6 years, ERG overexpression carried a hazard ratio of 0.99 for biochemical recurrence and 0.93 for lethal disease, and a meta-analysis over 48 further studies found risk ratios of 1.00 and 0.99 (Pettersson 2012).","asOf":"2026-09-25","links":[{"label":"Tomlins et al., Science 2005: recurrent fusion of TMPRSS2 to ERG or ETV1 in prostate cancer (29 samples by fluorescence in situ hybridisation)","url":"https://doi.org/10.1126/science.1117679"},{"label":"Pettersson et al., Cancer Epidemiol Biomarkers Prev 2012: TMPRSS2-ERG, ERG expression and outcome in a 1,180-man cohort and a meta-analysis of 48 studies","url":"https://doi.org/10.1158/1055-9965.EPI-12-0042"},{"label":"cBioPortal study prad_tcga_pub (TCGA, Cell 2015; the 333 primary tumours of the published molecular taxonomy)","url":"https://www.cbioportal.org/study/summary?id=prad_tcga_pub"}],"tags":["biomarker","prostate"],"related":["spop-mutation"],"cancers":["prostate"],"sections":[],"technologies":["cytogenetics-fish","rna-seq","histopathology-ihc","cgp"],"targets":["erg","etv1","tmprss2","androgen-receptor"],"drugs":[],"companies":[],"institutions":[],"pathways":["prostate-cancer-signalling","ar-signaling","transcription-addiction"],"terms":["gene-fusion","fish","ihc","driver-mutation","biochemical-recurrence"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-tomlins-tmprss2-ets-fusion-science-2005","paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","paper-pettersson-tmprss2-erg-outcome-meta-analysis-cebp-2012","paper-ren-chinese-prostate-whole-genome-eur-urol-2018"],"journals":[],"dependsOn":[],"notes":[],"target":"erg","measurement":"sequencing-variant","scoringRule":{"text":"Detection of a rearrangement joining TMPRSS2, or another androgen-responsive partner such as SLC45A3, to ERG or another ETS family gene, by RNA sequencing, by a DNA panel that baits the breakpoint introns, by fluorescence in situ hybridisation, or inferred from nuclear ERG protein by immunohistochemistry.","quote":"By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1.","source":"https://doi.org/10.1126/science.1117679","sourceLabel":"Tomlins et al., Science 2005"},"thresholds":[],"definedBy":{"label":"Pettersson et al., Cancer Epidemiol Biomarkers Prev 2012: the TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes","url":"https://doi.org/10.1158/1055-9965.EPI-12-0042"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"Finding this change is common and it is not bad news. It does not make prostate cancer more likely to come back or to spread, and no treatment is chosen because of it. Its main practical use is to confirm that a deposit found elsewhere in the body came from the prostate."},{"id":"tp53-del17p","kind":"biomarker","name":"TP53 mutation and del(17p)","aka":["TP53 mutation","TP53-mutated","del(17p)","17p deletion","17p-","TP53 aberration","p53 abnormal","TP53 disruption","TP53mut"],"tldr":"TP53 mutation, or deletion of the 17p arm that carries the gene, is the single most common change in cancer and carries a worse outlook almost everywhere. In chronic lymphocytic leukaemia it decides treatment: chemotherapy is avoided and venetoclax's first approval was for del(17p) disease.","summary":"TP53 status is read by sequencing (mutations in exons 4 to 10) and del(17p) by FISH; in endometrial and other cancers p53 immunohistochemistry (overexpression or complete absence) is the surrogate. Venetoclax (Venclexta) was first approved in 2016 for CLL with 17p deletion as detected by an FDA-approved test, the Vysis CLL FISH Probe Kit being the companion diagnostic; its CLL indications have since broadened to all patients, and guidelines (iwCLL, NCCN) keep TP53 status as the reason to prefer targeted agents over chemoimmunotherapy. In AML and MDS, TP53 mutation defines an adverse-risk group in ELN 2022 and the WHO and ICC 2022 classifications; in endometrial cancer p53-abnormal is one of the four molecular classes.","asOf":"2026-09-23","links":[{"label":"Venclexta prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b118a40d-6b56-cee3-10f6-ded821a97018"},{"label":"FDA: List of FDA-Authorized Companion Diagnostic Devices","url":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"label":"Eskelund et al., Blood 2017: TP53 mutations in 183 younger mantle cell lymphoma patients from Nordic MCL2 and MCL3","url":"https://doi.org/10.1182/blood-2017-04-779736"},{"label":"Rossi et al., Blood 2011: the genetics of Richter syndrome in 86 pathologically proven cases","url":"https://doi.org/10.1182/blood-2010-09-302174"}],"tags":["biomarker","tp53"],"related":["dmmr-ihc","idh1-r132","cyclin-d1-t11-14"],"cancers":["cll","cll-relapsed","aml","mds","endometrial","endometrial-p53-abnormal","tnbc","ovarian","mantle-cell-lymphoma","richter-transformation-cll","dlbcl","non-hodgkin-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["venetoclax"],"companies":[],"institutions":[],"pathways":[],"terms":["tp53-mutated","del17p-tp53","li-fraumeni","fish"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: