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. Clin Cancer Res; 22(10); 2396-404. ©2015 AACR.

Figure 1

Overall survival curves for patients with high, intermediate, and low levels of SMARCA4 (212520_s_at) expression in the Director’s Challenge Study. (A) all patients; (B) patients without adjuvant treatment. Log-rank P-values are shown.

Figure 2

Overall and five-year disease-specific survival curves by treatment arm (ACT or OBS) for patients with low (A and C) and high (B and D) levels of SMARCA4 (213719_s_at) expression, and low (E) and high (F) levels of both SMARCA4 (213719_s_at) and SMARCA2 (206543_at) expression in the JBR.10 trial. OBS, observation. ACT, adjuvant chemotherapy.

Figure 3

Comparison of overall survival and five-year overall survival by treatment arm for patients with low (A and C) and high (B and D) level of SMARCA4 (213719_s_at) in the JBR.10 trial. OBS, observation. ACT, adjuvant chemotherapy.