Genomic Profiling of Biliary Tract Cancers and Implications for Clinical Practice.

Abstract

Biliary tract cancers are relatively uncommon, have an aggressive disease course and a dismal clinical outcome. Until recently, there have been very few clinical advances in the management of these patients and gemcitabine-based chemotherapy has been the only widely accepted systemic therapy. The advent of next generation sequencing technologies can potentially change the treatment paradigm of this disease. Targeted therapy directed against actionable mutations and identification of molecular subsets with distinct prognostic significance is now feasible in clinical practice. Mutation profiling has highlighted the genomic differences between the intra, extrahepatic cholangiocarcinoma, and gallbladder cancer. The mutational spectrum of intrahepatic cholangiocarcinoma differs according to geographic location and ethnicity. There is a higher incidence of chromatin modulating gene mutations in Western patients as compared with Asian patients with liver fluke-associated cholangiocarcinoma. KRAS and p53 mutations are associated with an aggressive disease prognosis while FGFR mutations may signify a relatively indolent disease course of intrahepatic cholangiocarcinoma. FGFR and IDH mutations have promising agents in clinical trials at this time. An estimated 15% of gallbladder cancers have Her2/neu amplification and can be targeted by trastuzumab. On the other hand, an estimated 10-15% of cholangiocarcinomas have DNA repair mutations and maybe candidates for immune therapies with checkpoint inhibitors. The promise of targeted therapies for biliary tract cancers can be fulfilled with well-designed, prospective, and multi-center clinical trials.