Abstract 1251: Decoding tumour evolution and relapse drivers in EGFR mutant NSCLC in never smokers

Abstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Unlike smoking-related NSCLC, the incidence of lung cancer among never-smokers in East Asia is rising, often driven by oncogenes such as EGFR. While Tyrosine Kinase Inhibitors (TKIs) have improved outcomes in EGFR-mutated NSCLC, resistance remains a significant challenge. Identifying the genomic and transcriptomic features that underpin tumour progression and relapse in early-stage EGFR-mutated NSCLC in non-smokers is crucial for developing novel therapeutic approaches to improve patient outcomes. Due to the diverse evolutionary trajectories of EGFR mutated NSCLC, our capacity to forecast disease trajectory is still limited. To address this, we performed 578 multi-region whole-exome and transcriptome sequencing from 180 treatment naïve early-stage EGFR-mutated resected NSCLC tumours. Among these, 56 (31%) patients eventually relapsed, while 124 (69%) did not, with a mean follow-up of 5.4 years. Our findings revealed that driver mutations in EGFR, TP53, and RBM10 were predominantly clonal, while a multitude of subclonal driver mutations contributed to increased tumour diversity. Interestingly, mutational signature SBS40a, of unknown origin, was prevalent as clonal alterations, suggesting early involvement in EGFR-mutated tumours. Notably, relapsed tumours exhibited distinct genomic features, including elevated subclonal APOBEC mutational signatures, higher rates of whole-genome doubling, and increased chromosomal aberrations, linking these features to greater mutational burden, intra-tumour heterogeneity and poorer outcomes. Overall, our results demonstrate the diversity of clonal and subclonal mutational processes that shape the clonal architecture of EGFR-mutated NSCLC in non-smokers and identify key features driving relapse. Ongoing efforts are focused on leveraging these features to identify potential prognostic markers for risk stratification and therapeutic targets for early-stage disease. Citation Format: Komal Gupta, Dawn Lau Pingxi, Ngak Leng Sim, Kenneth Chow, Lan Ying Wang, Mengyuan Pang, Stephanie Saw, Wanjin Hong, Anders Martin Jacobsen Skanderup, Regina Hoo, Daniel Shao Weng Tan. Decoding tumour evolution and relapse drivers in EGFR mutant NSCLC in never smokers [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 1251.