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PurposeCirculating tumor DNA (ctDNA) analyses allow for postoperative risk stratification in patients with curatively treated colon and breast cancers. Use of ctDNA in esophagogastric cancers (EGC) is less characterized and could identify high-risk patients who have been treated with curative intent.MethodsIn this retrospective analysis of real-world data, ctDNA levels were analyzed in the preoperative, postoperative, and surveillance settings in patients with EGC using a personalized multiplex polymerase chain reaction-based next-generation sequencing assay. Plasma samples (n = 943) from 295 patients at > 70 institutions were collected before surgery, postoperatively, and/or serially during routine clinical follow-up from September 19, 2019, to February 21, 2022. ctDNA detection was annotated to clinicopathologic features and recurrence-free survival.ResultsA total of 295 patients with EGC were analyzed, and 212 patients with stages I-III disease were further explored. Pretreatment ctDNA was detected in 96% (23/24) of patients with preoperative time points. Postoperative ctDNA was detected in 23.5% (16/68) of patients with stage I-III EGC within 16 weeks (molecular residual disease window) after surgery without receiving systemic therapy. ctDNA detection at any time point after surgery (hazard ratio [HR], 23.6; 95% CI, 10.2 to 66.0; P < .0001), within the molecular residual disease window (HR, 10.7; 95% CI, 4.3 to 29.3; P < .0001), and during the surveillance period (HR, 17.7; 95% CI, 7.3 to 50.7; P < .0001) was associated with shorter recurrence-free survival. In multivariable analysis, ctDNA status and clinical stage of disease were independently associated with outcomes.ConclusionUsing real-world data, we demonstrate that postoperative tumor-informed ctDNA detection in EGC is feasible and allows for enhanced patient risk stratification and prognostication during curative-intent therapy.