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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.
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.
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.
Right-sided tumours behave differently from left-sided and rectal ones; the colon drains along its mesenteric vessels, the rectum into the mesorectum and pelvic side wall.
Same organ: Colon cancer (adenocarcinoma of the colon), Micropapillary adenocarcinoma of the colon and rectum, Adenoma-like adenocarcinoma of the colon and rectum, Lynch syndrome-associated colorectal cancer, Familial adenomatous polyposis-associated colorectal cancer, Mucinous adenocarcinoma of the colon and rectum, Signet ring cell carcinoma of the colon and rectum, Medullary carcinoma of the colon, Serrated adenocarcinoma of the colon and rectum, Peritoneal mesothelioma, Colorectal cancer, Rectal cancer, Mismatch-repair deficient (MSI-high) colorectal cancer, BRAF V600E-mutant colorectal cancer, KRAS G12C-mutant colorectal cancer, Early-onset colorectal cancer (under 50), Anal cancer (squamous cell carcinoma), Appendiceal cancer and pseudomyxoma peritonei, Small intestine cancer (small bowel adenocarcinoma), Small intestinal neuroendocrine tumours, Anal high-grade squamous intraepithelial lesions (precursor), Localised anal squamous cell carcinoma (stage I to III), Metastatic and recurrent anal squamous cell carcinoma, Low-grade appendiceal mucinous neoplasm and pseudomyxoma peritonei, Appendiceal adenocarcinoma (mucinous and non-mucinous, including signet ring cell), Goblet cell adenocarcinoma of the appendix, Localised small bowel adenocarcinoma (stage I to III, resected), Advanced and metastatic small bowel adenocarcinoma
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Also on OnCo: Symptoms and red flags · Early detection roadmap.
Tucatinib plus trastuzumab (MOUNTAINEER); trastuzumab plus pertuzumab or lapatinib where tucatinib is unavailable.
Trastuzumab deruxtecan (DESTINY-CRC02; tumour-agnostic approval for immunohistochemistry 3+), watching for pneumonitis.
Standard doublet chemotherapy with bevacizumab; anti-EGFR antibodies are less effective in HER2-amplified tumours; tucatinib-trastuzumab-FOLFOX is under test in MOUNTAINEER-03.
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The first United States approval of a HER2-directed regimen in colorectal cancer, and the basis for MOUNTAINEER-03, which is testing the combination with chemotherapy in the first line.
The antibody-drug conjugate route into HER2-positive colorectal cancer, extended by DESTINY-CRC02 at a lower dose; interstitial lung disease is the class risk that defines how the drug is monitored.
The first demonstration that HER2 is actionable in colorectal cancer, and the trial that defined the colorectal-specific HER2 scoring criteria every later trial has used.
It is the reference description of the disease and the source of the hypermutated split that decides who gets immunotherapy; it also put HER2 on the colorectal map as a drug target.
Query for this cancer: (TITLE:"HER2-amplified colorectal cancer" OR ABSTRACT:"HER2-amplified colorectal cancer" OR TITLE:"HER2-positive colorectal cancer" OR ABSTRACT:"HER2-positive colorectal cancer" OR TITLE:"ERBB2-amplified colorectal cancer" OR ABSTRACT:"ERBB2-amplified colorectal cancer" OR TITLE:"HER2-overexpressing bowel cancer" OR ABSTRACT:"HER2-overexpressing bowel cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about HER2-amplified colorectal cancer, not a curated reading list.
The targets of this cancer's medicines and the ones linked to it directly.
Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Any new or worsening cough, breathlessness or fever. The label says to interrupt treatment for any suspected ILD and to permanently discontinue for grade 2 or higher.
Temperature of 38 C or higher, or feeling shivery and unwell even without a fever. Antibody-drug conjugates suppress the bone marrow, and several carry a boxed warning for severe neutropenia.
Interstitial lung disease in 10-15%: hold for any respiratory symptom and image; permanently discontinue for grade 2 or above. Moderately emetogenic: three-drug prophylaxis.
See all on the product pages:BevacizumabFOLFIRI (5-FU, leucovorin, irinotecan)FOLFOX (5-FU, leucovorin, oxaliplatin)Trastuzumab deruxtecanTucatinib·Printable cards in the navigator
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Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record.
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