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DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum. This dossier gathers the 6 products (5 approved), 71 trials, 7 pathways and 9 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Homologous recombination repair; loss forces reliance on error-prone pathways.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Triple-negative breast cancer | 15-20% | Germline BRCA1/2 | BRCA1 predominant | Wikipedia |
| Ovarian cancer | 15-20% | Germline BRCA1/2; ~25% including somatic | Wikipedia | |
| Prostate cancer | 8-12% | Germline or somatic BRCA2 (metastatic) | cBioPortal (TCGA) | |
| Triple-negative breast cancer | 7-11% | Germline pathogenic variant | 8.5% of 1,824 TNBC patients unselected for family history (Couch 2015); 11.1% of 207 registry patients (Sharma 2014); BRCA1 and BRCA2 together 17.2% (50 of 291) in GeparSixto (Hahnen 2017) and 11.2% (Couch 2015); pathogenic variants in the TNBC risk genes BARD1, BRCA1, BRCA2, PALB2 and RAD51D in 12.0% of 10,901 patients, 3.7% outside BRCA1/2 (Shimelis 2018). Biallelic loss of BRCA1 or BRCA2 in 29 of 237 whole genomes, 20 germline and 9 somatic (Staaf 2019). | doi.org |
| Prostate cancer | 3-11% | Inactivating mutation, germline or somatic, plus deep deletion | cBioPortal mutation: 8 of 494, 1.6%, in prad_tcga_pan_can_atlas_2018; 29 of 1,013, 2.9%, in prad_p1000; 19 of 424, 4.5%, in prad_mcspc_mskcc_2020; 91 of 2,260, 4.0%, in prostate_msk_2024; 37 of 444, 8.3%, in prad_su2c_2019; 10 of 150, 6.7%, in prad_su2c_2015. Deep deletion adds 2.2 to 11.5% (17 of 489, 3.5%, in prad_tcga_pan_can_atlas_2018; 13 of 444, 2.9%, in prad_su2c_2019; 7 of 61, 11.5%, in prad_mich). Germline: 37 of 692 men with metastatic disease unselected for family history, 5.3% (Pritchard 2016). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 5-8% | Germline BRCA1/2 | cBioPortal (TCGA) | |
| HR-positive / HER2-negative breast cancer | 3-5% | Germline BRCA1/2 | BRCA2 predominant | Wikipedia |
| Triple-negative breast cancer | 3-4% | Germline pathogenic variant | 2.7% of 1,824 unselected patients (Couch 2015); 4.3% of 207 (Sharma 2014); somatic calls in 5 of 123, 4.1%, in brca_tcga_pan_can_atlas_2018, 7 of 299, 2.3%, in brca_metabric and 8 of 176, 4.5%, in breast_msk_2018 (cBioPortal). Metastatic TNBCs carried somatic biallelic loss-of-function mutations in homologous recombination genes in 7% against 2% of early TNBCs (Bertucci 2019). | doi.org |
| Gallbladder cancer | 1-5% | Mutation (somatic or germline) | BRCA2 mutation in 13 of 244 samples, 5.3%, and BRCA1 in 3 of 244, 1.2%, in cBioPortal gbc_mskcc_2022; oncogenic BRCA1/2 variants among the actionable findings (Giraldo 2022); deleterious germline variants in BRCA1, BRCA2, RAD51D, MLH1 or MSH2 in 11% (16 of 146) of biliary tract cancer patients (Wardell 2018); gallbladder tumours had the highest rate of homologous recombination repair deficiency among biliary sites (Weinberg 2019). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 1.4-2% | Germline pathogenic variant | 1.9% of 3,030 patients against 0.3% of controls, odds ratio 6.20 (Hu 2018); 12 of 854 apparently sporadic patients, 1.4% (Shindo 2017); 4 of 289 resected patients (Yurgelun 2019); 49 of 71 BRCA carriers in a three-centre series were BRCA2 (Golan 2014). Tumour sequencing (germline and somatic together): 67 of 2,336, 2.9%, in pdac_msk_2024; 8 of 383, 2.1%, in paad_qcmg_uq_2016; 11 of 395, 2.8%, in pancreas_msk_2024; 2 of 179 in paad_tcga_pan_can_atlas_2018 (cBioPortal). POLO screened 3,315 metastatic patients to randomise 154 germline BRCA1/2 carriers (Golan 2019). | doi.org |
