The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer
Schoenfeld AJ, Bandlamudi C, Lavery JA, Montecalvo J, Namakydoust A, Rizvi H, Egger JV, Concepcion CP, Paul S, Arcila ME, Daneshbod Y, Chang JC, Sauter JL, Beras A, Ladanyi M, Jacks T, Rudin CM, Taylor BS, Donoghue MTA, Heller G, Hellmann MD, Rekhtman N, and Riely GJ. The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer. Clin Cancer Res 2020.
Clinical cancer research
PURPOSE: SMARCA4 mutations are among the most common recurrent alterations in NSCLC, but the relationship to other genomic abnormalities and clinical impact has not been established.
EXPERIMENTAL DESIGN: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering.
RESULTS: In 4813 tumors from patients with NSCLC, we identified 8% (n= 407) patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 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%, (P < 0.001)). Both classes of mutation co-occured more frequently with KRAS, STK11, and KEAP1 mutations compared to SMARCA4 wildtype tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with Class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with Class 1 mutations having the best response to ICIs (p = 0.027).
CONCLUSIONS: SMARCA4 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 KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.
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