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[Cancer Research 66, 3992-3995, April 15, 2006]
© 2006 American Association for Cancer Research

Priority Reports

KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer

Astrid Lièvre1,3, Jean-Baptiste Bachet3, Delphine Le Corre1, Valérie Boige4, Bruno Landi2, Jean-François Emile3, Jean-François Côté1,2, Gorana Tomasic4, Christophe Penna3, Michel Ducreux4, Philippe Rougier3, Frédérique Penault-Llorca5 and Pierre Laurent-Puig1,2

1 Université Paris-Descartes, Institut National de la Sante et de la Recherche Medicale UMR-775; 2 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; 3 Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne Billancourt, France, Université de Versailles Saint-Quentin-en-Yvelines, Versailles, France; 4 Institut Gustave Roussy, Villejuif, France; and 5 Centre Jean Perrin, Clermont-Ferrand, France, Université Auvergne, Clermont-Ferrand, France

Requests for reprints: Pierre Laurent-Puig, Institut National de la Sante et de la Recherche Medicale U775, Molecular Basis of Response to Xenobiotics, 45 rue des Saints-Pères, 75006 Paris, France. Phone: 33-1-4286-2081; Fax: 33-1-4286-2072; E-mail: pierre.laurent-puig{at}univ-paris5.fr.

The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment. (Cancer Res 2006; 66(8): 3992-5)




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