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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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[Abstract] [Full Text] [PDF]

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W. Guo, S. Wu, J. Liu, and B. Fang
Identification of a Small Molecule with Synthetic Lethality for K-Ras and Protein Kinase C Iota
Cancer Res., September 15, 2008; 68(18): 7403 - 7408.
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L. Quaye, S. A. Gayther, S. J. Ramus, R. A. Di Cioccio, V. McGuire, E. Hogdall, C. Hogdall, J. Blaakr, D. F. Easton, B. A.J. Ponder, et al.
The Effects of Common Genetic Variants in Oncogenes on Ovarian Cancer Survival
Clin. Cancer Res., September 15, 2008; 14(18): 5833 - 5839.
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M.-C. Etienne-Grimaldi, J.-L. Formento, M. Francoual, E. Francois, P. Formento, N. Renee, P. Laurent-Puig, M. Chazal, D. Benchimol, J.-R. Delpero, et al.
K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy
Clin. Cancer Res., August 1, 2008; 14(15): 4830 - 4835.
[Abstract] [Full Text] [PDF]

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B. Vincenzi, D. Santini, S. Galluzzo, A. Russo, F. Fulfaro, M. Silletta, F. Battistoni, L. Rocci, B. B. Zobel, V. Adamo, et al.
Early Magnesium Reduction in Advanced Colorectal Cancer Patients Treated with Cetuximab Plus Irinotecan as Predictive Factor of Efficacy and Outcome
Clin. Cancer Res., July 1, 2008; 14(13): 4219 - 4224.
[Abstract] [Full Text] [PDF]

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 JCOHome page
A. Lievre and P. Laurent-Puig
In Reply
J. Clin. Oncol., May 20, 2008; 26(15): 2601 - 2602.
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A. F. Sobrero, J. Maurel, L. Fehrenbacher, W. Scheithauer, Y. A. Abubakr, M. P. Lutz, M. E. Vega-Villegas, C. Eng, E. U. Steinhauer, J. Prausova, et al.
EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer
J. Clin. Oncol., May 10, 2008; 26(14): 2311 - 2319.
[Abstract] [Full Text] [PDF]

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A. de Reynies, V. Boige, G. Milano, J. Faivre, and P. Laurent-Puig
KRAS Mutation Signature in Colorectal Tumors Significantly Overlaps With the Cetuximab Response Signature
J. Clin. Oncol., May 1, 2008; 26(13): 2228 - 2230.
[Full Text] [PDF]

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 The OncologistHome page
S. Sleijfer and E. Wiemer
Editorial: The Long and Winding Road to Better Cancer Cell-Specific Therapies
Oncologist, May 1, 2008; 13(5): 593 - 595.
[Full Text] [PDF]

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J. Baselga and N. Rosen
Determinants of RASistance to Anti-Epidermal Growth Factor Receptor Agents
J. Clin. Oncol., April 1, 2008; 26(10): 1582 - 1584.
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R. G. Amado, M. Wolf, M. Peeters, E. Van Cutsem, S. Siena, D. J. Freeman, T. Juan, R. Sikorski, S. Suggs, R. Radinsky, et al.
Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer
J. Clin. Oncol., April 1, 2008; 26(10): 1626 - 1634.
[Abstract] [Full Text] [PDF]

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 Ann OncolHome page
F. Cappuzzo, G. Finocchiaro, E. Rossi, P.A. Janne, C. Carnaghi, C. Calandri, K. Bencardino, C. Ligorio, F. Ciardiello, T. Pressiani, et al.
EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients
Ann. Onc., April 1, 2008; 19(4): 717 - 723.
[Abstract] [Full Text] [PDF]

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 Ann OncolHome page
A. Pessino, S. Artale, S. Sciallero, A. Guglielmi, G. Fornarini, I.C. Andreotti, S. Mammoliti, D. Comandini, F. Caprioni, E. Bennicelli, et al.
First-line single-agent cetuximab in patients with advanced colorectal cancer
Ann. Onc., April 1, 2008; 19(4): 711 - 716.
[Abstract] [Full Text] [PDF]

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M. Jhawer, S. Goel, A. J. Wilson, C. Montagna, Y.-H. Ling, D.-S. Byun, S. Nasser, D. Arango, J. Shin, L. Klampfer, et al.
PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab
Cancer Res., March 15, 2008; 68(6): 1953 - 1961.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
F. Ciardiello and G. Tortora
EGFR Antagonists in Cancer Treatment
N. Engl. J. Med., March 13, 2008; 358(11): 1160 - 1174.
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 Ann OncolHome page
W. De Roock, H. Piessevaux, J. De Schutter, M. Janssens, G. De Hertogh, N. Personeni, B. Biesmans, J.-L. Van Laethem, M. Peeters, Y. Humblet, et al.
KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab
Ann. Onc., March 1, 2008; 19(3): 508 - 515.
[Abstract] [Full Text] [PDF]