| Prostate cancer | 0.2-2% | Inactivating mutation, germline or somatic | cBioPortal mutation: 1 of 494, 0.2%, in prad_tcga_pan_can_atlas_2018; 6 of 1,013, 0.6%, in prad_p1000; 1 of 424, 0.2%, in prad_mcspc_mskcc_2020; 18 of 2,260, 0.8%, in prostate_msk_2024; 8 of 444, 1.8%, in prad_su2c_2019. Germline: 6 of 692, 0.9% (Pritchard 2016). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 0.4-1% | Germline pathogenic variant | 0.6% of 3,030 against 0.2% of controls, odds ratio 2.58 (Hu 2018); 3 of 854, 0.4% (Shindo 2017); 3 of 289 (Yurgelun 2019); 21 of 71 BRCA carriers (Golan 2014). Tumour sequencing: 16 of 2,336, 0.7%, in pdac_msk_2024; 5 of 383 in paad_qcmg_uq_2016; 2 of 179 in paad_tcga_pan_can_atlas_2018 (cBioPortal). | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
| Modality | Approved | Withdrawn or failed |
|---|---|---|
| Small molecule 4 | ||
| Test or device 2 | - |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
| 3 | Active | A Randomised, Double-blind, Placebo-controlled, Multicentre Phase III Study of Olaparib Plus Abiraterone Relative to Placebo Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer (PROpel Study) | - | ||
DUO-E / GOG-3041 / ENGOT-EN10 NCT04269200 | 3 | Positive | Newly diagnosed advanced or recurrent endometrial cancer: chemotherapy + durvalumab, then durvalumab ± olaparib maintenance, vs chemotherapy | PFS HR 0.42 (dMMR, durvalumab); 0.57 (pMMR, durvalumab + olaparib). | |
DUO-O / ENGOT-ov46 NCT03737643 | 3 | Mixed | Newly diagnosed non-BRCA-mutated advanced ovarian cancer: chemotherapy + bevacizumab + durvalumab, then durvalumab + bevacizumab ± olaparib maintenance, vs standard | PFS HR 0.63; interim OS HR 0.95. | |
TALAPRO-2 NCT03395197 | 3 | Positive | First-line mCRPC: enzalutamide + talazoparib vs enzalutamide + placebo (all-comers and HRR-mutant cohorts) | rPFS HR 0.63 (ITT); OS HR 0.80 (ITT), 0.62 (HRR-mutant). | |
TRITON3 NCT02975934 | 3 | Mixed | Metastatic castration-resistant prostate cancer with a BRCA1, BRCA2 or ATM alteration and progression after a second-generation androgen receptor pathway inhibitor: rucaparib 600 mg twice daily against physician's choice of docetaxel or a second androgen receptor pathway inhibitor, randomised 2:1, with imaging-based progression-free survival by independent review as the primary outcome | Median imaging-based progression-free survival 11.2 against 6.4 months in the BRCA subgroup (hazard ratio 0.50, 95 percent confidence interval 0.36 to 0.69) and 10.2 against 6.4 months overall (0.61, 0.47 to 0.80); no effect in the ATM subgroup (0.95, 0.59 to 1.52). | |
ATHENA-MONO / GOG-3020 NCT03522246 | 3 | Positive | Newly diagnosed advanced ovarian cancer after response to first-line platinum: rucaparib maintenance vs placebo | PFS 20.2 vs 9.2 months (HR 0.52). | |
MAGNITUDE NCT03748641 | 3 | Mixed | First-line mCRPC: abiraterone + niraparib vs abiraterone + placebo, HRR-mutant and HRR-negative cohorts | BRCA cohort rPFS HR 0.53; HRR-negative futility. | |
PROpel NCT03732820 | 3 | Positive | First-line mCRPC, all-comers: abiraterone + olaparib vs abiraterone + placebo | rPFS HR 0.66 (ITT); OS HR 0.81 (NS). | |
OlympiA NCT02032823 | 3 | Positive | Adjuvant olaparib for one year in germline BRCA-mutated, HER2-negative, high-risk early breast cancer | iDFS HR 0.58; OS HR 0.72. | |
