Abstract
BACKGROUND: Biliary tract cancer (BTC) is an aggressive malignancy often diagnosed at an advanced stage and is associated with a poor prognosis. Non-invasive approaches can facilitate the early detection and identification of biomarkers to inform treatment strategies. Liquid biopsy, particularly through the analysis of circulating tumor DNA (ctDNA), has recently emerged as a valuable clinical and prognostic tool for guiding BTC management. METHODS: The PubMed, Cochrane Library, and Wiley databases were searched for terms related to BTC and ctDNA, aiming to include studies evaluating the value of ctDNA as a predictor of overall (OS), progression-free (PFS), disease (DFS), and recurrence-free survival (RFS). RESULTS: Twelve studies encompassing 2374 patients were considered eligible. The detection of ctDNA was associated with higher mortality and progression risk (HR 2.61, 95%CI 2.19-3.11 and HR 2.69, 95%CI 1.82-3.98, respectively), regardless of the ctDNA sampling time. The variant allele frequency (VAF) emerged as a valuable predictive marker, with higher VAF values being associated with higher mortality and progression risk (HR 2.37, 95%CI 1.83-3.06, and HR 2.22, 95%CI 1.40-3.53, respectively) compared with low levels of VAF. This association was observed regardless of chemotherapy administration, suggesting that VAF may serve as a potential marker of treatment resistance. CONCLUSIONS: This review underscores the clinical relevance of ctDNA status and related markers, such as VAF, in the management and prognostic evaluation of BTC. The findings support the integration of liquid biopsy into clinical practice to improve risk stratification, enable the early detection of relapse, and inform personalized treatment strategies, ultimately contributing to more precise and effective patient care in BTC.