The Genomic Landscape of <i>SMARCA4</i> Alterations and Associations with Outcomes in Patients with Lung Cancer.

Abstract

<i>SMARCA4</i> mutations are among the most common recurrent alterations in non-small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established. To characterize <i>SMARCA4</i> alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with <i>SMARCA4</i> alterations treated at Memorial Sloan Kettering. In 4,813 tumors from patients with NSCLC, we identified 8% (<i>n</i> = 407) of patients with <i>SMARCA4</i>-mutant lung cancer. We describe two categories of <i>SMARCA4</i> mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, <i>P</i> < 0.001). Both classes of mutation co-occurred more frequently with <i>KRAS, STK11</i>, and <i>KEAP1</i> mutations compared with <i>SMARCA4</i> wild-type tumors (<i>P</i> < 0.001). In patients with metastatic NSCLC, <i>SMARCA4</i> alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (<i>P</i> < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with <i>SMARCA4</i>-mutant tumors (<i>P</i> = 0.01), with class 1 mutations having the best response to ICIs (<i>P</i> = 0.027). <i>SMARCA4</i> alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with <i>KEAP1, STK11</i>, and <i>KRAS</i> mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, <i>SMARCA4</i>-mutant lung cancers may be more sensitive to immunotherapy.