Next generation sequencing of circulating tumor DNA for precision medicine in patients with advanced biliary tract cancers

PURPOSE: NGS tissue testing is recommended in advanced biliary tract cancers (aBTC) due to increasing approval of targeted therapies. However, tissue NGS is frequently limited by poor access and insufficient tumor. We exploited ctDNA as an alternative for molecular profiling in aBTC. METHODS: We retrospectively analyzed 10,937 patients with aBTC to characterize the molecular landscape and assess the clinical validity of ctDNA profiling. In a second retrospective cohort of 126 pts from nine Spanish referral centers with available clinical and tumor tissue annotations, paired tissue and ctDNA NGS testing and turnaround time (TAT), were evaluated. Blood samples were analyzed using a comprehensive ctDNA NGS assay (Guardant Health). Genomic alterations (GA) were classified according to ESCAT. RESULTS: In the global cohort, ctDNA-NGS revealed a molecular landscape comparable to tissue-based sequencing, including detection rates of ESCAT actionable GA. Higher ctDNA burden was associated with worse overall survival (27.7 months (95%CI 24.1-33.8) in undetectable ctDNA, 18.5 months (95%CI 16.7-20.2) in low ctDNA burden, and 13.6 months (95%CI 12.5-15.0) in high ctDNA burden; log-rank p< 0.0001). In the independent cohort, ctDNA-NGS was available in 90% of patients versus 50% for tissue NGS. Overall concordance for ESCAT GA was 83%, including 80% for FGFR2 fusions. Median TAT was shorter for ctDNA than tissue (8 vs. 27 days). Survival appeared longer in the small subset receiving ESCAT-matched therapy. CONCLUSIONS: In this retrospective analysis, ctDNA represents a practical alternative to tumor tissue for NGS-based biomarker testing in aBTC, offering improved access and faster results.