Circulating tumor DNA and prognosis in gastric cancer patients undergoing surgery: meta-analysis and trial sequential analysis

Background: Circulating tumor DNA (ctDNA) is a promising biomarker for monitoring minimal residual disease (MRD) and recurrence risk in gastric cancer. Prior meta-analyses were limited by heterogeneous cohorts, inconsistent HR extraction, and lack of trial sequential analysis (TSA). This study provides an updated, methodologically rigorous synthesis focusing exclusively on resectable gastric cancer. Methods: A systematic search of four major databases was performed to May 2025 (PROSPERO: CRD42025107578). Eligible studies included surgically treated gastric cancer patients with perioperative ctDNA assessment and reported hazard ratios (HRs) for overall survival (OS) or disease-free survival (DFS). Multivariate Cox HRs were prioritized, with one HR extracted per time window to ensure independence. Random-effects models, subgroup and sensitivity analyses, and publication bias assessments were conducted in R 4.5.0. TSA used O'Brien-Fleming monitoring boundaries to evaluate evidence sufficiency. Results: Twenty-five studies (60 datasets) were included. ctDNA positivity was associated with significantly worse OS (HR = 2.31, 95% CI 1.78-3.00) and DFS (HR = 2.36, 95% CI 1.69-3.29). Subgroup analyses showed consistent effects across detection platforms, sample sources, regions, and stages. Post-operative ctDNA demonstrated stronger prognostic value than pre-operative measurements for both OS (HR = 3.47 vs. 1.99) and DFS (HR = 4.14 vs. 1.97). Results were robust in sensitivity analyses. Publication bias was present for OS but did not materially alter pooled estimates. TSA showed that cumulative Z-curves crossed the O'Brien-Fleming boundaries and met or exceeded the required information size. Conclusion: ctDNA positivity reliably predicts poorer postoperative survival in resectable gastric cancer, with post-operative ctDNA providing the strongest prognostic signal. TSA confirms that current evidence is sufficiently conclusive to support clinical relevance. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42025107578.