Biliary tract cancers, which are also known as cholangiocarcinomas (CCA), describe malignancies that occur in the biliary tract and include the pancreas, gallbladder and bile ducts. These are relatively rare cancers but are associated with a poor prognosis given that these cancers are difficult to detect and are usually diagnosed at later stages of disease. Histologically, CCAs are predominantly adenocarcinomas and are classified by growth patterns (mass forming, intraductal, or periductal) and anatomical locations (intrahepatic, perihilar, or distal), and mixed hepatocellular CCAs are defined as a separate subtype of primary hepatic cancer.
CCAs can arise de novo with no discernable risk factors, but a variety of genetic and nongenetic risk factors are associated with CCA, including liver cirrhosis, obesity, type 2 diabetes, chronic hepatitis B or C infection, or infection with hepatobiliary flukes. Individuals with primary sclerosing cholangitis have higher levels of chronic liver inflammation and increased incidence of CCA as well.
CCAs are typically aggressive cancers with a median overall survival of < 24 months, and the only treatment options have been surgical resection or liver transplantation for early-stage patients or aggressive chemotherapy for patients with advanced stages of disease. Next-generation sequencing technology has identified several gene mutations that are linked to increased CCA risk, including mutations in chromatin remodeling genes (ARID1A, BAP1 and PBRM1). IDH1 mutations have been linked to intrahepatic CCA and mutations in ERBB2 are more closely associated with extrahepatic CCA. Mutations in the fibroblast growth factor (FGF) signaling pathway, including mutations or translocations in FGF receptor (FGFR) genes have also been identified in CCA, and an FGFR fusion has been linked specifically to intrahepatic CCA. Moreover, patients with IDH1/2 mutations also exhibit elevated expression of FGFRs, even in the absence of other FGFR mutations or fusions, further affirming a role for FGF/FGFR signaling in CCA progression.
The FGF/FGFR pathway has become one of the most encouraging targets for novel CCA therapeutics. FGFRs are receptor tyrosine kinases and nonselective FGFR inhibitors that target the conserved ATP-binding domain were the first drugs to be tested in clinical trials. A recent trial exploring the use of the nonselective FGFR kinase inhibitor pazopanib combined with a MEK inhibitor showed little efficacy. Selective FGFR inhibitors have been considered more promising but also have a more severe toxicity profile. Infigratinib is a selective pan-FGFR kinase inhibitor has shown modest clinical efficacy in chemotherapy refractory CCA patients with an FGFR2 fusion. More recently the irreversible pan-FGFR inhibitor TAS-120 showed efficacy in CCA patients (with or without a FGFR fusion) that had been given prior FGFR inhibitors.
Pemagatinib is the first FDA-approved targeted therapy for advanced CCA for tumors with FGFR2 fusions or rearrangements. Pemagatinib is a selective inhibitor of FGFR1, 2, and 3 and was approved in 2020 and was given breakthrough therapy designation as the first drug to specifically treat CCA.
Alternative FGF/FGFR inhibitors are also under development and target the extracellular domain or function as FGF ligand traps. These alternative inhibitors can be used potentially in combination with FGFR kinase inhibitors that have lost efficacy due to the development of resistance. Different mutations can arise in the ATP binding site or tyrosine kinase domain, and resistance seems to develop more readily with reversible inhibitors.
New research on novel inhibitors and combination therapies will likely identify other therapeutic options for CCA, and these cancers will not be the death sentence they once were.
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