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

Abstract

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. This review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development. 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. 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.

L-Fucose inhibits the progression of cholangiocarcinoma by causing microRNA-200b overexpression

“…CCA is a type of cancer that exhibits poor responses to the therapeutic options that are currently available, [ 16 ] and thus, the identification of innovative agents for the treatment of CCA is urgently needed. The present study yielded a number of novel findings.…”

New Insights into Surgical Management of Intrahepatic Cholangiocarcinoma in the Era of “Transplant Oncology”

“…New tumor biomarkers emerged in the diagnostic assessment and the choice of tailored therapies [7]. The introduction of liquid biopsy into the diagnostic panel allowed us to better define the disease genetic profile by making use of new sequencing technologies to perform next-generation sequencing [8].…”

Unveiling the immunogenomic landscape of cholangiocarcinoma: Identifying new prognostic markers and therapeutic targets based on CCL5 expression

“…17 However, despite this increased understanding, the prognosis of patients with CCA remains poor, with a median survival of less than 2 years. 18 A promising approach to improving patient outcomes involves the manipulation of the immune system to recognize and eradicate tumor cells, which is a strategy known as immunotherapy. [19][20][21] Immune checkpoints, such as PD-1/PD-L1 and CTLA-4, have been identified as potential therapeutic targets in numerous malignancies, including CCA.…”

“…Moreover, changes in cellular processes, such as DNA repair, cell cycle regulation and epigenetic modifications, have been implicated in CCA tumorigenesis 17 . However, despite this increased understanding, the prognosis of patients with CCA remains poor, with a median survival of less than 2 years 18 …”