Investigation of the role of personalized molecular residual disease in the assessment of high-risk non-small cell lung cancer (NSCLC) post-operation.

8027 Background: Radical surgical resection is preferred treatment for early-stage Non-Small Cell Lung Cancer (NSCLC) patients. Despite this, recurrence and metastasis significantly impact patient survival. High-risk factors like Tumor Thrombus (TT) and Spread Through Air Spaces (STAS) are known to exacerbnate the recurrence and metastasis rates, yet there is lacking research exploring the association between these riskes and treatment outcomes. The study aims to evaluate the utility of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) in assessing and monitoring high-risk NSCLC post-operatively. Methods: NSCLC patients underwent curative surgery (R0) were recruited in this study and their tissue samples were collected after surgical resection. Whole exome sequencing (WES) was performed to identify somatic mutation information across individual, from which bespke molecular residual disease (MRD) detection panel was designed and used in later detection. Plasma samples were collected 3-4 weeks post-surgery and analyzed for MRD status through using next-generation sequencing (NGS) at 100,000x sequencing depths. Results: The study enrolled 124 NSCLC patients with a median age of 60 years (ranged 29-86)., The cohort comprised 63 male (77.3%) and 61 females (22.7%). Pathologically, 92 patients were classified in stage I, 5 as stage II, 17 as stage III, and 10 as stage IV. A total of 10,260 somatic mutationwere identified across 6,315 genes, including 639 insertions/deletions (InDels), 9613 single nucleotide variants (SNVs), and 8 gene fusions. The most prevalent mutations were EGFR (58.87%), followed by TTN (45.97%), TP53 (40.32%), CEP192 (20.97%), XIRP2 (19.35%), ZFHX4 (19.35%), and TOPAZ1 (16.94%). The MRD positivity was observed in 29.0% (36/124) of patients, with a higher incidence in males (34.9%, 22/63) than females (22.9%, 14/61). By stage, MRD positivity was 16.3% (16/92) in stage I, 40.0% (2/5) in stage II, 47.0% (8/17) in stage III, and 100% (10/10) in stage IV patients. Among patients with risk factors, 31.6% (12/38) with STAS, , 60.0% (6/10) with TT, and 53.8% (7/13) with pleural invasion were MRD positive, which indicating a higher postoperative MRD positivity in high-risk groups. Conclusions: NSCLC patients with high-risk factors, such as STAS and TT, , exhibit a high rate postoperative MRD positivity, even after R0 resection. Current research reports indicate that the MRD post-operation is an indicator of recurrence, metastasis, and poor prognosis. The findings imply that NSCLC patients harboring these high-risk factors are more susceptible to recurrence and metastasis, possibly necessitating postoperative adjuvant therapy for effective management.