Circulating Tumor DNA in Cholangiocarcinoma: A Precision Oncology Roadmap

Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with a rising global incidence and few therapeutic options for advanced disease. In recent decades, precision oncology for CCA has advanced rapidly, particularly through the development of targeted therapies for patients with actionable genetic alterations. These therapies have markedly prolonged survival and improved other clinical outcomes among patients with unresectable, advanced CCA. The implementation of precision oncology largely depends on detecting genetic mutations to guide patient selection and treatment, using tumor tissue biopsies or liquid biopsies, including circulating tumor DNA (ctDNA) from blood or bile. As a minimally invasive biomarker, ctDNA shows great promise for transforming the clinical management of CCA. This review provides a comprehensive overview of the roles of ctDNA in CCA, including early detection, prognostic stratification, minimal residual disease assessment, recurrence monitoring, therapeutic target identification, and treatment response evaluation. A synthesis of existing studies indicates that bile-derived ctDNA shows superior sensitivity compared with blood-based ctDNA in capturing the genetic profiles and heterogeneity of CCA. We also propose an integrative framework that illustrates how ctDNA profiling can inform diagnosis, treatment, and surveillance across the disease continuum. Because research on ctDNA in CCA remains in its infancy, we discuss current challenges and outline future directions for translating these findings into clinical practice. Collectively, the evidence positions ctDNA-particularly bile-derived ctDNA-as a dynamic tool for real-time genomic profiling, sensitive residual disease detection, and therapy monitoring. This integrative framework provides a roadmap for translating these capabilities into clinical practice, with the potential to enable earlier, more personalized interventions and improve outcomes for patients with CCA.