Background: HER2 amplifications and activating mutations are an emerging drug target in the treatment of colorectal cancer (CRC). Ongoing studies, such as MyPathway (Clinicaltrials.gov NCT02091141), include basket trials of targeted therapies for multiple solid tumor types. The frequency of HER2 mutations in GI cancers and a drug resistance mechanism to the HER2 kinase inhibitor, afatinib, are presented here. Methods: The Foundation Medicine database of 53,126 cases was searched and clinical data from patients with GI tumors enrolled in the HER2 basket of MyPathway was included. Results: 10,358 patients with GI cancers and FoundationOne (FO) testing were identified and compared to the HER2 mutation frequency reported by The Cancer Genome Atlas (TCGA). In MyPathway, 28 GI tumors with HER2 alterations are enrolled: CRC (n = 13, all amplified), liver/biliary (n = 5), pancreatic (n =4), small intestine (n = 3), and esophageal (n = 2). Several CRC patients demonstrated responses to trastuzumab/pertuzumab (reported separately). The HER2 mutant CRC cell lines, CW-2 and CCK-81, are highly sensitive to afatinib (IC₅₀=7-20 nM). Addition of the HER3 ligand, neuregulin1 caused afatinib resistance, but pertuzumab prevented HER3/HER2 activation and reversed this drug resistance. Conclusions: HER2 mutations or amplifications are commonly found in a wide range of GI cancers. Pre-clinical data provide rationale for inclusion of pertuzumab in the treatment strategy for these cancers. The MyPathway Trial is testing this approach.

*includes GE junction tumors.