EGFR/ERBB2 aberrations in Chinese biliary tract carcinomas.

Abstract

e16208 Background: Biliary tract carcinoma (BTC) accounts for 3% gastrointestinal cancers in China. BTCs are mainly classified as gallbladder cancer (GBC) and cholangiocarcinomas (CCA) with dismal prognosis. Current chemotherapy regimens for BTC yield poor outcomes. We aimed to describe the genomic landscape of a BTC patient cohort using next-generation sequencing (NGS), focusing on the EGFR/ERBB2 aberrations and exploring the possibility of therapeutic intervention. Methods: We analyzed BTC tissue/blood samples including GBCs and CCAs with targeted sequencing (NGS) for EGFR/ERBB2 activating mutations, copy number amplifications (copy number≥5) and rearrangements (containing the kinase domain). A cohort of 1033 Chinese BTC patients were analyzed including 783 GBC patients and 250 CCA patients. Results: Data analysis revealed EGFR/ERBB2 alteration rates were 9.0% in Chinese BTC patients. The majority of these alterations were in fact ERBB2 alterations at a rate of 15.8% in GBC and 6.4% in CCA（P<0.05). A further subanalysis of ERBB2 mutation types showed that 46.7% in GBC and 64.6% in CCA were activating mutations, 37.8% in GBC and 31.3% in CCA were gene amplifications, 8.9% in GBC and 2.1% in CCA were gene rearrangements and 6.7% of GBC and 2.1% of CCA cases had multiple ERBB2 alterations. The top activating ERBB2 mutation were p.S310F（10/45） followed by p.R678Q(4/45) in GBC and were p.S310F (11/48) followed by p.V777L(5/48) in CCA. EGFR alteration rates were 3.5% in GBC and 1.3% in CCA（P<0.05). Among these, 30% of the GBCs and 60% of the CCAs had an activating EGFR mutation, 70% of the GBCs and 30% of the CCAs had EGFR copy number amplification and 10% of the GBCs and no CCA case had an EGFR rearrangement. Three EGFR activating mutations detected in GBC were p.G719A, p.L861Q, p.A289V. Six EGFR activating mutations detected in CCA were p.G719D, p.E746_S752delinsV, p.L858R, p.N771_H773dup, p.D770_N771insG, p.R222C. Conclusions: We report characteristics of EGFR/ERBB2 alterations in Chinese GBC and CCA patients. In general, 19.4% of GBC and 7.7% CCA may benefit from EGFR/ERBB2 targeted therapy. EGFR/ERBB2 targeted therapies should be further explored in Chinese BTC patients.