in mantle cell lymphoma this is the single result that most changes the plan, even though no label depends on it. Among 183 younger patients treated on the Nordic MCL2 and MCL3 protocols, TP53 mutation was present in 11% and TP53 deletion in 16%; only mutation kept its weight in multivariable analysis, with a hazard ratio of 6.2 for overall survival, median overall survival of 1.8 years against 12.7 years, and half of the mutated group relapsing within a year, with worse responses to both induction and high-dose chemotherapy (Eskelund 2017). In Richter transformation of chronic lymphocytic leukaemia, TP53 disruption was present in 47.1% of 86 cases and was the main prognostic variable (Rossi 2011). Mutation and deletion are not interchangeable: an immunohistochemical p53 stain approximates missense mutation and misses truncating ones, and FISH for del(17p) misses mutation without deletion, so sequencing is the complete test."],"target":"tp53","measurement":"sequencing-variant","scoringRule":{"text":"A pathogenic TP53 mutation by sequencing, deletion of 17p13 by FISH (the Vysis CLL probe set), or an abnormal p53 immunohistochemistry pattern (strong diffuse nuclear overexpression, complete absence, or cytoplasmic staining) as a surrogate.","quote":"TP53: Deletion chromosome 17p (17p-)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"17p deletion by FISH (historic first indication; the CLL indication is now unrestricted)","drugId":"venetoclax","cancerId":"cll","regulator":"FDA","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","quote":"Vysis CLL FISH Probe Kit (Abbott Molecular, Inc.) B-cell Chronic Lymphocytic Leukemia - Peripheral Blood Venclexta (venetoclax) NDA 208573 P150041 (04/11/2016)","status":"historic","note":"The 2016 accelerated approval was for CLL with 17p deletion after at least one prior therapy; the current Venclexta label covers CLL and SLL without a TP53 restriction."}],"definedBy":{"label":"European LeukemiaNet 2022 recommendations for AML (Döhner et al., Blood 2022): TP53 mutation as adverse risk","url":"https://doi.org/10.1182/blood.2022016867"},"tests":["foundationone-cdx","foundationone-heme","tempus-xt","neotype-profiles","caris-mi-profile"],"assays":[],"companionDiagnostics":[{"device":"Vysis CLL FISH Probe Kit","maker":"Abbott Molecular","companyId":"abbott","drugs":["venetoclax"],"indication":"B-cell Chronic Lymphocytic Leukemia - Peripheral Blood","pma":"P150041 (04/11/2016)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A TP53 mutation or 17p deletion usually means the cancer is harder to treat with chemotherapy. In chronic lymphocytic leukaemia it means your team will choose a BTK inhibitor or venetoclax-based treatment instead of chemoimmunotherapy. In leukaemia and womb cancer it places the disease in a higher-risk group that changes how intensively it is treated and followed."},{"id":"nepc-transformation","kind":"biomarker","name":"Treatment-emergent neuroendocrine transformation (recognising it)","aka":["neuroendocrine transformation","NEPC","t-NEPC","CRPC-NE","small cell transformation prostate","neuroendocrine differentiation prostate","aggressive variant prostate cancer"],"tldr":"The test result that shows a prostate cancer has changed into a different, faster kind of cancer under hormone treatment. It is made on a biopsy, usually prompted by disease that is growing while the PSA stays flat.","summary":"This readout is about recognition rather than about the entity itself, which is a WHO tumour type with its own record. Morphology comes first: a Prostate Cancer Foundation working committee set out named categories, separating usual adenocarcinoma with neuroendocrine differentiation from small cell carcinoma, large cell neuroendocrine carcinoma and mixed neuroendocrine carcinoma with acinar adenocarcinoma, and naming the situation in which castration-resistant disease presents clinically like small cell cancer (Epstein 2014). Supporting molecular features are loss of both RB1 and TP53, which is what permits the lineage change (Ku 2017, Mu 2017), and AURKA with MYCN co-amplification, present in 40% of neuroendocrine tumours against 5% of adenocarcinomas (Beltran 2011). In 59 samples from 40 men meeting clinical aggressive variant criteria, RB1 stained in under 10% of cells in 61% and androgen receptor in 36%, and RB1 copy loss was the strongest single discriminator from unselected castration-resistant disease (Aparicio 2016). The transition is epigenetic before