Abstract 3263: Assessing molecular residual disease via early postoperative plasma circulating tumor DNA for recurrence risk evaluation in non-small cell lung cancer following radical resection

Abstract Background: The significant risk of tumor relapse in resectable non-small cell lung cancer (NSCLC) highlights the need for biomarkers to identify patients at increased risk of recurrence and inform personalized treatment. Investigating the potential of plasma-derived circulating tumor DNA (ctDNA) for molecular residual disease (MRD) detection and prognosis is essential, particularly in the context of lung cancer risk variations. Xuanwei, a city in Yunnan province, China, provides a valuable model for exploring molecular features related to lung cancer susceptibility. Methods: This study included 226 stage I-III NSCLC patients who received radical tumor resection. Paired surgical tumor and postoperative plasma samples within 3-7 days (median: 4.5 days, interquartile range: 4.0-6.0 days) were analyzed to evaluate post-surgical ctDNA detection and its association with disease-free survival (DFS) and overall survival (OS) using a tumor-informed method. Results: Among the 226 patients with surgically resectable NSCLC, 31 were from the Xuanwei region, exhibiting a higher incidence of multifocal lesions (P<0.01) and elevated tumor mutation burden (P<0.001). Subgroup analysis revealed that Xuanwei patients had a higher prevalence of uncommon EGFR mutations (P<0.001 and P<0.01 for p.G719X and p.S768I, respectively), as well as mutations in oncogenes and tumor suppressor genes, including KRAS (P<0.001), LRP1B (P<0.01), MED12 (P<0.01), and PIK3CA (P=0.03). Detectable ctDNA demonstrated high specificity for predicting tumor relapse (0.96; 95% confidence interval [CI]: 0.92-0.98), with specificity increased to 0.97 (95% CI: 0.94-0.99) in stage I patients and 0.73 (95% CI: 0.39-0.94) in stage II-III patients. While sensitivity was relatively lower, it still reached 0.67 (95% CI: 0.49-0.81) in the overall population, with 0.38 (95% CI: 0.14-0.68) for stage I and 0.83 (95% CI: 0.61-0.95) for stage II-III patients. Multivariate Cox regression analysis, incorporating clinical and mutational features with a mutation frequency of ≥ 5%, revealed that post-surgical MRD status was significantly associated with DFS independent of clinical stage and RB1 variants, and served as the most significant predictor among all these clinicopathological risk factors (hazard ratio [HR]: 9.25; 95% CI: 3.57-24.00; P<0.001). Detectable ctDNA also effectively stratified OS in subgroups, including patients above 60 years of age and those with stage II-III disease. Conclusions: Our findings reinforce the clinical significance of evaluating ctDNA status within one-week post-surgery for detecting MRD, thereby informing precise individualized treatment and surveillance strategies for NSCLC patients. Citation Format: Jie Tang,Yingsong Tian,Song Wang,Yong Liu,Manjun Chen,Xudong Yang,Xinghe Tong,Mengtian Wang,Yunping Zhao,Jiaohui Pang,Qiuxiang Ou,Haimeng Tang,Xiaobo Chen. Assessing molecular residual disease via early postoperative plasma circulating tumor DNA for recurrence risk evaluation in non-small cell lung cancer following radical resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3263.