Current challenges to underpinning the genetic basis for cholangiocarcinoma

ABSTRACT

Introduction: Cholangiocarcinoma (CCA) is an aggressive cancer type with a dismal prognosis. CCA typically presents at an advanced stage when surgical resection is not feasible, and systemic chemotherapy is generally of limited benefit. Thus, developing effective therapies against this deadly tumor is imperative and remains an unmet need. The advent of high-throughput approaches has led to a better delineation of each CCA subtype’s molecular landscape and the identification of promising candidates for targeted therapies. In this scenario, the recent approval of pemigatinib, a pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, for the treatment of the CCA subtype characterized by FGFR2 mutations, represents the first of numerous novel therapies against this disease.

Areas covered

This review provides an overview regarding the current scenario and knowledge of the CCA genomic landscape and the potentially actionable molecular aberrations in each CCA subtype.

Expert opinion

The establishment and advances of high-throughput methodologies applied to genetic and epigenetic profiling are changing many cancer types' therapeutic landscape , including CCA.The large body of data generated must be interpreted appropriately and eventually implemented in clinical practice. The following advancements toward precision medicine in CCA management will require designing better clinical trials with improved methods to stratify biliary tumor patients.

KEYWORDS:

• Cholangiocarcinoma
• genomic landscape
• epigenetics
• next-generation sequencing
• molecular pathogenesis
• molecular profiling
• targeted therapies
• driver mutations
• predictive biomarkers
• precision medicine

Article highlights

• Cholangiocarcinoma (CCA) is an aggressive cancer type with an overall poor prognosis due to limited therapeutic options and intrinsic chemoresistance.

• CCA pathogenesis is associated with genetic and epigenetic alterations in tumor cells as well as significant changes in the tumor microenvironment, resulting in the alteration of various signaling pathways.

• There is a pertinent need to advance our understanding of the molecular landscape in advanced CCA and integrate these data with targeted therapies and immunotherapies in novel combination strategies.

• Integrative genomics analysis of CCA, regarding mutational landscape, copy number variations transcriptome, and epigenetic modifications, allows molecular stratification of patients and tumor subtypes for precision-targeted therapy.

• Encouraging results and hopes come from the FDA approval of the pan-FGFR inhibitor pemigatinib for the treatment of CCA patients harboring FGFR2 fusions or other rearrangements.

• Several novel drugs for the advanced-stage disease are continuously developed, hitting potentially driver genetic aberrations.

Declaration of interest

Xin Chen was supported by a grant from the NIH (R01 CA19606 and R01 CA228483). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded in part by a grant from the NIH (R01 CA19606 and R01 CA228483) to Xin Chen.