title: Epidermal growth factor receptor immunohistochemistry: comparison of antibodies and cutoff points to predict benefit from gefitinib in a phase 3 placebo-controlled study in advanced nonsmall-cell lung cancer.
abstract: BACKGROUND
  The ISEL (Iressa Survival Evaluation in Lung Cancer) clinical trial evaluated the efficacy of gefitinib versus placebo in pretreated nonsmall-cell lung cancer patients. Two different antibodies, scoring systems, and cutoff points of epidermal growth factor receptor (EGFR) protein expression were compared to predict response and survival of enrolled patients.
  
  
  METHODS
  EGFR expression was assessed in tumor samples by immunohistochemistry using the Dako EGFR pharmDx kit (scoring percent of tumor cells with positive staining) and Zymed monoclonal antibody clone 31G7 (scoring staining index derived from proportion of positive cells times staining intensity).
  
  
  RESULTS
  Data for EGFR expression were available for 379 patients for Dako and 357 patients for Zymed antibody (22% and 21%, respectively, of trial population). Objective response rates in gefitinib-treated EGFR-positive patients defined with various cutpoints with Dako antibody varied between 8% and 12%, and with Zymed antibody between 10% and 13%. Lower cutoff points with Dako antibody provided the best discrimination between EGFR-positive and EGFR-negative patients for survival hazard ratios comparing gefitinib to placebo, with a significant treatment/cutoff point interaction for 10% cutoff point (P = .049). A similar but less apparent trend was noted for Zymed antibody, although the discrimination between hazard ratios was not significant for any cutoff point analyzed.
  
  
  CONCLUSIONS
  Assessment with the Dako PharmDx kit and percentage of cells with positive staining may provide more accurate prediction of differential effect on survival with gefitinib than assessment with Zymed antibody and staining index. Using higher cutpoints to define positivity does not improve test discrimination.
authors.affiliation: Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO 80045, USA. Fred.Hirsch@UCHSC.edu
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Rafal
authors.initials: R
authors.lastname: Dziadziuszko
authors.forename: Nick
authors.initials: N
authors.lastname: Thatcher
authors.forename: Helen
authors.initials: H
authors.lastname: Mann
authors.forename: Claire
authors.initials: C
authors.lastname: Watkins
authors.forename: Dinah V
authors.initials: DV
authors.lastname: Parums
authors.forename: Georgina
authors.initials: G
authors.lastname: Speake
authors.forename: Brian
authors.initials: B
authors.lastname: Holloway
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
mesh_terms: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D066246:ErbB Receptors / Q000032:analysis*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D010919:Placebos; D011237:Predictive Value of Tests; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D010919:Placebos; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib