Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments

Abstract

Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.

Cholangiocarcinoma Insights: Established Foundations and Cutting-Edge Innovations from Dr. James Cleary’s Pioneering Research

“…One of the most prevalent actionable immunohistochemistry (IHC) mutations is the FGFR alteration [1,13]. Upon protein dimerization activation, FGFR initiates cascades of signaling pathways, including PI3K-AKT or RAS-MAPK pathways, regulating tissue development and repair [14,15]. Various mutations in FGFR, such as amplifications, rearrangements, mutations, fusions, and indels, are implicated in carcinogenesis [12,16].…”

“…Various mutations in FGFR, such as amplifications, rearrangements, mutations, fusions, and indels, are implicated in carcinogenesis [12,16]. These mutations induce FGFR protein dimerization, leading to heightened signaling that prompts cell proliferation, angiogenesis, and immune escape [14].…”

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma

“…Alterations in genes that are related to the control of DNA damage response (DDR) and cell cycle regulation are also frequent in all CCA subtypes. Mutations of BAP1, PTEN, and PBRM1 are predominantly found in iCCA, whereas mutations of TP53, ARID1A, CDKN2A, CHK1/2, ATM, ATR, and BRCA occur in all CCA subtypes [103][104][105]. DDR pathways encompass a network of signaling cascades and effector mechanisms that maintain genomic integrity and ensure proper cellular responses to DNA damage.…”

“…Prevalence of druggable targets in CCA[103][104][105].Currently planned, initiated, and recruiting clinical studies on the specific molecular targets are listed in their respective sections (see Sections 4.2-4 19…”