Genetic analysis in the clinical management of biliary tract cancer

Abstract

Biliary tract cancer (BTC) is clinically and pathologically heterogeneous and responds inadequately to treatment. A small section of patients develop resectable disease, although the relapse rates are high; the benefits of adjuvant capecitabine chemotherapy for BTC are now understood, and gemcitabine‐based combination chemotherapy is the first line of therapeutic strategy for BTC; however, alternative therapy for BTC is not known. Genomic profiling can provide detailed information regarding the carcinogenesis, identification, and therapy for BTC. Currently, confirmed restorative targets for BTC are lacking. In this review, we aimed to analyze the preclinical and clinical implications of a spectrum of genomic alterations associated with new potentially remedial targets. We focused on eight draggable genes for BTC, which were described as having evidence of therapeutic impact (evidence level 2A‐3B) based on the clinical practice guidance for next‐generation sequencing in cancer diagnosis and treatment; these include ERBB2, NTRK1, RNF43, CDK6, CDKN2B, FGFR2, IDH1, and IDH2. Moreover, some of the BTC present microsatellite instability, hypermutation, and germline variants, which we also reviewed. Finally, we discussed the therapeutic options based on the next‐generation sequencing findings in BTC. Studies have demonstrated that BTC includes subgroups with individually distinct driver mutations, most of which will be targeted with new treatment plans.

Clinical outcomes of second‑line chemotherapy after gemcitabine and cisplatin plus S‑1 treatment for patients with advanced biliary tract cancer in the KHBO1401‑3A study

“…Recently, the development of genomic sequencing in BTC has rapidly progressed, and favorable treatment effects of molecular targeting agents, such as isocitrate dehydrogenase-1 inhibitors and fibroblast growth factor receptor inhibitors, in BTC, have been reported (17)(18)(19). Furthermore, the development of immune checkpoint inhibitors is promising, and for tumors with high microsatellite instability, pembrolizumab can be administered for multiple cancer types in various organs, including BTC (20).…”

Role of molecular genetics in the clinical management of cholangiocarcinoma

“…KRAS mutations occur in ∼9%-40% of CCAs, 83 with some of these being KRAS G12C mutations. The phase I/II KRYSTAL-1 study examined the use of adagrasib, a KRAS G12C inhibitor, in patients with advanced solid tumors harboring a KRAS G12C mutation.…”

Advanced Bile Duct Cancers: A Focused Review on Current and Emerging Systemic Treatments

“…Despite approval for use in patients with >10 mut/mb, much debate exists around tumor mutational burden (TMB) and its use as a predictor of response to immunotherapy. Genomic assessment of 412 BTC revealed that 11% had germline mutations in genes associated with the development of a high tumor mutational burden (RAD51D, MLH1, MSH2, POLD1, POLE and ATM), making it an attractive biomarker to assess [ 31 ]. In other disease subtypes, however, when MSI-high is excluded from the analysis of patients with high-TMB, its predictive value appears to be limited [ 32 ].…”