title: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.
abstract: 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.
authors.affiliation: Université Paris-Descartes, Institut National de la Sante et de la Recherche Medicale UMR-775, Paris, France.
authors.forename: Astrid
authors.initials: A
authors.lastname: Lièvre
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Bachet
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Corre
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.forename: Bruno
authors.initials: B
authors.lastname: Landi
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.forename: Gorana
authors.initials: G
authors.lastname: Tomasic
authors.forename: Christophe
authors.initials: C
authors.lastname: Penna
authors.forename: Michel
authors.initials: M
authors.lastname: Ducreux
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D018773:Genes, erbB-1; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab