Clinicopathological characteristics and therapeutic outcomes in patients with non-small cell lung cancer harboring SMARCA4 mutations

Objective To investigate the clinical characteristics and impact of SMARCA4 mutations in patients with non-small cell lung cancer (NSCLC).Methods A total of 2,821 patients with NSCLC who underwent next-generation sequencing were retrospectively included. The frequency and types of SMARCA4 mutations and co-mutations were determined, and the clinical outcomes were assessed.Results SMARCA4 mutations were identified in 100 samples (3.54%), and 36% were missense mutations. The most frequent co-mutations were TP53 (67%) and EGFR (31%); 13% of SMARCA4 mutations occurred in samples carried EGFR and TP53 mutations. Notably, 63% SMARCA4 mutations did not present druggable driver mutations. SMARCA4 mutations were most prevalent in males and smokers. Patients with SMARCA4 mutant lung adenocarcinoma (LUAD) and EGFR mutations who received EGFR-tyrosine kinase inhibitors (EGFR-TKI) as first-line therapy had a lower objective response rate (ORR, 52.94%). In SMARCA4 mutation and EGFR wild-type (wt) NSCLC cohort who received first-line chemotherapy, age (hazard ratio [HR], 3.090; p = 0.026) and performance score (HR, 5.848; p = 0.045) were identified as independent predictors of progression-free survival (PFS). Conversely, brain metastasis was an independent predictor of superior overall survival (HR, 0.188; p = 0.011). The patients with EGFR wt and SMARCA4 mutant Stage IV LUAD who received chemotherapy plus anti-angiogenic therapy significantly improved median PFS compared to chemotherapy alone (p = 0.04).Conclusions SMARCA4 mutations were predominantly males and smokers in NSCLC. SMARCA4 mutations conferred a poorer response for EGFR-mutant LUAD subgroups who received EGFR-TKIs. Additionally, chemotherapy plus anti-angiogenesis as first-line therapy may be more effective for Stage IV-SMARCA4 mutant LUAD with EGFR wt.