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Clinicopathologic Characteristics of BRG1-Deficient NSCLC
Ibiayi Dagogo-Jack1, Alexa B Schrock2, Marina Kem3
1Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Introduction:
Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations.
Methods:
Data sets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed.
Results:
We detected SMARCA4 genomic alterations in 9% (n = 117 of 1422) and 11% (n = 3188 of 27,281) of NSCLCs in the institutional and Foundation Medicine data sets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine of 64 SMARCA4-mutant NSCLCs (45%) assessed for BRG1 expression reported loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, 84% (n = 26 of 31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n = 11) or chemotherapy plus immunotherapy (n = 5), median progression-free survival was 38 days and 35 days, respectively.
Conclusions:
BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state.
Insights
Ten percent of non-small cell lung cancers (NSCLCs) with SMARCA4 mutations show deficient BRG1 expression. This molecular subgroup has poor clinical outcomes, indicating a need for new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ten percent of non-small cell lung cancers (NSCLCs) harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1.
- BRG1 inactivation in preclinical models increases tumor aggressiveness and sensitivity to specific targeted therapies.
- Translating preclinical findings into clinical studies requires understanding the clinical features of patients with BRG1-inactivating mutations.
Purpose of the Study:
- To assess the clinical features of patients with tumors harboring BRG1-inactivating mutations.
- To determine the prevalence and clinicopathologic characteristics of SMARCA4-mutant NSCLC.
- To evaluate BRG1 expression and its correlation with SMARCA4 mutations and treatment outcomes.
Main Methods:
- Reviewed data sets from Massachusetts General Hospital and Foundation Medicine for NSCLC patients.
- Determined the prevalence of SMARCA4-mutant NSCLC and described its clinicopathologic characteristics.
- Evaluated BRG1 expression by immunohistochemistry, correlated it with SMARCA4 mutations, and retrospectively assessed treatment outcomes.
Main Results:
- SMARCA4 genomic alterations were detected in 9-11% of NSCLCs, with truncating mutations comprising over one-third.
- Forty-five percent of SMARCA4-mutant NSCLCs showed loss of BRG1 expression, predominantly in those with truncating mutations (90%).
- BRG1-deficient NSCLC patients receiving first-line chemotherapy had a median progression-free survival of 38 days, and those receiving chemotherapy plus immunotherapy had 35 days.
Conclusions:
- BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations.
- Patients with BRG1-deficient NSCLC exhibit poor clinical outcomes.
- Novel strategies are needed to target the unique vulnerabilities associated with the BRG1-deficient state in NSCLC.
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