Utilization of Circulating Tumor DNA Testing in Biliary Tract Cancers

Background: Circulating tumor DNA is a promising biomarker for molecular residual disease and recurrence surveillance in biliary tract cancers. We evaluated the association between postoperative tumor-informed ctDNA and recurrence-free survival (RFS) and assessed the performance of initial and longitudinal ctDNA surveillance. Methods: We performed a single-institution retrospective cohort study of 51 patients with resected non-metastatic biliary tract cancers who underwent postoperative ctDNA testing. Kaplan–Meier, log-rank, univariable Cox regression, and limited multivariable Cox regression analyses were used to evaluate associations between ctDNA status and RFS. A 3-month landmark sensitivity analysis was performed to address time-related bias. Results: Twenty-five patients (49.0%) developed recurrence. Recurrence occurred in 18 of 20 patients (90.0%) with postoperative ctDNA positivity compared with 7 of 31 patients (22.6%) without ctDNA positivity. Median RFS was 10.8 versus 47.4 months, respectively. Postoperative ctDNA positivity was associated with shorter RFS (HR, 7.85; 95% CI, 3.03–20.29; p < 0.001). In a pre-specified multivariable Cox model adjusting for stage III/IV disease and CA 19-9 > 37 U/mL, postoperative ctDNA positivity remained associated with shorter RFS (adjusted HR, 5.09; 95% CI, 1.82–14.26; p = 0.002). Longitudinal ctDNA surveillance demonstrated a sensitivity of 72.0%, specificity of 92.3%, PPV of 90.0%, and NPV of 77.4% for recurrence. Median lead time to recurrence was 69.5 days. In a 3-month landmark cohort of 37 evaluable patients, postoperative ctDNA positivity was associated with shorter subsequent RFS after exploratory adjustment for stage and CA 19-9 (adjusted HR, 6.45; 95% CI, 1.47–28.34; p = 0.014). Conclusions: Postoperative ctDNA positivity was associated with recurrence and shorter RFS. Longitudinal ctDNA surveillance improved recurrence detection and frequently preceded clinically documented recurrence.