title: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting.
  
  
  METHODS
  Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118).
  
  
  RESULTS
  High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations.
  
  
  CONCLUSIONS
  EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.
authors.affiliation: University of Colorado Cancer Center, PO Box 6511, Mail Stop 8111, Aurora, CO 80045, USA. Fred.Hirsch@UCHSC.edu
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Rafal
authors.initials: R
authors.lastname: Dziadziuszko
authors.forename: Nick
authors.initials: N
authors.lastname: Thatcher
authors.forename: Alex
authors.initials: A
authors.lastname: Chang
authors.forename: Purvish
authors.initials: P
authors.lastname: Parikh
authors.forename: José Rodrigues
authors.initials: JR
authors.lastname: Pereira
authors.forename: Tudor
authors.initials: T
authors.lastname: Ciuleanu
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.forename: Claire
authors.initials: C
authors.lastname: Watkins
authors.forename: Angela
authors.initials: A
authors.lastname: Flannery
authors.forename: Gillian
authors.initials: G
authors.lastname: Ellison
authors.forename: Emma
authors.initials: E
authors.lastname: Donald
authors.forename: Lucy
authors.initials: L
authors.lastname: Knight
authors.forename: Dinah
authors.initials: D
authors.lastname: Parums
authors.forename: Nicholas
authors.initials: N
authors.lastname: Botwood
authors.forename: Brian
authors.initials: B
authors.lastname: Holloway
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000188:drug therapy*; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D018631:ras Proteins
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib