Precision Oncology in Cholangiocarcinoma: Two Fusion-Positive Case Reports and a Literature Review

Background and Clinical Significance: Cholangiocarcinoma (CCA) is molecularly heterogeneous, and the expanding number of actionable alterations has made comprehensive molecular profiling central to the management of advanced disease. This report presents two rare fusion-positive cases and reviews the molecular landscape, biomarker-directed therapies, resistance mechanisms, and clinically applicable sequencing strategies in CCA. Case Presentation: The first patient was a 63-year-old woman with metastatic biliary tract adenocarcinoma who experienced progression after multiple systemic therapies. Next-generation sequencing identified an NTRK1 fusion, and larotrectinib produced rapid metabolic regression, improvement in Eastern Cooperative Oncology Group performance status from 2 to 0, and durable disease control through June 2025. The second patient was a 29-year-old man with intrahepatic cholangiocarcinoma and primary resistance to gemcitabine–cisplatin. Detection of a RET fusion enabled treatment with selpercatinib, resulting in complete metabolic response and 19 months of disease control. At hepatic oligoprogression, thermal ablation permitted continuation of selpercatinib before subsequent progression. Conclusions: These cases demonstrate that rare NTRK1 and RET fusions can be clinically decisive in CCA. Routine DNA- and RNA-based molecular profiling, longitudinal reassessment, and multidisciplinary management may expand therapeutic opportunities and support individualized treatment beyond conventional histology-based pathways.