it is genetic, since methylation separates the two states far more sharply than mutation does (Beltran 2016), and cell-free DNA methylation discriminated the two with an area under the curve of 0.96 and 1.0 in two small cohorts (Berchuck 2022).","asOf":"2026-09-25","links":[{"label":"Epstein et al., Am J Surg Pathol 2014: proposed morphologic classification of prostate cancer with neuroendocrine differentiation (Prostate Cancer Foundation working committee)","url":"https://doi.org/10.1097/PAS.0000000000000208"},{"label":"Beltran et al., Nat Med 2016: divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (114 samples)","url":"https://doi.org/10.1038/nm.4045"},{"label":"Aparicio et al., Clin Cancer Res 2016: combined RB1, TP53 and PTEN defects characterise clinically defined aggressive variant prostate cancer (59 samples from 40 trial participants)","url":"https://doi.org/10.1158/1078-0432.CCR-15-1259"}],"tags":["biomarker","resistance"],"related":["ar-amplification","ar-v7-splice-variant"],"cancers":["prostate","prostate-mcrpc","prostate-nepc"],"sections":[],"technologies":["histopathology-ihc","cgp","liquid-biopsy"],"targets":["rb1","tp53","androgen-receptor","aurka","mycn"],"drugs":[],"companies":[],"institutions":[],"pathways":["lineage-plasticity-neuroendocrine","epigenetic-reprogramming","p53-cell-cycle","ar-signaling"],"terms":["histologic-transformation","castration-resistance","resistance","ihc","biopsy","psa"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014","paper-beltran-nepc-divergent-evolution-nat-med-2016","paper-beltran-nepc-aurka-mycn-cancer-discov-2011","paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016","paper-ku-rb1-trp53-lineage-plasticity-science-2017","paper-mu-sox2-lineage-plasticity-science-2017","paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022"],"journals":[],"dependsOn":[],"notes":[],"noParentReason":"The readout is a lineage state recognised from morphology plus a combination of markers and tumour suppressor losses; it has no single parent gene or protein.","measurement":"ihc-score","scoringRule":{"text":"Morphological diagnosis on a biopsy of the progressing lesion, using the named categories, supported by neuroendocrine marker immunohistochemistry and by loss of androgen receptor and PSA staining; RB1 and TP53 status from sequencing raises or lowers the prior before the biopsy is taken.","quote":"The classification system consists of: Usual prostate adenocarcinoma with NE differentiation; 2) Adenocarcinoma with Paneth cell NE differentiation; 3) Carcinoid tumor; 4) Small cell carcinoma; 5) Large cell NE carcinoma; and 5) Mixed NE carcinoma - acinar adenocarcinoma.","source":"https://doi.org/10.1097/PAS.0000000000000208","sourceLabel":"Epstein et al., American Journal of Surgical Pathology 2014"},"thresholds":[],"definedBy":{"label":"Epstein et al., Am J Surg Pathol 2014: proposed morphologic classification of prostate cancer with neuroendocrine differentiation","url":"https://doi.org/10.1097/PAS.0000000000000208"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This is the result that changes the treatment plan most. It usually means moving from hormone treatment to chemotherapy of the kind used for small cell lung cancer, because that is what the cancer now resembles. It is found on a biopsy, which is why a repeat biopsy is sometimes asked for when scans and the PSA blood test stop agreeing with each other."},{"id":"trop2-expression","kind":"biomarker","name":"TROP2 expression","aka":["TROP2","TROP-2","Trop-2 expression","TACSTD2 expression","TROP2 QCS","TROP2 normalised membrane ratio"],"tldr":"TROP2 is on the surface of most breast and lung cancers. Sacituzumab govitecan and datopotamab deruxtecan are given without measuring it; a computational TROP2 score is being tested as a selector in lung cancer.","summary":"Sacituzumab govitecan (Trodelvy) is labelled for triple-negative and HR-positive HER2-negative breast cancer and urothelial cancer, datopotamab deruxtecan (Datroway) for HR-positive HER2-negative breast cancer and EGFR-mutant NSCLC, in both cases without a TROP2 test. The TROPION-Lung01 exploratory analysis introduced a quantitative continuous scoring (normalised membrane ratio) that separated responders in non-squamous NSCLC; it is being validated prospectively (TROPION-Lung12, NCT06564844 and other studies) and is not in any label.","asOf":"2026-09-23","links":[{"label":"TRODELVY prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57a597d2-03f0-472e-b148-016d7169169d"}],"tags":["biomarker","surface-antigen","no-threshold"],"related":["her2-low","nectin-4-expression"],"cancers":["tnbc","tnbc-metastatic","breast-hr-positive","urothelial","nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["sacituzumab-govitecan","datopotamab-deruxtecan","sacituzumab-tirumotecan"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bardia-ascent-trop2-biomarker-ann-oncol-2021"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: