Clinical utility of liquid biopsy in biliary tract cancer: Diagnosis to treatment monitoring

Biliary tract cancer (BTC) represents a formidable clinical challenge characterized by extensive genomic heterogeneity and a poor prognosis, primarily due to advanced stage diagnosis. Although systemic therapies, including chemotherapy, targeted therapies, and immune checkpoint inhibitors, have become the standard of care, their efficacy remains modest, and subsequent treatment options are limited. BTC management is further complicated by the inherent difficulty of obtaining high-quality tissue biopsies, impeding timely genomic profiling and subsequent therapeutic decision-making. Liquid biopsy has emerged as a minimally invasive alternative, facilitating comprehensive tumor characterization through circulating tumor cells, cell-free DNA, RNA, and proteins. These approaches hold promise for early detection, assessment of minimal residual disease, identification of actionable targets, and real-time monitoring of treatment response and resistance, thereby supporting precision oncology. Despite technical challenges such as limited sensitivity for structural variations, variability across platforms, and the need for standardized validation, liquid biopsy offers transformative potential in BTC. This review discusses current strategies, clinical applications, and future directions for integrating liquid biopsy into routine practice to improve survival and quality of life in patients with BTC.