# HER2-amplified colorectal cancer

Source: https://onco.cc/cancers/her2-amplified-colorectal/  
OnCo record `her2-amplified-colorectal` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

MOUNTAINEER (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.

MOUNTAINEER-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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: HER2-positive colorectal cancer; ERBB2-amplified colorectal cancer; HER2-overexpressing bowel cancer
- Tags: subtype-page
- 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

## Standard of care

- Metastatic, RAS wild-type, previously treated: Tucatinib plus trastuzumab (MOUNTAINEER); trastuzumab plus pertuzumab or lapatinib where tucatinib is unavailable. ([MOUNTAINEER & MOUNTAINEER-03](https://onco.cc/trials/mountaineer/), [Tucatinib](https://onco.cc/drugs/tucatinib/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Pertuzumab](https://onco.cc/drugs/pertuzumab/), [HER2 tyrosine kinase inhibitors](https://onco.cc/technologies/her2-tyrosine-kinase-inhibitors/))
- After HER2 antibodies, or with RAS mutation: Trastuzumab deruxtecan (DESTINY-CRC02; tumour-agnostic approval for immunohistochemistry 3+), watching for pneumonitis. ([DESTINY-CRC02](https://onco.cc/trials/destiny-crc02/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/))
- Metastatic, first line: Standard doublet chemotherapy with bevacizumab; anti-EGFR antibodies are less effective in HER2-amplified tumours; tucatinib-trastuzumab-FOLFOX is under test in MOUNTAINEER-03. ([FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer](https://onco.cc/trials/nct05253651/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/HER2/neu
- Wikipedia: https://en.wikipedia.org/wiki/HER2/neu
- NCCN Guidelines: Colon Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428

## Connected records

- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [HER2 tyrosine kinase inhibitors](https://onco.cc/technologies/her2-tyrosine-kinase-inhibitors/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [HER2](https://onco.cc/targets/her2/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Pertuzumab](https://onco.cc/drugs/pertuzumab/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Tucatinib](https://onco.cc/drugs/tucatinib/), [Zanidatamab](https://onco.cc/drugs/zanidatamab/)
- pathways: [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- trials: [A Clinical Study of SPH5030 Tablets in the Treatment of Her2-positive/Mutated Biliary Tract OR Colorectal Cancer Patients.](https://onco.cc/trials/nct06434597/), [A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors](https://onco.cc/trials/nct06695845/), [A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer](https://onco.cc/trials/nct05253651/), [DESTINY-CRC02](https://onco.cc/trials/destiny-crc02/), [MOUNTAINEER & MOUNTAINEER-03](https://onco.cc/trials/mountaineer/), [MyPathway](https://onco.cc/trials/mypathway/), [TL938 and Trastuzumab for Patients With HER2-positive Metastatic Colorectal Cancer](https://onco.cc/trials/nct06589830/)
- people: [Tanios Bekaii-Saab](https://onco.cc/people/tanios-bekaii-saab/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)

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