Targeted Therapies for Perihilar Cholangiocarcinoma

SIMPLE SUMMARY: Perihilar cholangiocarcinoma is a type of biliary tract cancer with a poor prognosis. There is growing interest in treatments targeting specific molecular changes within these cancers, and a broad range of these treatments (targeted therapies) is currently in development. This article reviews knowledge of the molecular changes within cholangiocarcinoma, which often group together to form so-called molecular subtypes, and reviews the targeted therapies used to exploit these molecular changes to improve outcomes for patients. Biliary tract cancer subtypes differ in their patterns of molecular alterations; therefore, targeted therapies are not equally applicable to all subtypes. This article examines the relevance of targeted therapies within biliary tract cancer to patients with perihilar cholangiocarcinoma. ABSTRACT: Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient’s cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.