title: SMARCA4/BRG1 Is a Novel Prognostic Biomarker Predictive of Cisplatin-Based Chemotherapy Outcomes in Resected Non-Small Cell Lung Cancer.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, Ohio. Erica.Bell@osumc.edu.
authors.forename: Erica Hlavin
authors.initials: EH
authors.lastname: Bell
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Arup R
authors.initials: AR
authors.lastname: Chakraborty
authors.affiliation: Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, Ohio. Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Kirste
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, Ohio. Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Stegmaier
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Maureen
authors.initials: M
authors.lastname: McNulty
authors.affiliation: Translational Research Unit, Dr. Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain.
authors.forename: Niki
authors.initials: N
authors.lastname: Karachaliou
authors.affiliation: Translational Research Unit, Dr. Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain. Catalan Institute of Oncology, Badalona, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.affiliation: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use*; D004265:DNA Helicases / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D014157:Transcription Factors / Q000378:metabolism*; D014747:Vinblastine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D014157:Transcription Factors; D014747:Vinblastine; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D002945:Cisplatin; D000077235:Vinorelbine