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F. Pinter, J. Papay, A. Almasi, Z. Sapi, E. Szabo, M. Kanya, A. Tamasi, B. Jori, E. Varkondi, J. Moldvay, et al.
Epidermal Growth Factor Receptor (EGFR) High Gene Copy Number and Activating Mutations in Lung Adenocarcinomas Are Not Consistently Accompanied by Positivity for EGFR Protein by Standard Immunohistochemistry
J. Mol. Diagn., March 1, 2008; 10(2): 160 - 168.
[Abstract] [Full Text] [PDF]

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A. Lievre, J.-B. Bachet, V. Boige, A. Cayre, D. Le Corre, E. Buc, M. Ychou, O. Bouche, B. Landi, C. Louvet, et al.
KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab
J. Clin. Oncol., January 20, 2008; 26(3): 374 - 379.
[Abstract] [Full Text] [PDF]

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L. M. Weiner, A. S. Belldegrun, J. Crawford, A. W. Tolcher, P. Lockbaum, R. H. Arends, L. Navale, R. G. Amado, G. Schwab, and R. A. Figlin
Dose and Schedule Study of Panitumumab Monotherapy in Patients with Advanced Solid Malignancies
Clin. Cancer Res., January 15, 2008; 14(2): 502 - 508.
[Abstract] [Full Text] [PDF]

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N. Normanno and A. De Luca
Erlotinib in Pancreatic Cancer: Are Tumor Cells the (only) Target?
J. Clin. Oncol., December 20, 2007; 25(36): 5836 - 5837.
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A. Grothey
Biological Therapy and Other Novel Therapies in Early-Stage Disease: Are They Appropriate?
Clin. Cancer Res., November 15, 2007; 13(22): 6909s - 6912s.
[Abstract] [Full Text] [PDF]

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R. H. Nakamoto, H. Uetake, S. Iida, Y. V. Kolev, L. T. Soumaoro, Y. Takagi, M. Yasuno, and K. Sugihara
Correlations between Cyclooxygenase-2 Expression and Angiogenic Factors in Primary Tumors and Liver Metastases in Colorectal Cancer
Jpn. J. Clin. Oncol., September 10, 2007; (2007) hym080v1.
[Abstract] [Full Text] [PDF]

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W. Zhang, M. Gordon, A. M. Schultheis, D. Y. Yang, F. Nagashima, M. Azuma, H.-M. Chang, E. Borucka, G. Lurje, A. E. Sherrod, et al.
FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab
J. Clin. Oncol., August 20, 2007; 25(24): 3712 - 3718.
[Abstract] [Full Text] [PDF]

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W. A. Messersmith and M. Hidalgo
Panitumumab, a Monoclonal Anti Epidermal Growth Factor Receptor Antibody in Colorectal Cancer: Another One or the One?
Clin. Cancer Res., August 15, 2007; 13(16): 4664 - 4666.
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S. Khambata-Ford, C. R. Garrett, N. J. Meropol, M. Basik, C. T. Harbison, S. Wu, T. W. Wong, X. Huang, C. H. Takimoto, A. K. Godwin, et al.
Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab
J. Clin. Oncol., August 1, 2007; 25(22): 3230 - 3237.
[Abstract] [Full Text] [PDF]

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A. Sartore-Bianchi, M. Moroni, S. Veronese, C. Carnaghi, E. Bajetta, G. Luppi, A. Sobrero, C. Barone, S. Cascinu, G. Colucci, et al.
Epidermal Growth Factor Receptor Gene Copy Number and Clinical Outcome of Metastatic Colorectal Cancer Treated With Panitumumab
J. Clin. Oncol., August 1, 2007; 25(22): 3238 - 3245.
[Abstract] [Full Text] [PDF]

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M. Toulany, M. Baumann, and H. P. Rodemann
Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity
Mol. Cancer Res., August 1, 2007; 5(8): 863 - 872.
[Abstract] [Full Text] [PDF]

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E. Van Cutsem, C. Verslype, and P. A. Grusenmeyer
Lessons Learned in the Management of Advanced Pancreatic Cancer
J. Clin. Oncol., May 20, 2007; 25(15): 1949 - 1952.
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E. Van Cutsem, M. Peeters, S. Siena, Y. Humblet, A. Hendlisz, B. Neyns, J.-L. Canon, J.-L. Van Laethem, J. Maurel, G. Richardson, et al.
Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer
J. Clin. Oncol., May 1, 2007; 25(13): 1658 - 1664.
[Abstract] [Full Text] [PDF]

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S. Benvenuti, A. Sartore-Bianchi, F. Di Nicolantonio, C. Zanon, M. Moroni, S. Veronese, S. Siena, and A. Bardelli
Oncogenic Activation of the RAS/RAF Signaling Pathway Impairs the Response of Metastatic Colorectal Cancers to Anti-Epidermal Growth Factor Receptor Antibody Therapies
Cancer Res., March 15, 2007; 67(6): 2643 - 2648.
[Abstract] [Full Text] [PDF]

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R. Rosell, M. Taron, N. Reguart, D. Isla, and T. Moran
Epidermal Growth Factor Receptor Activation: How Exon 19 and 21 Mutations Changed Our Understanding of the Pathway
Clin. Cancer Res., December 15, 2006; 12(24): 7222 - 7231.
[Abstract] [Full Text] [PDF]


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