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Growing 85 patients' bowel cancers in mice and treating them like a clinical trial reproduced the pattern seen in people, and revealed that the tumours resisting cetuximab despite normal RAS often have extra copies of HER2.
Large xenograft cohorts were produced from 85 patient-derived, genetically characterised metastatic colorectal cancer samples. Serially passaged tumours retained the morphological and genomic features of their originals, and a validation trial confirmed that they responded to cetuximab with rates and extents analogous to those seen in the clinic, and could be prospectively stratified as responders or non-responders using predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS, NRAS, BRAF and PIK3CA wild-type cases, and HER2 amplification was also enriched among clinically non-responding KRAS wild-type patients. A proof-of-concept, multi-arm study in HER2-amplified xenopatients showed that combined inhibition of HER2 and EGFR induced overt, long-lasting tumour regression.
It is where HER2-directed colorectal therapy came from: the xenopatient result led directly to HERACLES and therefore to every HER2 regimen now used in the disease.
Shares HERACLES, Lapatinib, Istituto di Candiolo IRCCS (FPO), Receptor tyrosine kinase activation.
Shares Wild-type (WT), Cetuximab, RAS / RAF / MEK / ERK (MAPK), EGFR.
Shares HERACLES, Lapatinib, Trastuzumab.
Shares HERACLES, Gene amplification and copy-number change, Istituto di Candiolo IRCCS (FPO), Trastuzumab.
Shares Gene amplification and copy-number change, Receptor tyrosine kinase activation, Trastuzumab, HER2.
Shares Wild-type (WT), Cancer Discovery, Receptor tyrosine kinase activation, RAS / RAF / MEK / ERK (MAPK).
Shares Gene amplification and copy-number change, Receptor tyrosine kinase activation, HER2, Colorectal cancer.
Shares HERACLES, Wild-type (WT), KRAS, HER2.