ASCENT's exploratory H-score analysis showed sacituzumab govitecan benefit at high and medium Trop-2 (response 44% and 38% versus 1% and 11% on chemotherapy) with the low group too small to interpret (Bardia 2021); neither sacituzumab govitecan nor datopotamab deruxtecan requires the test."],"target":"trop2","measurement":"ihc-score","scoringRule":{"text":"The label names the antigen in the drug's description but does not require it to be measured before treatment; no approval threshold exists for this readout.","quote":"TRODELVY is a Trop-2-directed antibody and topoisomerase inhibitor conjugate","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57a597d2-03f0-472e-b148-016d7169169d","sourceLabel":"TRODELVY prescribing information (DailyMed)"},"thresholds":[],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"You will not be tested for TROP2 before sacituzumab govitecan or datopotamab deruxtecan; the labels do not require it because nearly all eligible cancers express it. A computerised TROP2 score is under study in lung cancer and may become a selection test later."},{"id":"brca-somatic","kind":"biomarker","name":"Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations","aka":["somatic BRCA","sBRCA","tumor BRCA","tBRCA","BRCAm","BRCA-mutated","HRR gene mutation","HRRm","homologous recombination repair gene alteration","ATM mutation","PALB2 mutation"],"tldr":"Tumour BRCA testing finds BRCA1/2 mutations in the cancer itself, whether inherited or acquired; wider panels add other repair genes such as ATM and PALB2. Ovarian and prostate cancer labels accept the tumour result for PARP inhibitors.","summary":"Sequencing tumour tissue or plasma DNA detects BRCA1/2 mutations regardless of origin (about a third of ovarian tumour BRCA mutations are somatic only) and, on larger panels, alterations in the homologous recombination repair genes. Olaparib is labelled for germline or somatic BRCA-mutated ovarian cancer (first-line and recurrent maintenance), for HRR gene-mutated metastatic castration-resistant prostate cancer after enzalutamide or abiraterone (PROfound; genes listed on the FoundationOne CDx claim), and with abiraterone for BRCA-mutated mCRPC; rucaparib for BRCA-mutated ovarian cancer and mCRPC from plasma; talazoparib with enzalutamide for HRR gene-mutated mCRPC, the label listing ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C. FoundationOne CDx and Liquid CDx, FoundationFocus CDxBRCA and myChoice CDx carry the tumour claims.","asOf":"2026-09-23","links":[{"label":"Lynparza prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa"},{"label":"Rubraca prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0295d202-1cfe-7659-e063-6294a90a476e"},{"label":"Talzenna prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13839d4f-6acf-4ffb-a128-79df59319273"}],"tags":["biomarker","brca"],"related":["brca-germline","hrd-positive","hrr-gene-mutation","ctdna-tumour-fraction"],"cancers":["ovarian","high-grade-serous-ovarian-cancer","platinum-sensitive-ovarian-cancer","prostate-mcrpc","tnbc","pancreatic","brca-palb2-pdac","prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["olaparib","rucaparib","talazoparib","niraparib","foundationone-cdx","mychoice-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["hrd","germline-vs-somatic","brca-reversion-mutations","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019","paper-bertucci-metastatic-breast-genomics-nature-2019","paper-loibl-geparsixto-survival-hrd-ann-oncol-2018","paper-park-hrd-pancreatic-platinum-ccr-2020","paper-reiss-rucaparib-maintenance-brca-palb2-pancreatic-jco-2021","paper-yurgelun-germline-second-hits-resected-pancreatic-genet-med-2019","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-abida-triton2-rucaparib-brca-jco-2020","paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: somatic biallelic BRCA1/2 loss was found in 9 of 237 whole genomes against 20 germline (Staaf 2019) and somatic biallelic homologous recombination gene loss rose from 2% in early to 7% in metastatic TNBC (Bertucci 2019); tumour BRCA mutation was one arm of the GeparSixto HRD definition (Loibl 2018). No breast label accepts a somatic-only BRCA result for a PARP inhibitor.","Pancreatic ductal adenocarcinoma: somatic homologous recombination gene mutations added 4 percentage points to the 15% germline rate among 262 advanced patients, and somatic and germline cases behaved alike for genomic instability and outcome, with core (BRCA1, BRCA2, PALB2) and biallelic alterations carrying the platinum