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Background Circulating tumor DNA (ctDNA) is a promising biomarker for detecting molecular residual disease (MRD) and recurrence in cancer patients. Here, we investigate the long-term utility of ctDNA-based MRD detection in a real-world cohort of patients with non-small cell lung cancer (NSCLC) who received curative-intent treatment.Methods Longitudinal plasma samples were collected following curative-intent treatment from 33 patients with NSCLC. A personalized, tumor-informed assay (SignateraTM) was used for ctDNA detection and quantification. We compared the recurrence-free survival (RFS) and overall survival (OS) of patients with ctDNA results within 6 months after curative-intent treatment (MRD window) and at any time post-treatment. Clinical follow-up data was collected from January 2018 through May 2025.Results A total of 33 patients were analyzed, including 26 adenocarcinoma and 8 squamous cell carcinoma with one overlapping. 32 (96.7%) had at least one ctDNA sample during the MRD window. Of these 32 patients, 5 (15.6%) were ctDNA(+). Among those, 4 (80.0%) recurred (average 5.6 months, range 3.3-8.1) and all (100.0%) died (average 5.6 months, range 3.2-8.0). Of the 27 ctDNA(-) patients during the MRD window, 3 (11.1%) recurred (average 28.9 months, range 11.9-54.5). One patient developed supraclavicular lymph node metastasis, and two developed pulmonary recurrence, one of whom died at 31.0 months. Among 33 patients with ctDNA results at any time post-treatment, 8 were ctDNA(+) (24.2%). Of those 8 patients, 6 (75.0%) relapsed (average 9.0 months, range 3.3-55.3) and 5 died (average 15.5 months, range 8.9-31.5). Of the 25 patients who were always ctDNA(-), 2 (8.0%) recurred (average 30.7 months, range 19.0-42.4). One developed pulmonary recurrence, and the other developed brain metastasis. Both remain alive. These recurrence and mortality trends were consistent with survival analysis findings, which showed that ctDNA(+) within 6 months and at any time after treatment was associated with increased risk of relapse (p <0.001 and p = 0.0013, respectively) and death (p <0.001 for both) ( figure 1). MRD window ctDNA(+) patients demonstrated inferior RFS (HR: 25.3, 95% CI: 4.3–148.1, p <0.001) and OS (HR: 44.4, 95% CI: 4.7–422.6, p <0.001) compared to ctDNA(-) patients.Conclusions Our extended follow-up demonstrates that longitudinal, tumor-informed ctDNA monitoring is a promising tool in predicting long-term outcomes in patients with NSCLC receiving curative-intent treatment. This highlights the importance of ctDNA as a prognostic marker and its utility in personalized management.Abstract 33 Figure 1ctDNA positivity within 6 months post-treatment was a predictor of inferior (a) PFS and (b) OS. ctDNA positivity at any time post-treatment was associated with worse (c) PFS and (d) OS