Prognostic value of circulating tumor DNA in gastric cancer: a systematic review and meta-analysis with emphasis on postoperative molecular residual disease

Abstract Background Despite curative-intent surgery, recurrence remains a major cause of mortality in gastric cancer, while conventional clinicopathological staging provides limited accuracy for postoperative risk stratification. Circulating tumor DNA (ctDNA), a promising biomarker of molecular residual disease (MRD), has emerged as a potential tool for identifying occult residual disease and guiding personalized postoperative management. However, the prognostic value of ctDNA across different clinical contexts and assay strategies remains incompletely defined. Methods A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. PubMed, Embase, and Web of Science were searched for eligible studies published between January 2019 and May 2025. Studies evaluating ctDNA or broader cfDNA-based biomarkers as prognostic markers in gastric cancer and reporting hazard ratios (HRs) for survival outcomes were included. Pooled HRs with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models according to heterogeneity. Prespecified subgroup analyses were performed based on sampling timing, detection strategy, and geographic region. Results Ten studies involving 1,487 patients were included. ctDNA positivity was significantly associated with inferior overall survival (HR = 4.06, 95% CI 2.45–6.74) and disease-free/relapse-free survival (HR = 7.13, 95% CI 3.17–16.01). In exploratory subgroup analysis, postoperative ctDNA assessment showed a larger pooled effect estimate than non-postoperative assessment (HR = 7.13 vs. 2.73, P for subgroup difference = 0.03), although the two subgroups represented different survival endpoints. Tumor-informed sequencing approaches yielded the largest pooled effect size, although no statistically significant difference was observed among detection methodologies. Sensitivity analyses confirmed the robustness of the pooled estimates. Conclusions Postoperative ctDNA is associated with adverse recurrence and survival outcomes in gastric cancer and shows potential as a biomarker for molecular residual disease assessment and postoperative risk stratification. However, substantial heterogeneity and differences in study design, sampling timing, assay methodology, and endpoint composition warrant cautious interpretation of pooled effect estimates.