Biliary tract cancer and genomic alterations in homologous recombinant deficiency: exploiting synthetic lethality with PARP inhibitors

Abstract

Biliary tract cancers (BTC) are a group of rare, chemoresistant solid tumor malignancies that arise from the bile ducts. BTC are typically associated with poor outcomes. Most patients present with advanced disease, where treatment is palliative with platinum based cytotoxic therapy. Response to chemotherapy is variable with limited duration of response. A subset of patients that will receive durable and meaningful responses to platinum-based chemotherapy is deemed to be platinum sensitive. The availability and implementation of next-generation sequencing allowed genomic profiling of BTC, which have identified potential targetable somatic genetic aberrations, which include kinases (FGFR, BRAF, ALK, ERBB2), oncogenes (IDH1/2, CCND1) and tumor suppressor genes, including germline or somatic mutations involved in DNA damage response (DDR) genes. These genes include, but are not limited to: ATM, ATR, BRCA1/2, RAD51, PALB2, PTEN, FANC, NBN, EMSY, MRE11, ARID1A. In BTC, alterations in DDR genes are identified in up to 20% of patients, with a higher proportion identified in those with extrahepatic cholangiocarcinoma. Patients harboring mutations exhibit varying patterns of clinical behavior and response to therapy. The presence of these mutations typically predicts for susceptibility to DNA damaging chemotherapy, such as platinum agents.

Keywords: Homologous recombinant deficiency; PARP; biliary tract cancer (BTC); cholangiocarcinoma.