Genetics of biliary tract cancers and emerging targeted therapies

Abstract

Biliary tract cancers (BTC), which encompass intra- and extrahepatic cholangiocarcinomas and gallbladder carcinomas, are a genetically diverse collection of cancers. Evidence suggests distinct models of molecular and pathologic progression, and a growing body of genetics data points to a heterogeneous collection of underlying mutations in key oncogenes and tumor suppressor genes. Although tumor genetics have been used to tailor individual treatment regimens and guide clinical decision making in other cancers, these principles have not been applied in BTC. Recent clinical trials with targeted therapies seem promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here, we summarize the molecular pathogenesis and genetics of BTCs and animal modeling and relate these to recent and ongoing clinical trials with targeted agents.

Fig 1.

Precursors to biliary tract carcinoma. (A) Biliary dysplasia of the common bile duct (biliary intraepithelial neoplasia-2 [BilIN-2]; hematoxylin and eosin [HE]). (B) Biliary dysplasia of the common bile duct (biliary intraepithelial neoplasia-3 [BilIN-3]). Compared with BilIN-2, BilIN-3 shows loss of cell polarity and marked nuclear atypia (HE). (C) Intraductal papillary neoplasm of the bile duct. This papillary neoplasm diffusely involved the intrahepatic biliary tree. The lining epithelium was of the biliary type (HE). The adjacent liver (*) was unremarkable. (D) Gallbladder adenoma lined predominantly by foveolar-type epithelium. There was no evidence of an associated invasive carcinoma (HE). (E) Severe dysplasia/carcinoma in situ of the gallbladder with involvement of Rokitansky-Aschoff sinuses (arrow). There was no evidence of invasive carcinoma (HE). (F) Invasive adenocarcinoma of the gallbladder. There is an extensive intramucosal component (smaller arrow) with focal invasion into the muscularis propria (larger arrow) (HE).