Originally published as JCO Early Release 10.1200/JCO.2007.14.8924 on July 14 2008

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Role of KRAS and EGFR As Biomarkers of Response to Erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21

Chang-Qi Zhu, Gilda da Cunha Santos, Keyue Ding, Akira Sakurada, Jean-Claude Cutz, Ni Liu, Tong Zhang, Paula Marrano, Marlo Whitehead, Jeremy A. Squire, Suzanne Kamel-Reid, Lesley Seymour, Frances A. Shepherd, Ming-Sound Tsao

From the Division of Applied Molecular Oncology and Departments of Pathology and Medical Oncology and Hematology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital; Departments of Laboratory Medicine and Pathobiology, Medical Biophysics, and Medicine, University of Toronto, Toronto; and National Cancer Institute of Canada Clinical Trials Group and Queen's University, Kingston, Ontario, Canada

Corresponding author: Ming-Sound Tsao, MD, FRCPC, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; e-mail: Ming.Tsao{at}uhn.on.ca

Purpose To evaluate the effect of KRAS and epidermal growth factor receptor (EGFR) genotype on the response to erlotinib treatment in the BR.21, placebo-controlled trial.

Patients and Methods We analyzed 206 tumors for KRAS mutation, 204 tumors for EGFR mutation, and 159 tumors for EGFR gene copy by fluorescent in situ hybridization (FISH). We reanalyzed EGFR deletion/mutation using two highly sensitive techniques that detect abnormalities in samples with 5% to 10% tumor cellularity. KRAS mutation was analyzed by direct sequencing.

Results Thirty patients (15%) had KRAS mutations, 34 (17%) had EGFR exon 19 deletion or exon 21 L858R mutations, and 61 (38%) had high EGFR gene copy (FISH positive). Response rates were 10% for wild-type and 5% for mutant KRAS (P = .69), 7% for wild-type and 27% for mutant EGFR (P = .03), and 5% for EGFR FISH-negative and 21% for FISH-positive patients (P = .02). Significant survival benefit from erlotinib therapy was observed for patients with wild-type KRAS (hazard ratio [HR] = 0.69, P = .03) and EGFR FISH positivity (HR = 0.43, P = .004) but not for patients with mutant KRAS (HR = 1.67, P = .31), wild-type EGFR (HR = 0.74, P = .09), mutant EGFR (HR = 0.55, P = .12), and EGFR FISH negativity (HR = 0.80, P = .35). In multivariate analysis, only EGFR FISH-positive status was prognostic for poorer survival (P = .025) and predictive of differential survival benefit from erlotinib (P = .005).

Conclusion EGFR mutations and high copy number are predictive of response to erlotinib. EGFR FISH is the strongest prognostic marker and a significant predictive marker of differential survival benefit from erlotinib.

published online ahead of print at www.jco.org on July 14, 2008.

Supported by grants from the Ontario Institute of Cancer Research, the Canadian Cancer Society/National Cancer Institute of Canada, the Jacqueline Seroussi Memorial Foundation for Cancer Research, and OSI Pharmaceuticals, Inc.

C.-Q.Z., G.d.C.S., and K.D. contributed equally to this study.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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