Background Growing evidence supports the prognostic and predictive value of circulating tumor DNA (ctDNA) in gastrointestinal cancers. This study evaluated ctDNA as a prognostic biomarker for detecting molecular residual disease (MRD) and recurrence in patients with resected biliary tract cancer (BTC). Materials and methods We retrospectively analyzed real-world data from patients ( N = 167) with stage I-III resectable BTC who underwent ctDNA analysis using a personalized, tumor-informed 16-plex multiplex PCR-coupled next-generation sequencing assay (Signatera TM ; Natera, Inc., Austin, TX) between July 2020 and February 2024. Plasma samples ( n = 751) were collected preoperatively, postsurgically (2-12 weeks; MRD window), and longitudinally (postdefinitive treatment surveillance). ctDNA results were compared with traditional biomarkers carbohydrate antigen 19-9 and carcinoembryonic antigen. Results The median follow-up was 21 months (range 2-97). ctDNA detection rates during MRD and postdefinitive treatment surveillance windows were 23% (19 of 82) and 38% (31 of 82), respectively. ctDNA positivity during MRD and postdefinitive treatment surveillance was significantly associated with inferior relapse-free survival (RFS) and overall survival (OS). ctDNA positivity was the most significant prognostic factor associated with RFS during the MRD window hazard ratio (HR) 15.86, 95% CI 4.69-53.6, P < 0.001 and during postdefinitive treatment surveillance (HR 14.93, 95% CI 5.33-41.9, P < 0.001) by multivariate analysis. In contrast, carbohydrate antigen 19-9 and carcinoembryonic antigen were not significantly prognostic in either setting. Conclusions Patients with ctDNA positivity during the MRD and postdefinitive treatment surveillance windows demonstrated significantly inferior RFS and OS, and ctDNA was more accurate than current clinical biomarkers. These findings highlight the value of ctDNA monitoring in improving prognostication in BTC, with the potential to enhance post-operative risk stratification and inform surveillance strategies through earlier detection of recurrence.
Malla et al. (2026) studied this question.