Novel biomarkers and the future of targeted therapies in cholangiocarcinoma: a narrative review

Background and Objectives: Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree, comprising 15% of all primary liver cancers. The nature of the disease and nonspecific presentation leads to late diagnosis and ultimately poor outcomes for patients. Combination gemcitabine and cisplatin has been the standard of care for cholangiocarcinoma (CCA) since 2010, with a median overall survival of 11.7 months. The five-year survival for CCA remains 5-10%, revealing a clear need for improved treatment options. Methods: This targeted review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development. Key Content and Findings: These tumor biomarkers or actionable mutations hold the potential to enable earlier diagnosis, provide prognostic information, and guide treatment decisions for patients with CCA. Specifically, the FGFR2 fusion and IDH1 mutation have shown considerable promise in development of targeted therapies. Clinical trials with inhibitors targeting FGFR2 fusion and IDH1 mutation have created expectations that these drugs will soon enter clinical practice. Other biomarkers including KRAS and B-raf protooncogenes, Her2/neu genes, and BRCA1 and 2 tumor-suppressor genes have also been touted as potential targets for future therapies, with early data showing promise for new drug development. Conclusions: The discovery of these actionable mutations and identification of targeted therapies have challenged the notion of a one-size fits all for treatment of CCA, and generated optimism that these novel treatments will soon be available for patients with CCA.

Automated summary

This targeted review discusses the important tumor biomarkers in the pathogenesis of cholangiocarcinoma, including FGFR2 fusion and IDH1 mutation, and explores the potential clinical applications of these biomarkers. The discovery of these biomarkers has significant implications for early diagnosis, prognostic evaluation, and guiding treatment decisions.