{"entity":{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","aka":["HER2-positive colorectal cancer","ERBB2-amplified colorectal cancer","HER2-overexpressing bowel cancer"],"tldr":"A few bowel cancers make too much of the HER2 protein, the same target as in HER2-positive breast cancer. Two HER2 drugs together, tucatinib and trastuzumab, shrink about four in ten of these tumours after chemotherapy has failed, and the antibody-drug conjugate trastuzumab deruxtecan works even when other HER2 drugs have stopped.","summary":"HER2 (ERBB2) amplification was recognised as a cause of primary resistance to cetuximab and panitumumab in patient-derived xenografts in 2011, and the HERACLES trial (2016) showed that dual HER2 blockade with trastuzumab and lapatinib produced responses in 30 percent of heavily pre-treated, RAS wild-type patients; MyPathway (2019) did the same with trastuzumab and pertuzumab. Testing is by immunohistochemistry 3+ or 2+ with in situ hybridisation, or by ERBB2 copy number on tumour or plasma sequencing, and is now recommended for every metastatic colorectal cancer alongside RAS, BRAF and mismatch repair.\n\nMOUNTAINEER (2022) treated 84 patients with previously treated, RAS wild-type, HER2-positive metastatic colorectal cancer with tucatinib and trastuzumab: the response rate was 38 percent, median response duration 12.4 months, progression-free survival 8.2 months and overall survival 24.1 months, with little of the diarrhoea seen with other HER2 kinase inhibitors, and the FDA granted accelerated approval in January 2023, the first HER2 approval in this cancer. DESTINY-CRC02 (2023) gave trastuzumab deruxtecan at 5.4 mg/kg to 122 patients, including those with RAS mutations and prior HER2 therapy, with a response rate of 38 percent; the tumour-agnostic approval for HER2 immunohistochemistry 3+ solid tumours in April 2024 covers colorectal cancer.\n\nMOUNTAINEER-03 is testing tucatinib, trastuzumab and mFOLFOX6 against standard first-line chemotherapy; zanidatamab and other bispecific HER2 antibodies, next-generation HER2 antibody-drug conjugates and HER2 kinase inhibitors are in trials. The open questions are whether HER2 blockade should start first line, how RAS co-mutations blunt it, and how to sequence the kinase inhibitor combination and the antibody-drug conjugate.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/HER2/neu","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HER2/neu"},{"label":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}],"tags":["subtype-page"],"related":["braf-v600e-colorectal","early-onset-colorectal","kras-g12c-colorectal","msi-high-colorectal","rectal-cancer"],"cancers":[],"sections":[],"technologies":["her2-tyrosine-kinase-inhibitors","monoclonal-antibody","adc","histopathology-ihc","bispecific-antibody"],"targets":["her2","egfr","vegf"],"drugs":["tucatinib","trastuzumab","trastuzumab-deruxtecan","pertuzumab","zanidatamab"],"companies":[],"institutions":[],"pathways":["ras-mapk","colorectal-cancer-signalling"],"terms":["sidedness","tumour-agnostic","ihc"],"trials":["mountaineer","destiny-crc02","mypathway","nct06695845","nct06589830","nct06434597","heracles"],"people":["tanios-bekaii-saab"],"bottlenecks":[],"keyPapers":["paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 3 to 5 percent of colorectal cancers, and about 5 to 8 percent of RAS and BRAF wild-type tumours, have HER2 amplification; they are mostly left-sided and rectal, and respond poorly to anti-EGFR antibodies.","subtypes":["HER2-amplified, RAS and BRAF wild-type, left-sided (the classic group, responsive to dual HER2 blockade)","HER2-amplified with RAS mutation (rarer; antibody-drug conjugates rather than dual antibody or kinase blockade)","HER2 activating mutations without amplification (uncertain response)","HER2 immunohistochemistry 3+ tumours eligible for tumour-agnostic trastuzumab deruxtecan"],"biomarkers":["HER2 immunohistochemistry 3+, or 2+ with in situ hybridisation amplification","ERBB2 copy number on tumour or circulating tumour DNA sequencing","RAS and BRAF wild-type status (predicts response to dual HER2 blockade)","Left-sided or rectal primary"],"standardOfCare":[{"setting":"Metastatic, RAS wild-type, previously treated","approach":"Tucatinib plus trastuzumab (MOUNTAINEER); trastuzumab plus pertuzumab or lapatinib where tucatinib is unavailable.","refs":["mountaineer","tucatinib","trastuzumab","pertuzumab","her2-tyrosine-kinase-inhibitors"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"After HER2 antibodies, or with RAS mutation","approach":"Trastuzumab deruxtecan (DESTINY-CRC02; tumour-agnostic approval for immunohistochemistry 3+), watching for pneumonitis.","refs":["destiny-crc02","trastuzumab-deruxtecan","adc"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic, first line","approach":"Standard doublet chemotherapy with bevacizumab; anti-EGFR antibodies are less effective in HER2-amplified tumours; tucatinib-trastuzumab-FOLFOX is under test in MOUNTAINEER-03.","refs":["folfox","folfiri","bevacizumab","mountaineer"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["Tucatinib plus trastuzumab is the first HER2-directed approval in colorectal cancer (2023).","Trastuzumab deruxtecan works after other HER2 drugs and in RAS-mutant tumours.","HER2 testing is now routine in metastatic disease, alongside RAS, BRAF and mismatch repair."],"history":[{"year":2011,"title":"HER2 amplification identified as a cause of anti-EGFR resistance in patient-derived xenografts","refs":["her2","egfr"]},{"year":2016,"title":"HERACLES: trastuzumab plus lapatinib produces responses in 30 percent","refs":["trastuzumab"]},{"year":2019,"title":"MyPathway: trastuzumab plus pertuzumab active in HER2-amplified colorectal cancer","refs":["mypathway","pertuzumab","trastuzumab"]},{"year":2022,"title":"MOUNTAINEER: tucatinib plus trastuzumab, response rate 38 percent, median survival 24 months","refs":["mountaineer","tucatinib","tanios-bekaii-saab"]},{"year":2023,"title":"FDA accelerated approval of tucatinib with trastuzumab, the first HER2 approval in colorectal cancer","refs":["tucatinib"]},{"year":2024,"title":"Tumour-agnostic approval of trastuzumab deruxtecan for HER2 3+ solid tumours after DESTINY-CRC02","refs":["trastuzumab-deruxtecan","destiny-crc02"]}],"pipeline":["mountaineer","zanidatamab","nct06695845","nct06589830","nct06434597","trastuzumab-deruxtecan"],"openProblems":["No randomised evidence yet for HER2 blockade in first line.","RAS co-mutation blunts dual HER2 blockade and the best option for those patients is unclear.","Optimal sequence of tucatinib-trastuzumab and trastuzumab deruxtecan is untested.","HER2 mutations without amplification have no proven therapy."],"parent":"colorectal"},"route":"/cancers/her2-amplified-colorectal/","neighbours":{"cancer":[{"id":"braf-v600e-colorectal","kind":"cancer","name":"BRAF V600E-mutant colorectal cancer","route":"/cancers/braf-v600e-colorectal/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"early-onset-colorectal","kind":"cancer","name":"Early-onset colorectal cancer (under 50)","route":"/cancers/early-onset-colorectal/"},{"id":"kras-g12c-colorectal","kind":"cancer","name":"KRAS G12C-mutant colorectal cancer","route":"/cancers/kras-g12c-colorectal/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"},{"id":"rectal-cancer","kind":"cancer","name":"Rectal cancer","route":"/cancers/rectal-cancer/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"her2-tyrosine-kinase-inhibitors","kind":"technology","name":"HER2 tyrosine kinase