DNA damage response and repair gene mutations predict clinical outcomes in biliary tract cancer.

Background: This study aims to explore the genetic characteristics of biliary tract cancer (BTC), with a particular focus on the impact of DNA damage response and repair (DDR) genes on clinical outcomes.

Methods: A total of 180 patients with BTC and next-generation sequencing data were retrospectively analyzed. Clinical outcomes were compared between DDR-positive and DDR-negative groups.

Results: DDR mutations were found in 28.3% of patients, with ATM (7.8%), BAP1 (5.6%), and BRCA2 (3.3%) being the most common. DDR-positive patients receiving first-line platinum-based chemotherapy (n = 73) had a significantly higher objective response rate (50.0% vs. 14.9 %; p = .001), longer median progression-free survival (mPFS) (7.7 vs. 3.8 months; p = .001) and longer median overall survival (28.6 vs. 11.9 months; p < .001). Multivariate analysis confirmed that deleterious DDR gene mutations were independently associated with prolonged mPFS (hazard ratio [HR], 0.37; 95% CI, 0.20-0.67; p < .001) and median overall survival (mOS) (HR, 0.19; 95% CI, 0.08-0.46; p < .001). In 56 patients receiving immunotherapy combined with chemotherapy, DDR-positive patients had a significantly higher overall response rate (45% vs. 8.3%; p = .001), longer mPFS (7.7 vs. 3.8 months; p = .009), and longer mOS (12.7 vs. 8.8 months; p = .011). Multivariate analysis showed that the presence of deleterious DDR gene mutations was associated with significantly longer mPFS (HR, 0.34; 95% CI, 0.16-0.73); p = .005] and mOS (HR, 0.23; 95% CI, 0.08-0.62; p = .004).

Conclusion: Deleterious DDR gene mutations are associated with improved clinical outcomes in patients with BTC treated with platinum-based chemotherapy or immunotherapy combined with chemotherapy.