Friday, September 6, 2013

Reproducibility of Immunohistochemical Scoring for EGFR Expression in Lung Cancer

http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2012-0605-OA


Reproducibility of Immunohistochemical Scoring for Epidermal Growth Factor Receptor Expression in Non–Small Cell Lung Cancer: Round Robin Test

Josef Rüschoff MDKeith M. Kerr MDHans J. Grote MDPeter Middel MDAnja von Heydebreck PhDVenâncio A. Alves ,MDStephan E. Baldus MDReinhard Büttner MDLina Carvalho MDLudger Fink MDWolfram Jochum MDAnthony W. I. LoMDFernando López-Ríos MDAlexander Marx MDThierry J. Molina MDWłodzimierz T. Olszewski MDRalf J. Rieker MD;Marco Volante MDErik Thunnissen MDFritz Wrba MDIlhan Celik MDStephan Störkel MD
From the Department of  Pathology, Institute of Pathology Nordhessen, Kassel, Germany (Drs Rüschoff and Middel); Targos Advance AG, Kassel, Germany (Drs Rüschoff and Middel); the  Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom (Dr Kerr);  Histopathology Biomarker Technologies, Merck KGaA, Darmstadt, Germany (Dr Grote);  Global Biostatistics, Merck KGaA, Darmstadt, Germany (Dr von Heydebreck); the Department of Pathology, LIM14-University of São Paulo School of Medicine & CICAP–Pathology, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil (Dr Alves);   the Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany (Dr Baldus); the  Institute of Pathology, University Hospital Cologne, Cologne, Germany (Dr Büttner); the Department of Pathology, Hospitais da Universidade de Coimbra, Coimbra, Portugal (Dr Carvalho); the  Institute of Pathology and Cytology, Interregional Group Practice, Wetzlar, Germany (Dr Fink); the  Institute of Pathology, Kantonsspital St Gallen, St Gallen, Switzerland (Dr Jochum); the  Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China (Dr Lo); the  Laboratory of Therapeutic Targets, Hospital Universitario Madrid Sanchinarro, Madrid, Spain (Dr López-Ríos); the  Department of Pathology, University Hospital of Mannheim, Mannheim, Germany (Dr Marx); the  Department of Anatomy and Cytology, Université Paris Descartes, Paris, France (Dr Molina); the  Department of Pathology, Institute of Oncology, Warsaw, Poland (Dr Olszewski);  Institute for Pathology, University Hospital, Erlangen, Germany (Dr Rieker); the  Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Turin, Italy (Mr Volante); the  Department of Pathology, VU Medical Centre, Amsterdam, The Netherlands (Dr Thunnissen); the  Department of Pathology, Clinical Institute of Pathology, Vienna, Austria (Dr Wrba); the  Global Clinical Development Unit Oncology, Merck KGaA, Darmstadt, Germany (Dr Celik); and the  Institute of Pathology, University of Witten/Herdecke and HELIOS Hospital Wuppertal, Wuppertal, Germany (Dr Störkel).
Context.—The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non–small cell lung cancer whose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of ≥200 on a scale of 0–300).
Objective.—To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0–3+) and the percentage of cells staining at each intensity.
Design.—In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non–small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low– (<200) and high– (≥200) EGFR expression groups.
Results.—After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean κ coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively.
Conclusions.—After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of non–small cell lung cancers into clinically relevant high– or low–EGFR expression groups.
Accepted: November 1, 2012 ;Published Online: December 27, 2012
The study was sponsored by Merck KGaA, Darmstadt, Germany. Drs Rüschoff and Büttner are cofounders of Targos Molecular Pathology GmbH, the parent company of Targos Advance AG. Targos Advance AG was in receipt of a contract from Merck KGaA, Darmstadt, Germany, to organize the EGFR RRT. Dr von Heydebreck holds shares in Merck KGaA. Travel costs for RRT raters (Drs Kerr, Alves, Baldus, Büttner, Carvalho, Fink, Jochum, Lo, López-Ríos, Marx, Molina, Olszewski, Rieker, Volante, Thunnissen, and Wrba) in relation to participation in this analysis were paid by Merck KGaA. Drs Rüschoff, Kerr, and Volante received honoraria and reimbursement of travel expenses from Merck KGaA for participation in advisory board meetings. Dr Störkel reported that his institution received consulting fees/honoraria from Merck KGaA. The other authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the 14th World Conference on Lung Cancer; July 5, 2011; Amsterdam, The Netherlands; the 23rd European Congress of Pathology; August 28, 2011; Helsinki, Finland; the European Multidisciplinary Cancer Congress; September 24, 2011; Stockholm, Sweden; and the 2011 Annual Meeting of the Deutsche Gesellschaft für Hämatologie und Onkologie; October 2, 2011; Basel, Switzerland.
Reprints: Josef Rüschoff, MD, Institute of Pathology Nordhessen, Germaniastraße 7, 34119 Kassel, Germany (e-mail:).

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