inhibitors","route":"/technologies/her2-tyrosine-kinase-inhibitors/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"monoclonal-antibody","kind":"technology","name":"Monoclonal antibodies","route":"/technologies/monoclonal-antibody/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"bevacizumab","kind":"drug","name":"Bevacizumab","route":"/drugs/bevacizumab/"},{"id":"folfiri","kind":"drug","name":"FOLFIRI (5-FU, leucovorin, irinotecan)","route":"/drugs/folfiri/"},{"id":"folfox","kind":"drug","name":"FOLFOX (5-FU, leucovorin, oxaliplatin)","route":"/drugs/folfox/"},{"id":"pertuzumab","kind":"drug","name":"Pertuzumab","route":"/drugs/pertuzumab/"},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"},{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"},{"id":"zanidatamab","kind":"drug","name":"Zanidatamab","route":"/drugs/zanidatamab/"}],"pathway":[{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"heracles-criteria","kind":"term","name":"HERACLES criteria (HER2 in bowel cancer)","route":"/terms/heracles-criteria/"},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"},{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","route":"/terms/sidedness/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"trial":[{"id":"nct06434597","kind":"trial","name":"A Clinical Study of SPH5030 Tablets in the Treatment of Her2-positive/Mutated Biliary Tract OR Colorectal Cancer Patients.","route":"/trials/nct06434597/"},{"id":"nct07483684","kind":"trial","name":"A Clinical Study to Evaluate Injection TQB2102 for the Treatment of Patients With HER2 IHC3+ Advanced Colorectal Cancer Who Progressed After Treatment With Oxal","route":"/trials/nct07483684/"},{"id":"nct07653685","kind":"trial","name":"A Clinical Trial Evaluating TQB2930 Injection and Chemotherapy With or Without Bevacizumab in Patients With HER2-Abnormally Expressed Unresectable Locally Advan","route":"/trials/nct07653685/"},{"id":"nct07796763","kind":"trial","name":"A Global Trial of Trastuzumab Rezetecan (SHR-A1811) in Combination With Chemotherapy and Bevacizumab as First-Line Treatment in Patients With Advanced Colorecta","route":"/trials/nct07796763/"},{"id":"nct06695845","kind":"trial","name":"A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors","route":"/trials/nct06695845/"},{"id":"nct07730489","kind":"trial","name":"A Study Comparing BL-M07D1 With Physician's Choice Therapy in Patients With HER2 IHC3+ Advanced Colorectal Cancer Who Failed Prior Treatment With Oxaliplatin, F","route":"/trials/nct07730489/"},{"id":"nct04172597","kind":"trial","name":"A Study of Poziotinib in Patients With Epidermal Growth Factor Receptor (EGFR) or Human Epidermal Growth Factor Receptor 2 (HER2) Activating Mutations in Advanced Malignancies","route":"/trials/nct04172597/"},{"id":"nct07691489","kind":"trial","name":"A Study of Trastuzumab Deruxtecan (T-DXd) and Cetuximab in People With Colorectal Cancer","route":"/trials/nct07691489/"},{"id":"nct05672524","kind":"trial","name":"A Study of Tucatinib and Trastuzumab in People With Rectal Cancer","route":"/trials/nct05672524/"},{"id":"nct06324357","kind":"trial","name":"Beamion BCGC-1: A Study to Find a Suitable Dose of Zongertinib Used Alone and in Combination With Other Treatments to Test Whether it Helps People Wit","route":"/trials/nct06324357/"},{"id":"nct07192068","kind":"trial","name":"Clinical Trial Evaluating the Activity of Zanidatamab for the Treatment of Patients With Solid Tumors With an Alteration of the HER2 Gene.","route":"/trials/nct07192068/"},{"id":"destiny-crc01","kind":"trial","name":"DESTINY-CRC01","route":"/trials/destiny-crc01/"},{"id":"destiny-crc02","kind":"trial","name":"DESTINY-CRC02","route":"/trials/destiny-crc02/"},{"id":"nct07059338","kind":"trial","name":"Dual EGFR/HER2 Blockade Combined With