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Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab

Shirin Khambata-Ford, Christopher R. Garrett, Neal J. Meropol, Mark Basik, Christopher T. Harbison, Shujian Wu, Tai W. Wong, Xin Huang, Chris H. Takimoto, Andrew K. Godwin, Benjamin R. Tan, Smitha S. Krishnamurthi, Howard A. Burris, III, Elizabeth A. Poplin, Manuel Hidalgo, Jose Baselga, Edwin A. Clark, David J. Mauro

From the Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton; The Cancer Institute of New Jersey, New Brunswick, NJ; Division of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Divisions of Medical Science and Population Science, Fox Chase Cancer Center, Philadelphia, PA; Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; Division of Medical Oncology, Washington University School of Medicine, St Louis, MO; Case Comprehensive Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH; Sarah Cannon Cancer Center, Nashville, TN; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Sir Mortimer B. David Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Oncology Program and Medical Oncology Service, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain

Address reprint requests to Shirin Khambata-Ford, PhD, Bristol-Myers Squibb Co, 311 Pennington-Rocky Hill Rd, 3B-2.06, Princeton, NJ 08543; e-mail: shirin.ford{at}bms.com

Purpose: The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab.

Patients and Methods: One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies.

Results: Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively).

Conclusion: Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

Supported by Bristol-Myers Squibb Co, Princeton, NJ. Mutation analysis work was supported by a grant from the Pennsylvania Department of Health (A.K.G. and N.J.M.).

Both S.K.-F. and C.R.G. contributed equally to this article.

The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.

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

Related Correspondence

• KRAS Mutation Signature in Colorectal Tumors Significantly Overlaps With the Cetuximab Response Signature
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  JCO 2008 26: 2228-2230 [Full Text]
• Mutations of KRAS and BRAF in Primary and Matched Metastatic Sites of Colorectal Cancer
  Salvatore Artale, Andrea Sartore-Bianchi, Silvio Marco Veronese, Valentina Gambi, Carolina Silvia Sarnataro, Marcello Gambacorta, Calogero Lauricella, and Salvatore Siena
  JCO 2008 26: 4217-4219 [Full Text]

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