SMARCA4/BRG1 is a novel prognostic biomarker predictive of cisplatin-based chemotherapy outcomes in resected non-small cell lung cancer

Abstract

Purpose: Identification of predictive biomarkers is critically needed to improve selection of patients who derive the most benefit from platinum-based chemotherapy. We hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a novel predictive biomarker of increased sensitivity to adjuvant platinum-based therapies in non-small cell lung cancer (NSCLC). Experimental Design: The prognostic value was tested using a gene-expression microarray from the Director's Challenge Lung Study (n = 440). The predictive significance of SMARCA4 was determined using a gene-expression microarray (n = 133) from control and treatment arms of the JBR.10 trial of adjuvant cisplatin/vinorelbine. Kaplan-Meier method and log-rank tests were used to estimate and test the differences of probabilities in overall survival (OS) and disease-specific survival (DSS) between expression groups and treatment arms. Multivariate Cox regression models were used while adjusting for other clinical covariates. Results: In the Director's Challenge Study, reduced expression of SMARCA4 was associated with poor OS compared with high and intermediate expression (P < 0.001 and P = 0.009, respectively). In multivariate analysis, compared with low, high SMARCA4 expression predicted a decrease in risk of death [HR, 0.6; 95% confidence interval (CI), 0.4-0.8; P = 0.002]. In the JBR.10 trial, improved 5-year DSS was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine [HR, 0.1; 95% CI, 0.0-0.5, P = 0.002 (low); HR, 1.0; 95% CI, 0.5-2.3, P= 0.92 (high)]. An interaction test was highly significant (P = 0.01). Conclusions: Low expression of SMARCA4/BRG1 is significantly associated with worse prognosis; however, it is a novel significant predictive biomarker for increased sensitivity to platinum-based chemotherapy in NSCLC.