Irinotecan for the Treatment of HER2-Positive Metastatic Colorectal Cancer","route":"/trials/nct07059338/"},{"id":"nct07462650","kind":"trial","name":"Dual-Target CAR-NK Cells for Biomarker-Selected Advanced Colorectal Cancer","route":"/trials/nct07462650/"},{"id":"nct07589517","kind":"trial","name":"Dual-Targeting CAR-NK Cells in Biomarker-Selected Advanced Colorectal Cancer","route":"/trials/nct07589517/"},{"id":"nct07108127","kind":"trial","name":"Efficacy and Safety of Trastuzumab Biosimilars and Pertuzumab Biosimilars Combined With Chemotherapy for Neoadjuvant Treatment of Patients With Locally Advanced","route":"/trials/nct07108127/"},{"id":"heracles","kind":"trial","name":"HERACLES","route":"/trials/heracles/"},{"id":"nct07384377","kind":"trial","name":"JSKN003 Versus Physician Choiced Treatment in Patients With HER2-positive and Advanced Colorectal Cancer Who Had Failed to Respond to Oxaliplatin, 5-Fu, and Iri","route":"/trials/nct07384377/"},{"id":"mountaineer","kind":"trial","name":"MOUNTAINEER","route":"/trials/mountaineer/"},{"id":"mountaineer-03","kind":"trial","name":"MOUNTAINEER-03","route":"/trials/mountaineer-03/"},{"id":"mypathway","kind":"trial","name":"MyPathway","route":"/trials/mypathway/"},{"id":"nct07509424","kind":"trial","name":"Neoadjuvant Short-course Radiotherapy Followed by a Combination of Disitamab Vedotin, Sintilimab, and Capecitabine in Locally Advanced HER2-expressing Rectal Ca","route":"/trials/nct07509424/"},{"id":"nct07243938","kind":"trial","name":"Phase II Basket Trial: Zanidatamab Plus Tislelizumab in HER2-Positive GI Tumors (UNION-HER2-BASKET)","route":"/trials/nct07243938/"},{"id":"nct05868226","kind":"trial","name":"PRE-ISPY Phase I/II Oncology Platform Program","route":"/trials/nct05868226/"},{"id":"nct04899908","kind":"trial","name":"Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases","route":"/trials/nct04899908/"},{"id":"nct06589830","kind":"trial","name":"TL938 and Trastuzumab for Patients With HER2-positive Metastatic Colorectal Cancer","route":"/trials/nct06589830/"},{"id":"triumph","kind":"trial","name":"TRIUMPH","route":"/trials/triumph/"},{"id":"nct07405476","kind":"trial","name":"Zanidatamab Before Surgery for the Treatment of HER2 Positive Colon and Rectal Cancer in Patients Planned for Curative Intent Treatment","route":"/trials/nct07405476/"}],"person":[{"id":"andrea-sartore-bianchi","kind":"person","name":"Andrea Sartore-Bianchi","route":"/people/andrea-sartore-bianchi/"},{"id":"john-strickler","kind":"person","name":"John H. Strickler","route":"/people/john-strickler/"},{"id":"salvatore-siena","kind":"person","name":"Salvatore Siena","route":"/people/salvatore-siena/"},{"id":"tanios-bekaii-saab","kind":"person","name":"Tanios Bekaii-Saab","route":"/people/tanios-bekaii-saab/"}],"paper":[{"id":"paper-tcga-colorectal-comprehensive-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","route":"/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/"},{"id":"paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","kind":"paper","name":"Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)","route":"/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/"},{"id":"paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021","kind":"paper","name":"Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01)","route":"/key-papers/paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021/"},{"id":"paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","kind":"paper","name":"Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER)","route":"/key-papers/paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"}],"biomarker":[{"id":"ras-wild-type","kind":"biomarker","name":"RAS wild-type (extended KRAS and NRAS testing)","route":"/biomarkers/ras-wild-type/"}]}}