HER2-amplified colorectal cancer
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowBowel perforation
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
- Emergency services nowFainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
- Emergency services nowSkin reaction
Blisters, peeling, or sores in the mouth or eyes with a rash. Enfortumab vedotin carries a boxed warning for Stevens-Johnson syndrome and toxic epidermal necrolysis, mostly in the first cycle.
- Call the 24-hour line nowInterstitial lung disease or pneumonitis
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.
- Check before combiningFood and drink: Trastuzumab deruxtecan
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
Anatomy and lymph node drainage
- Right colon (MSI-high, BRAF commoner)
- Left colon and sigmoid
- Rectum
- Anal canal (HPV squamous)
- Appendix
- Peritoneum and omentum (mesothelioma, peritoneal spread)
- Nodes: pericolic
- Nodes: mesenteric root
- Nodes: para-aortic
- Nodes: mesorectal
- Nodes: lateral pelvic and inguinal (anal)
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.
- Right colon (MSI-high, BRAF commoner)HER2-amplified, RAS and BRAF wild-type, left-sided (the classic group, responsive to dual HER2 blockade)
- Left colon and sigmoidHER2-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
- Rectum
- Anal canal (HPV squamous)
- Appendix
- Peritoneum and omentum (mesothelioma, peritoneal spread)
- pericolic
- mesenteric root
- para-aortic
- mesorectal
- lateral pelvic and inguinal (anal)
Same organ: 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)
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Subtypes & biomarkers
top- 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
- 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
How often this target appears
- 2011HER2 amplification identified as a cause of anti-EGFR resistance in patient-derived xenografts
- 2016HERACLES: trastuzumab plus lapatinib produces responses in 30 percent
- 2019MyPathway: trastuzumab plus pertuzumab active in HER2-amplified colorectal cancer
- 2022MOUNTAINEER: tucatinib plus trastuzumab, response rate 38 percent, median survival 24 months
- 2023FDA accelerated approval of tucatinib with trastuzumab, the first HER2 approval in colorectal cancer
- 2024Tumour-agnostic approval of trastuzumab deruxtecan for HER2 3+ solid tumours after DESTINY-CRC02
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 10 changes by month →- 2026-09-17This recordHER2-amplified colorectal cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2024MilestoneTrastuzumab deruxtecanTumour-agnostic approval of trastuzumab deruxtecan for HER2 3+ solid tumours after DESTINY-CRC02
A milestone in how this cancer is treated.
- 2023Trial resultDESTINY-CRC02DESTINY-CRC02 reported
ORR 37.
- 2023MilestoneTucatinibFDA accelerated approval of tucatinib with trastuzumab, the first HER2 approval in colorectal cancer
A milestone in how this cancer is treated.
- 2022Trial resultMOUNTAINEER & MOUNTAINEER-03MOUNTAINEER & MOUNTAINEER-03 reported
Phase 2 ORR 38.
- 2022MilestoneMOUNTAINEER & MOUNTAINEER-03MOUNTAINEER: tucatinib plus trastuzumab, response rate 38 percent, median survival 24 months
A milestone in how this cancer is treated.
What is in development for HER2-amplified colorectal cancer, drawn from the whole corpus: 7 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Technologies being tested · 1
Trials under way · 4
- A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer · phase 3 · Seagen, a wholly owned subsidiary of Pfizer
- A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors · phase 2 · Jazz Pharmaceuticals
- TL938 and Trastuzumab for Patients With HER2-positive Metastatic Colorectal Cancer · phase 2 · Suzhou Teligene Ltd.
- A Clinical Study of SPH5030 Tablets in the Treatment of Her2-positive/Mutated Biliary Tract OR Colorectal Cancer Patients. · phase 2 · Shanghai Pharmaceuticals Holding Co., Ltd
Trials reported · 2
- DESTINY-CRC02 · phase 2 · 2023 · positive
- MOUNTAINEER & MOUNTAINEER-03 · phase 2 · 2022 · completed
Open problems and what is being done
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.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Rochester, MN · hospital | United States | 0 | 4,511 | 44,748 | #5 | ||
Villejuif · cancer center | France | none recorded | 0 | 1,855 | 31,182 | #6 | |
Tokyo · government | Japan | none recorded | 0 | 1,599 | 21,937 | none recorded | #13 |
Los Angeles · cancer center | United States | 0 | 2,019 | 32,934 | - | ||
Beijing · cancer center | China | none recorded | 0 | 1,344 | 18,195 | - | |
Wuhan · hospital | China | none recorded | 0 | 1,174 | 14,691 | - | |
Padua · cancer center | Italy | none recorded | 0 | 962 | 12,326 | - | |
Taipei · hospital | Taiwan | none recorded | 0 | 746 | 8,966 | - | |
Guangzhou · hospital | China | none recorded | 0 | 704 | 7,832 | - | |
Nagoya · cancer center | Japan | none recorded | 0 | 657 | 8,832 | - | |
Shanghai · hospital | China | none recorded | 0 | 539 | 6,491 | - | |
Singapore · cancer center | Singapore | none recorded | 0 | 493 | 5,212 | - | |
Brussels · cancer center | Belgium | none recorded | 0 | 489 | 8,689 | - | |
Frankfurt am Main · cancer center | Germany | none recorded | 0 | 466 | 5,556 | - | |
Shanghai · hospital | China | none recorded | 0 | 464 | 6,795 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with HER2-amplified colorectal cancer but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about HER2-amplified colorectal cancer
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example 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, Left-sided or rectal primary), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include HER2-amplified, RAS and BRAF wild-type, left-sided, HER2-amplified with RAS mutation, HER2 activating mutations without amplification.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Metastatic, RAS wild-type, previously treated
- For my situation (metastatic, ras wild-type, previously treated), which of the standard options do you recommend and why?Why: Guideline options include: Tucatinib plus trastuzumab (MOUNTAINEER); trastuzumab plus pertuzumab or lapatinib where tucatinib is unavailable.
- Am I a candidate for Tucatinib, Trastuzumab, Pertuzumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of MOUNTAINEER & MOUNTAINEER-03 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
After HER2 antibodies, or with RAS mutation
- For my situation (after her2 antibodies, or with ras mutation), which of the standard options do you recommend and why?Why: Guideline options include: Trastuzumab deruxtecan (DESTINY-CRC02; tumour-agnostic approval for immunohistochemistry 3+), watching for pneumonitis.
- Am I a candidate for Trastuzumab deruxtecan, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of DESTINY-CRC02 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Metastatic, first line
- For my situation (metastatic, first line), which of the standard options do you recommend and why?Why: Guideline options include: Standard doublet chemotherapy with bevacizumab; anti-EGFR antibodies are less effective in HER2-amplified tumours; tucatinib-trastuzumab-FOLFOX is under test in MOUNTAINEER-03.
- Am I a candidate for FOLFOX (5-FU, leucovorin, oxaliplatin), FOLFIRI (5-FU, leucovorin, irinotecan), Bevacizumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Any stage
- Are there clinical trials I could join, for example of A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer, Zanidatamab, A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors, TL938 and Trastuzumab for Patients With HER2-positive Metastatic Colorectal Cancer?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No randomised evidence yet for HER2 blockade in first line”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “RAS co-mutation blunts dual HER2 blockade and the best option for those patients is unclear”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with HER2-amplified colorectal cancer, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
11targets
4drugs
8companies
10pathways
2terms
3trials
7people
1Latest papers
topQuery 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.
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