Clinical and molecular features of concomitant EGFR and SMARCA4 mutations in an East Asian cohort.

Abstract

e20645 Background: SMARCA4 is a subunit of the SWI/SNF complex and is frequently mutated in non-small cell lung cancer (NSCLC). Recent studies have identified SMARCA4 mutation as a poor prognostic factor in KRAS-mutant NSCLC. Preclinical research suggests that SMARCA4 may also contribute to resistance against EGFR tyrosine kinase inhibitors (TKIs). Traditionally, these mutations are thought to be mutually exclusive. However, there is a small amount of data on co-occurrence of SMARCA4 and EGFR mutation in NSCLC, although most supporting evidence is derived from Western populations. The tumor mutational landscape of Asian NSCLC patient differs drastically from western patients. Our study represents the first to focus on concurrent EGFR and SMARCA4 mutations within a Taiwanese cohort, where EGFR mutations are highly prevalent. Methods: We retrospectively analyzed medical records from a single tertiary medical center in Taiwan. Patients with stage IV NSCLC and available next-generation sequencing data from 2019 to 2024 were included. We evaluated patients with SMARCA4 mutations, clinical presentations, tumor pathology, molecular profiles, concomitant mutations, and treatment outcomes. Results: A total of 452 patients with documented NGS reports were included, of whom 42 (9.29%) harbored SMARCA4 mutations. Among the SMARCA4-mutant NSCLC cases, 9 patients (1.99%) exhibited concomitant EGFR mutations. We also investigated the concomitant mutations from a cohort of early-stage, non-smoker NSCLC in Taiwan (Chen, Y. J., et al. (2020)). Of all the 103 patients, three reported SMARCA4 and EGFR co-mutations (2.91%). Compared with SMARCA4-mutant NSCLC cases without EGFR co-mutations, the co-mutant cohort was predominantly female and composed of never-smokers (p<0.001). Most SMARCA4 mutations were class 2 (missense mutations, 88.9%). None of these co-mutation cases had coexisting mutations in KEAP1 or STK11. We plotted all the mutation hotspots on the lollipop diagram of the SMARCA4 gene. The figure indicated that SMARCA4 mutations cluster near 2 regions: one region clustering around the helicase domain, and another region clustering near the QLO domain. The median PFS with first-line TKI treatment in the co-mutant cohort was 8.5 months (95% CI: 3.0–14.1 months). Median OS was significantly longer for patients with druggable driver SMARCA4-mutant NSCLC than those without druggable mutations (53.0 vs. 11.4 months, p=0.035). Conclusions: Concomitant EGFR and SMARCA4 mutations were observed in 1.99% of this Taiwanese, East Asian cohort. Preliminary data indicated the trend with inferior outcome to first-line TKI, suggesting a mechanical role for SMARCA4 in this group of patients. Overall, the role of SMARCA4 mutations in EGFR-mutant NSCLC remains unclear, warranting further basic and clinical investigations.