Clinicopathologic Characteristics of BRG1-Deficient NSCLC

Abstract

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 BRG1inactivating 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 ¼ 117 of 1422) and 11% (n ¼ 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. Twentynine 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 ¼ 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 ¼ 11) or chemotherapy plus immunotherapy (n ¼ 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.

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

“…A relatively new type of thoracic cancer, in particular lung cancer, with a poor prognosis has been identified to have mutations in SMARCA4 [250][251][252][253][254][255][256][257][258]. These mutations have been found in about 5% to 10% of NSCLC patients, mostly NS-NSCLC patients [259]. These mutations are mutually exclusive, with genomic alterations in ALK, ROS1, MET, and RET [260].…”

“…However, co-mutations in KEAP1, STK11, and KRAS are more frequent in SMARCA4-mutated tumors [261]. A few therapeutic medications targeting these mutations are under development, mostly tested in vitro but some are being evaluated in clinical trials, too [259,[262][263][264][265][266]. ICIs have been found to be efficacious in patients with SMARCA4-mutated tumors [267][268][269].…”

“…Indeed, when a cytological sample from a patient with lung cancer is negative for TTF1 and BRG1, a mutation in SMARCA4 must be sought and confirmed using molecular biology approaches, mainly NGS [275] (Figure 1). These mutations can be detected with NGS not only on tissue biopsies but certainly on cytological samples and liquid biopsies, too [259].…”

Hyper‐progressive disease after immune checkpoint inhibitor in SMARCA4‐deficient small‐cell lung carcinoma

“…SMARCA4 (switch/sucrose non‐fermentable‐related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily A, member 4) is a catalytic subunit essential for the function of the switch/sucrose non‐fermentable complex that plays important roles in transcription, differentiation, and DNA repair. SMARCA4 mutations were detected in 5% of non‐small cell lung carcinoma (NSCLC) patients [1].…”

“…Recently, SMARCA4‐deficient thoracic tumours have clinically been recognized because of its poor prognosis in clinical settings. The correlation of the loss of SMARCA4 with poor prognosis is remarkable in thoracic tumours compared with that in other tumours [1]. Although the optimal treatment for SMARCA4‐deficient thoracic tumours remains unclear, several reports have indicated a beneficial effect of immune checkpoint inhibitors (ICIs) [2].…”