Prognostic significance of preoperational circulating tumor DNA detection in early-stage NSCLC using a tissue-free blood test.

3045 Background: There is a growing need for risk evaluation and treatment monitoring in cancer care. However, current methods, mainly imaging, can be burdensome for patients over time and prone to variability among readers. Recent research has highlighted the potential of tumor-informed circulating tumor DNA (ctDNA) testing for identifying postoperative minimal residual disease (MRD) due to its high sensitivity by tracking individualized mutations. Nevertheless, its use in early-stage patients prior to surgery is constrained by limited tissue availability and extended turnaround times. MUSETALK-Lung01 (multiomics sequencing technique application kick-start) is a prospective, longitudinal, observational study designed to evaluate the clinical utility of a tumor-naïve ctDNA assay in patients with early-stage non-small cell lung cancer (NSCLC). Methods: Pretreatment plasma samples were prospectively collected from participants with stage I-IIIA NSCLC. Cell-free DNA was extracted and analyzed using a blood assay that interrogates both epigenetic and genetic information. The detection status and the estimated fraction of ctDNA were reported by a machine learning classifier and an independent statistical model, respectively. The calling threshold corresponding to a 99% clinical specificity was verified in a subgroup from the THUNDER study (NCT04820868). Longitudinal data, including vital status, cancer status, and treatment, were collected for up to 5 years. The study was approved by the institutional review board and all participants were required to provide informed consent. Results: A total of 289 participants from the MUSETALK-Lung01 study were analyzed. Of these, 49% (141/289) reached the 5-year follow-up, with a median follow-up duration of 59 months. To assess the prognostic value of preoperative ctDNA levels, relapse-free survival (RFS) and overall survival (OS) were evaluated across different stages and pathological subtypes separately. In stage I LUAD patients (N = 179), ctDNA-positive patients (N = 20) had significantly inferior RFS compared to ctDNA-negative patients (2-year RFS: 70% [95% CI: 46%–88%] vs. 94% [95% CI: 90%–97%]; log-rank p < 0.001). In contrast, no association was found between preoperative ctDNA detection and RFS in stage II-IIIA LUAD or non-LUAD NSCLC, irrespective of the clinical stage. Specifically, among the 179 stage I LUAD patients, 11 relapsed within 2 years, and 6 of these had positive ctDNA test results. This rate was significantly higher than in patients who relapsed between 2 and 5 years (1/12) or never relapsed (13/156; χ 2 test, p < 0.001). Conclusions: These findings indicate that presurgical ctDNA can serve as a prognostic indicator in early-stage NSCLC. Tumor-naive ctDNA testing may enhance the standard workflow by identifying high-risk patients who could benefit from innovative treatments. Clinical trial information: NCT04820868 .