49P Perioperative circulating tumor DNA redefines induced oligometastatic non-small cell lung cancer at the molecular level

Substantial heterogeneity exists in the benefits from local treatments for oligometastatic non-small cell lung cancer (NSCLC). We propose that circulating tumor DNA (ctDNA) can molecularly redefine populations with induced oligopersistence disease and those more likely to benefit from surgery in NSCLC. In this prospective, observational study, we enrolled patients with oligometastatic NSCLC identified through 18F-FDG-PET/CT following systemic therapy. Patients underwent resection targeting residual lesions. Comprehensive ctDNA monitoring was conducted perioperatively. Tumor tissues were pathologically assessed per the IASLC multidisciplinary recommendations for neoadjuvant therapy assessment, and multi-region sampling and whole-exome sequencing (WES) were performed. A total of 68 patients with induced oligometastases were enrolled, predominantly with adenocarcinoma (n=63, 92.6%), EGFR mutations (n=44, 64.7%), and oligopersistence (n=58, 85.3%). Patients who achieved major pathological response had better prognosis compared to those who did not (HR=4.57, 95% CI 2.16-9.65, p<0.05). Patients with preoperative ctDNA negative status had significantly better outcomes than those with positive status (HR=3.42, 95% CI 1.19-9.87, p=0.001). Patients who maintained or transitioned to negative ctDNA 1 month after surgery exhibited better outcomes than those who maintained or transitioned to positive ctDNA (maintaining negative vs. transition to positive: HR=3.22, p=0.041; transition to negative vs. maintaining positive HR=4.57, p=0.03). Thus, patients who maintained or transitioned to ctDNA negative status may represent a subgroup with molecular-level oligometastases who were more likely to benefit from surgery. Moreover, WES of tumors revealed resistant clones to systemic therapy in a subset of patients, emphasizing the importance of surgery. Collectively, patients without acquired resistance mutations detected in tumor tissue had a better prognosis than those with detection (HR=3.67, 95% CI 0.92-14.7, p=0.006). We redefine oligopersistence disease and identify a pre-respondent subgroup more likely to benefit from surgery in NSCLC through ctDNA at the molecular level.