benefit (Park 2020). Maintenance rucaparib produced a response in 1 of 2 somatic BRCA2 patients (Reiss 2021). A germline variant without a somatic second hit, the case in more than half of carriers, may not give a repair-deficient tumour (Yurgelun 2019). No pancreatic label accepts a somatic-only result.","Prostate cancer: BRCA2, BRCA1 and ATM aberrations together were 19.3% of 150 metastatic castration-resistant tumours (Robinson 2015), and cBioPortal gives BRCA2 mutation in 37 of 444 samples, 8.3%, in prad_su2c_2019 with deep deletion in 13 more.","Somatic and germline alterations behave the same way on treatment: in TRITON2, response rates to rucaparib were similar whether the BRCA alteration was germline or somatic, and similar for BRCA1 and BRCA2, with higher PSA response rates in BRCA2 (Abida 2020).","Plasma detects them reliably when the tumour sheds enough DNA: 67 of 72 tissue-detected BRCA1 or BRCA2 mutations were also found in plasma, 93%, including 100% of predicted germline variants (Tukachinsky 2021). At PARP inhibitor resistance the gene is often repaired by a multiclonal reversion that only plasma reveals (Quigley 2017)."],"target":"brca","measurement":"sequencing-variant","scoringRule":{"text":"A deleterious or suspected deleterious BRCA1 or BRCA2 mutation (germline and/or somatic) in tumour tissue or plasma; for the HRR indications, an alteration in one of the label's listed homologous recombination repair genes. A negative plasma result does not exclude a tumour mutation.","quote":"A negative result from a plasma specimen does not mean that the patient's tumor is negative for BRCA mutations.","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0295d202-1cfe-7659-e063-6294a90a476e","sourceLabel":"Rubraca prescribing information"},"thresholds":[{"value":"Germline or somatic BRCA mutation","drugId":"olaparib","cancerId":"ovarian","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA -mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.","status":"current"},{"value":"Germline or somatic HRR gene mutation","drugId":"olaparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.","status":"current"},{"value":"BRCA mutation (germline and/or somatic)","drugId":"rucaparib","cancerId":"ovarian","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0295d202-1cfe-7659-e063-6294a90a476e","quote":"for the maintenance treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.","status":"current"},{"value":"HRR gene alteration (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C)","drugId":"talazoparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13839d4f-6acf-4ffb-a128-79df59319273","quote":"Select patients for the treatment of HRR gene-mutated mCRPC with TALZENNA based on the presence of alterations in genes directly or indirectly involved in HRR ( ATM , ATR , BRCA1 , BRCA2 , CDK12 , CHEK2 , FANCA , MLH1 , MRE11A , NBN , PALB2 , or RAD51C )","status":"current"}],"tests":["foundationone-cdx","foundationone-liquid-cdx","mychoice-cdx","tempus-xt","caris-mi-cancer-seek","trusight-oncology-comprehensive"],"assays":["foundationone-cdx-panel","foundationone-liquid-cdx","foundationfocus-brca","mychoice-cdx"],"companionDiagnostics":[{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["olaparib"],"indication":"Ovarian Cancer - Tissue","pma":"P170019/S004 (07/01/2019)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["olaparib"],"indication":"Metastatic Castrate Resistant Prostate Cancer (mCRPC) - Tissue (HRR genes)","pma":"P170019/S015 (05/19/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne Liquid CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["rucaparib"],"indication":"Metastatic Castrate Resistant Prostate Cancer (mCRPC) - Plasma","pma":"P190032 (08/26/2020)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationFocus CDxBRCA Assay","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["rucaparib"],"indication":"Ovarian Cancer - Tissue","pma":"P160018 (12/19/2016)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"FoundationOne CDx","maker":"Foundation Medicine","companyId":"foundation-medicine","drugs":["talazoparib","enzalutamide"],"indication":"Metastatic Castrate Resistant Prostate cancer (mCRPC) - Tissue (HRR genes)","pma":"P170019/S060 (05/27/2026)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"A BRCA mutation found in the tumour opens PARP inhibitor maintenance in ovarian cancer and PARP inhibitor treatment in advanced prostate cancer, whether or not the change is inherited; a follow-up blood test tells you whether it is, which matters for your family. In prostate cancer a wider list of repair genes also counts. If the tumour test was done on blood (ctDNA) and was negative, the labels say tissue should still be tested."}]