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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
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.
| Setting | Approach | Guideline |
|---|---|---|
| Metastatic, RAS wild-type, previously treated | Tucatinib plus trastuzumab (MOUNTAINEER); trastuzumab plus pertuzumab or lapatinib where tucatinib is unavailable. | not mapped |
| After HER2 antibodies, or with RAS mutation | Trastuzumab deruxtecan (DESTINY-CRC02; tumour-agnostic approval for immunohistochemistry 3+), watching for pneumonitis. | not mapped |
| 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. | not mapped |