title: Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21.
abstract: BACKGROUND
  Erlotinib is an oral, reversible inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. A survival advantage for erlotinib compared with placebo was demonstrated in the National Cancer Institute of Canada Clinical Trials Group study BR.21, a randomized double-blind study of 731 patients with advanced-stage non-small-cell lung cancer.
  
  
  METHODS
  In this retrospective, exploratory investigation, univariate and multivariate analyses of survival of the 311 patients with available EGFR status by immunohistochemistry and known smoking history were performed to determine which factor might be more important for predicting clinical outcome.
  
  
  RESULTS
  A marginally significant interaction was observed between smoking history and treatment (P = 0.054). The hazard ratios (HRs) were 0.42 among never-smokers and 0.87 for smokers, indicating that erlotinib was beneficial in both subsets but more effective in patients who had never smoked. The HRs for patients with EGFR-positive and EGFR-negative tumors were 0.65 and 0.83, respectively; however, the interaction between EGFR status and treatment was not significant in univariate or multivariate analyses. Patients with EGFR-positive tumors who never smoked had the greatest survival benefit from erlotinib relative to placebo (HR, 0.28; P = 0.0007).
  
  
  CONCLUSIONS
  These data suggest that never-smokers and patients with EGFR-positive tumors might experience an enhanced benefit from erlotinib compared with placebo but that smoking history might be more predictive of survival benefit than EGFR expression. Subset analyses of ever-smokers revealed significant survival advantages for men and patients with squamous cell histology. Male ever-smokers with squamous cell non-small-cell lung cancer derived a significant survival benefit from erlotinib (HR, 0.66; P = 0.015) despite a very low tumor response rate.
authors.affiliation: OSI Pharmaceuticals, Inc, Boulder, CO 80301, USA. gclark@osip.com
authors.forename: Gary M
authors.initials: GM
authors.lastname: Clark
authors.forename: Denni M
authors.initials: DM
authors.lastname: Zborowski
authors.forename: Pedro
authors.initials: P
authors.lastname: Santabarbara
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Marlo
authors.initials: M
authors.lastname: Whitehead
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
mesh_terms: D000368:Aged; D002170:Canada / Q000453:epidemiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D012189:Retrospective Studies; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D016019:Survival Analysis
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors