AbstractBackgroundCirculating tumor DNA (ctDNA) is a promising biomarker for predicting relapse in multiple solid cancers. However, the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer (GC). Here, we aimed to evaluate the predictive value of ctDNA in this context.MethodsFrom 2016 to 2019, 100 patients with stage II/III resectable GC were recruited in this prospective cohort study (NCT02887612). Primary tumors were collected during surgical resection, and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer‐related genes. The plasma was defined as ctDNA‐positive only if one or more variants detected in the plasma were presented in at least 2% of the primary tumors.ResultsCompared with ctDNA‐negative patients, patients with positive postoperative ctDNA had moderately higher risk of recurrence [hazard ratio (HR) = 2.74, 95% confidence interval (CI) = 1.37–5.48; P = 0.003], while patients with positive post‐ACT ctDNA showed remarkably higher risk (HR = 14.99, 95% CI = 3.08‐72.96; P < 0.001). Multivariate analyses indicated that both postoperative and post‐ACT ctDNA positivity were independent predictors of recurrence‐free survival (RFS). Moreover, post‐ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and serial cancer antigen. A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C‐index (0.78; 95% CI = 0.71–0.84) than the model without ctDNA (0.71; 95% CI = 0.64–0.79; P = 0.009).ConclusionsResidual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC, and the combination of tissue‐based and circulating tumor features could achieve better risk prediction.