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

To investigate the clinical characteristics and impact of SMARCA4 mutations in patients with non-small cell lung cancer (NSCLC). 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. 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). 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. SMARCA4 mutations predominantly occur in males and smokers with NSCLC.Age, PS, and brain metastasis are independent prognostic factors for patients with SMARCA4 mutant NSCLC who received first-line chemotherapy; Advanced LUAD patients with SMARCA4 mutation had poorer response to first-line EGFR-TKI but had a better response to chemotherapy plus anti-angiogenesis therapy. SMARCA4 mutations predominantly occur in males and smokers with NSCLC. Age, PS, and brain metastasis are independent prognostic factors for patients with SMARCA4 mutant NSCLC who received first-line chemotherapy; Advanced LUAD patients with SMARCA4 mutation had poorer response to first-line EGFR-TKI but had a better response to chemotherapy plus anti-angiogenesis therapy.