Abstract 2047: Homologous recombination deficiency in lung cancer in the INSPIRE study

Abstract Introduction: Evaluating genomic signatures may improve prognostic information and outcomes for patients with lung cancer. Objective: To determine if homologous recombination deficiency (HRD) is associated with clinical features or overall survival in patients with lung cancer. Methods: This is a retrospective cohort study derived from City of Hope’s Implementing Next-Generation Sequencing for Precision Intervention and Risk Evaluation (INSPIRE) study. Study participants with histologically confirmed lung cancer and adequate tissue for comprehensive paired tumor-normal whole exome sequencing were eligible for analysis. 197 patients were sequenced, excluding 14 with rare histologies. Clinical and treatment variables were obtained from cancer registries and the electronic medical record and were recorded by experienced data curation and abstraction specialists. HRD scores were calculated using the scarHRD R package. Mutational signatures were analyzed using SigProfiler and SigEstimation. Associations between clinical variables and HRD status were measured using univariate and multivariate methods. Unsupervised analysis was performed to identify genes in HRD-high (sum score greater than or equal to 42) and HRD-low samples (sum score less than 42). Overall survival was quantified using non-parametric Kaplan-Meier statistics and multivariate Cox-proportional hazards models. Results: Of the 183 lung cancer samples analyzed, 63 (34.4%) samples were HRD-high. Of these, 43 had a TP53 alteration and 20 did not; 120 (65.6%) samples were HRD-low, 50 with a TP53 alteration and 70 without (OR 3.01 (95%CI 1.58, 5.72), p=0.0008). Conclusion: TP53 alterations were strongly associated with high HRD scores. Overall survival was improved in patients with HRD-high tumors treated with platinum therapy, although this difference did not reach statistical significance. Citation Format: Katherine G. Roth, Kevin J. McDonnell, Ernest Nadal, Joseph D. Bonner, Arman Seuylemezian, Suravi Nahar, Lawrence Shaktah, Jonathan Salazar, Sidney Lindsey, Xiaoyu Xia, Sara A. Byron, Jonathan J. Keats, Allen Mao, Adrien Larsen, Bryce Turner, Ravi Salgia, Stacy W. Gray, Stephen B. Gruber. Homologous recombination deficiency in lung cancer in the INSPIRE study [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 2047.