Fred R. Hirsch has participated on advisory boards and received honoraria from AstraZeneca. Helen Mann owns stock in AstraZeneca and has received honoraria and research support from AstraZeneca, Roche, Lily, and Sanofi-Aventis. Claire Watkins, Georgina Speake, and Brian Holloway own stock in AstraZeneca.
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
Article first published online: 24 JAN 2008
Copyright © 2008 American Cancer Society
Volume 112, Issue 5, pages 1114–1121, March 2008
How to Cite
Hirsch, F. R., Dziadziuszko, R., Thatcher, N., Mann, H., Watkins, C., Parums, D. V., Speake, G., Holloway, B., Bunn, P. A. and Franklin, W. A. (2008), Epidermal growth factor receptor immunohistochemistry. Cancer, 112: 1114–1121. doi: 10.1002/cncr.23282
- Issue published online: 19 FEB 2008
- Article first published online: 24 JAN 2008
- Manuscript Accepted: 7 SEP 2007
- Manuscript Revised: 16 AUG 2007
- Manuscript Received: 1 JUN 2007
- Specialized Program of Research Excellence. Grant Number: P01-CA58187
- nonsmall-cell lung cancer;
- epidermal growth factor receptor;
- phase 3 trial;
- cutoff point
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.
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).
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.
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. Cancer 2008. © 2008 American Cancer Society.