BROCADE3 NCT02163694 | 3 | Mixed | Germline BRCA1 or BRCA2-mutated HER2-negative metastatic or locally advanced unresectable breast cancer, up to two prior chemotherapy lines: carboplatin and paclitaxel with veliparib or placebo, continued as veliparib monotherapy if chemotherapy stopped, 147 hospitals in 36 countries | PFS 14.5 vs 12.6 months (HR 0.71, p 0.0016); final OS 32.4 vs 28.2 months (HR 0.92, p 0.43). Not licensed. | |
PROfound NCT02987543 | 3 | Positive | mCRPC with HRR gene alterations after ARPI: olaparib vs enzalutamide/abiraterone switch | rPFS HR 0.34; OS HR 0.69 (cohort A). | |
PAOLA-1 / ENGOT-ov25 NCT02477644 | 3 | Positive | Newly diagnosed advanced ovarian cancer already on bevacizumab maintenance: adding olaparib vs placebo | PFS HR 0.59 overall, 0.33 HRD-positive; 5-year OS 65.5% vs 48.4% in HRD-positive. | |
POLO NCT02184195 | 3 | Mixed | Germline BRCA-mutated metastatic PDAC not progressed on ≥16 weeks of platinum: olaparib maintenance vs placebo | PFS HR 0.53; OS HR 0.83 (not significant). | |
BrighTNess NCT02032277 | 3 | Completed | Stage II to III triple-negative breast cancer before surgery: paclitaxel with carboplatin and the PARP inhibitor veliparib, paclitaxel with carboplatin and placebo, or paclitaxel alone, each followed by doxorubicin and cyclophosphamide | Carboplatin added to neoadjuvant paclitaxel raised the pathological complete response rate and improved event-free survival in triple-negative breast cancer; veliparib added nothing to carboplatin. | |
EMBRACA NCT01945775 | 3 | Positive | Germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer: talazoparib vs physician's choice chemotherapy | PFS 8.6 vs 5.6 months, HR 0.54; OS HR 0.85, not significant. | |
| 3 | Active | Phase III Randomised, Double Blind, Placebo Controlled Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed BRCA Mutated Ovarian Cancer Patients With a Complete or Partial Response Following Platinum Based Chemotherapy | - | ||
SOLO-1 NCT01844986 | 3 | Positive | Newly diagnosed advanced BRCA-mutated ovarian cancer in response to platinum chemotherapy: olaparib maintenance for 2 years vs placebo | PFS HR 0.30; 7-year OS 67.0% vs 46.5% (HR 0.55). | |
TNT (Triple Negative Trial) NCT00532727 | 3 | Mixed | Metastatic or recurrent locally advanced triple-negative or BRCA1/2 breast cancer: carboplatin versus docetaxel, with crossover at progression | No superiority of carboplatin over docetaxel in unselected triple-negative disease; higher response to carboplatin in the germline BRCA1/2 subgroup (Nature Medicine 2018). | |
OlympiAD NCT02000622 | 3 | Positive | Germline BRCA-mutated, HER2-negative metastatic breast cancer after up to two chemotherapy lines: olaparib vs physician's choice chemotherapy | PFS 7.0 vs 4.2 months, HR 0.58; OS 19.3 vs 17.1 months, not significant. | |
| 3 | Active | AVELUMAB MASTER PROTOCOL: AN OPEN-LABEL CONTINUATION STUDY FOR PARTICIPANTS CONTINUING FROM PFIZER-SPONSORED AVELUMAB CLINICAL STUDIES. | - | ||
D9319C00001- 1L OC Mono Global RCT NCT04884360 | 3 | Active | A Randomised, Double-blind, Placebo-controlled, Phase III Study of Olaparib Maintenance Monotherapy in Participants With BRCA Wild Type Advanced High Grade Serous or Endometrioid Ovarian Cancer Following Response to Standard First-line Platinum-based Chemotherapy (MONO-OLA1) | - | |
| 3 | Completed | Molecular Profiling of Advanced Soft-tissue Sarcomas. A Phase III Study | - | ||
| 3 | Planned | PembroLizumab Adjuvant in Patients With Early-stage Triple NEgaTive Breast Cancer With Residual Disease After Neoadjuvant Pembrolizumab Plus Chemotherapy - the Multicenter, Randomized Phase III, Pragmatic PLANET Trial | - | ||
| 3 | Recruiting | A Randomized Phase 3 Trial Evaluating the Safety & Efficacy of IP IMNN-001 Administered in Combination w/ Standard Neoadjuvant & Adjuvant Chemotherapy in Newly Diagnosed Patients w/ Advanced EOC, Fallopian Tube or Primary Peritoneal Cancer | - | ||
| 3 | Active | A Randomized, Double-blind, Placebo-controlled Phase 3 Study of Pembrolizumab (MK-3475) in Combination With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib (MK-7339), Compared to Concurrent Chemoradiation Therapy Alone in Participants With Newly Diagnosed Treatment-Naïve Limited-Stage Small Cell Lung Cancer (LS-SCLC) | - | ||
| 3 | Active | Roll Over StudY for Patients Who Have Completed a Previous Oncology Study With Olaparib and Are Judged by the Investigator to Clinically Benefit From Continued Treatment | - | ||
| 3 | Active | A Phase 3 Study of Pembrolizumab (MK-3475) in Combination With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib vs Concurrent Chemoradiation Therapy Followed by Durvalumab in Participants With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer (NSCLC) | - | ||
| 3 | Active | TALAPRO-3: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, STUDY OF TALAZOPARIB WITH ENZALUTAMIDE VERSUS PLACEBO WITH ENZALUTAMIDE IN MEN WITH DDR GENE MUTATED METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER | - | ||
PARTNER NCT03150576 | 2/3 | Positive | Neoadjuvant: olaparib added to platinum-based chemotherapy in triple-negative and/or germline BRCA early breast cancer, with the timing of olaparib after carboplatin tested | Germline BRCA group: three-year survival 100 percent (39 patients, one relapse) with the gap schedule versus 88 percent (45 patients, nine relapses) with chemotherapy alone (University of Cambridge release on the Nature 2024 paper). | |
RAINBO NCT05255653 | 2/3 | Recruiting | Endometrial cancer stratified by molecular class after surgery: four linked trials that test olaparib with chemoradiotherapy for p53-abnormal tumours (p53abn-RED), durvalumab with radiotherapy for mismatch-repair-deficient tumours (MMRd-GREEN), progestin with radiotherapy for tumours with no specific molecular profile (NSMP-ORANGE), and de-escalation to radiotherapy alone or observation for POLE-ultramutated tumours (POLEmut-BLUE) | - |
Secondary mutations restore the open reading frame and homologous recombination; also confers platinum resistance.
Loss of end-protection factors lets BRCA1-deficient cells resect DNA ends and repair by HR.
Stabilised forks tolerate PARP trapping; PARP1 mutations abolish trapping.
Olaparib and rucaparib are P-gp substrates.
More receptor, or mutations (F877L, T878A) that turn antagonists into agonists.
Truncated receptor lacking the ligand-binding domain is constitutively active and invisible to enzalutamide.
RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.
Reciprocal feedback between AR and PI3K pathways.
GR drives an AR-like transcriptional programme under enzalutamide.
Tens of thousands of times a day a single DNA letter is oxidised or chemically scarred. A small crew snips it out and PARP marks the nick so it gets sealed. PARP inhibitors do not just switch PARP off; they trap it on the DNA, turning a harmless nick into a lethal break when the cell copies its DNA.
Which nodes have drugs →KEGG's breast cancer map lays out the three clinical subtypes as signalling routes: oestrogen receptor driving cyclin D and CDK4/6 in hormone-receptor-positive disease, HER2 driving PI3K/AKT and MAPK in HER2-positive disease, and EGFR, Notch, Wnt and BRCA defects in triple-negative disease. Each route has its own drug class.
