Abstract 3249: The development of a tissue-agnostic genome-wide methylome enrichment assay for lung cancer

Abstract Background: Lung cancer remains the leading cause of cancer-related death in the United States. Precision oncology is revolutionizing early-stage non-small cell lung cancer (NSCLC) treatment, showing promising results in improving outcomes. Utilization of molecular residual disease (MRD) testing has the potential to improve outcomes by detecting relapse ahead of clinical presentation. Currently, up to 38% of patients are ineligible for tumor-informed MRD tests due to insufficient tissue, often resulting from risks associated with invasive procedures, small biopsy sizes (e.g., FNAs), low tumor purity, competing demands for tissue (e.g., PD-L1 staining), or complete response to neoadjuvant treatment.1, 2 Herein, we demonstrate the feasibility of a tissue-agnostic genome-wide methylome enrichment platform utilizing cell-free methylated DNA immunoprecipitation followed by high-throughput sequencing (cfMeDIP-seq) for cancer detection, cancer signal quantification, and prognostication in lung cancer. 3, 4 Methods: In this feasibility study, a total of 24 patients (136 samples) with early-stage lung cancers (87.5% Stage I [IA (50%), IB (37.5%), IIA (4.2%) and IIB (8.3%)]); 19 were analyzed based on inclusion/exclusion criteria and assessed for their correlation with recurrence-free survival (RFS). Blood collections for each patient occurred prior to surgery, after surgery and at irregular intervals before recurrence or last clinical follow-up. 5-10 ng of cfDNA isolated from each plasma sample was used for cfMeDIP-seq. The analysis considers multiple MRD tests over a surveillance period following surgery. RFS is compared between groups using a log-rank test. The Hazard Ratio (HR) is estimated using Cox proportional hazards model. Results: With a median follow up duration of 85.6 months, 10 patients experienced recurrence, and 9 patients remained recurrence-free. Patients with a positive MRD test showed significantly worse RFS than those who tested negative (HR 3.58; 95% CI, 1.00, 12.89). The lead time between MRD positivity and clinical recurrence was up to 35.91 months, with a median of 13.08 months. Conclusions: The analysis demonstrates that MRD detection with a tissue-agnostic, genome-wide methylome enrichment platform in patients with lung cancer after curative intent treatment correlates strongly with RFS. References: 1. Khan S, et al. JCO 2024. 2. Aggarwal C, et al. JAMA Oncology 2019.3. Shen SY, et al. Nature 2018 4. Liu G, et al. Annals Oncol 2024 Citation Format: Harvey I. Pass, Collin A. Melton, Shu Yi Shen, Ben Brown, Justin M. Burgener, Junjun Zhang, Yarong Wang, Jun Min, Owen Hall, Karan Budhraja, Abel Licon, Alan Williams, Scott V. Bratman, Brian A. Allen, Jing Zhang, Daniel D. De Carvalho, Anne-Renee Hartman. The development of a tissue-agnostic genome-wide methylome enrichment assay for lung cancer [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 3249.