Which nodes have drugs →The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work.
Which nodes have drugs →A break through both strands of DNA is the most dangerous lesion a cell faces. Two crews compete to fix it: homologous recombination copies the answer from the sister chromosome (accurate, needs BRCA), while end joining simply glues the ends (fast, sloppy). Which crew wins decides whether PARP inhibitors and radiation kill the cell.
Which nodes have drugs →Every cause of DNA damage leaves its own fingerprint in the genome: sunlight, tobacco, a faulty repair enzyme, a gut bacterium. Reading these fingerprints tells you what caused a cancer and which repair crews it is missing, which in turn predicts which drugs will work.
Which nodes have drugs →This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.
Which nodes have drugs →Two genes are synthetically lethal when losing either alone is fine but losing both kills the cell. Cancers that have already lost one (a tumour suppressor you cannot put back) become uniquely dependent on the other, which you can drug. BRCA and PARP was the first proof; a dozen more pairs are now in trials.
Which nodes have drugs →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| FoundationOne Liquid CDx Foundation Medicine (Roche) · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib, erlotinib, gefitinib), ALK (alectinib), BRCA1/2 and ATM (olaparib, rucaparib), PIK3CA (alpelisib), FGFR3 (erdafitinib), NTRK and RET; negative plasma results reflex to tissue | |
| BRACAnalysis CDx Myriad Genetics · FDA CDx 2014 | Germline NGS | Deleterious or suspected deleterious germline variant | |
| myChoice CDx Myriad Genetics · FDA CDx 2019 | NGS tissue | Genomic instability score at least 42, or BRCA1/2 mutation, defines HRD-positive (olaparib plus bevacizumab, PAOLA-1; niraparib) | |
| FoundationFocus CDxBRCA Foundation Medicine · FDA CDx 2016 | NGS tissue | Deleterious BRCA1/2 alteration (rucaparib, ovarian cancer) |
| Cell line | Identifiers | Why it is used |
|---|---|---|
| MDA-MB-436 | CVCL_0623 · ACH-000573 | Breast, BRCA1 5396+1G>A; PARP-inhibitor sensitive. |
| HCC1937 | CVCL_0290 · ACH-000223 | Breast, BRCA1 5382insC; relatively PARP-inhibitor resistant despite BRCA1 loss. |
| SUM149PT | CVCL_3422 · ACH-001390 | Breast, BRCA1 2288delT. |
| Capan-1 | CVCL_0237 · ACH-000354 | Pancreatic, BRCA2 6174delT; olaparib-resistant derivatives carry reversions. |
| PEO1 | CVCL_2686 · ACH-001630 | Ovarian, BRCA2 5193C>G; PEO4 sister line has a reversion. |
| UWB1.289 | CVCL_B079 · ACH-001418 | Ovarian, BRCA1-null; BRCA1-restored isogenic pair available. |
| COV362 | CVCL_2420 · ACH-000278 | Ovarian, BRCA1-mutant. |
| DLD-1 BRCA2-/- | CVCL_HD56 | Isogenic colorectal knock-out pair (Horizon). |
Why unresolved. Reversions restore homologous recombination and predict PARP-inhibitor and platinum failure, and they are detectable in plasma, but no trial has switched therapy on that signal alone.
What would answer it. A ctDNA-guided switch trial (reversion detected: switch to a non-DDR agent versus continue) with progression-free survival.
Query for this target: (TITLE:"BRCA1 / BRCA2" OR ABSTRACT:"BRCA1 / BRCA2" OR TITLE:"HRD" OR ABSTRACT:"HRD" OR TITLE:"BRCA1" OR ABSTRACT:"BRCA1" OR TITLE:"BRCA2" OR ABSTRACT:"BRCA2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BRCA1 / BRCA2 (HRD), not a curated reading list.
The dossier as machine-readable JSON, at /api/v1/dossiers/brca.json: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/brca.json. Licence CC BY-NC 4.0.