This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, W. Articles by Lenz, H.-J. Search for Related Content PubMed PubMed Citation Articles by Zhang, W. Articles by Lenz, H.-J.

FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab

Wu Zhang, Michael Gordon, Anne M. Schultheis, Dong Yun Yang, Fumio Nagashima, Mizutomo Azuma, Heung-Moon Chang, Eva Borucka, Georg Lurje, Andy E. Sherrod, Syma Iqbal, Susan Groshen, Heinz-Josef Lenz

From the Division of Medical Oncology and the Departments of Pathology and Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA

Address reprint requests to Heinz-Josef Lenz, MD, FACP, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon A. Carpenter Laboratory, 1441 Eastlake Ave, Suite 3456, Los Angeles, CA 90033; e-mail: lenz{at}usc.edu

Purpose: Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcR) play an important role in initiating ADCC. Studies have shown that two IgG FcR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) independently predict response to rituximab in patients with follicular lymphoma. We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic CRC patients treated with single-agent cetuximab.

Patients and Methods: Thirty-nine metastatic CRC patients were enrolled onto the ImClone0144 trial. Using an allele-specific polymerase chain reaction (PCR) –based method, gene polymorphisms of FCGA2A-H131R and FCGA3A-V158F were assessed from genomic DNA extracted from peripheral blood samples.

Results: FCGR2A-H131R and FCGR3A-V158F polymorphisms were independently associated with progression-free survival (PFS; P = .037 and .055, respectively; log-rank test). Combined analysis of these two polymorphisms showed that patients with the favorable genotypes (FCGR2A, any histidine allele, and FCGR3A, any phenylalanine allele) showed a median PFS of 3.7 months (95% CI, 2.4 to 4.4 months), whereas patients with any two unfavorable genotypes (FCGR2A arginine/arginine or valine/valine) had a PFS of 1.1 months (95% CI, 1.0 to 1.4 months; P = .004; log-rank test).

Conclusion: Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.

Supported by the National Institutes of Health Grants No. 5 P30CA14089-271, San Pedro Guild Research Fund, and the Dhont Family Foundation.

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

This article has been cited by other articles:

				R. Trotta, J. D. Col, J. Yu, D. Ciarlariello, B. Thomas, X. Zhang, J. Allard II, M. Wei, H. Mao, J. C. Byrd, et al. TGF-{beta} Utilizes SMAD3 to Inhibit CD16-Mediated IFN-{gamma} Production and Antibody-Dependent Cellular Cytotoxicity in Human NK Cells J. Immunol., September 15, 2008; 181(6): 3784 - 3792. [Abstract] [Full Text] [PDF]

				M. Dechant, W. Weisner, S. Berger, M. Peipp, T. Beyer, T. Schneider-Merck, J. J. Lammerts van Bueren, W. K. Bleeker, P. W.H.I. Parren, J. G.J. van de Winkel, et al. Complement-Dependent Tumor Cell Lysis Triggered by Combinations of Epidermal Growth Factor Receptor Antibodies Cancer Res., July 1, 2008; 68(13): 4998 - 5003. [Abstract] [Full Text] [PDF]

				A. Musolino, N. Naldi, B. Bortesi, D. Pezzuolo, M. Capelletti, G. Missale, D. Laccabue, A. Zerbini, R. Camisa, G. Bisagni, et al. Immunoglobulin G Fragment C Receptor Polymorphisms and Clinical Efficacy of Trastuzumab-Based Therapy in Patients With HER-2/neu-Positive Metastatic Breast Cancer J. Clin. Oncol., April 10, 2008; 26(11): 1789 - 1796. [Abstract] [Full Text] [PDF]

				L. Gianni The "Other" Signaling of Trastuzumab: Antibodies Are Immunocompetent Drugs J. Clin. Oncol., April 10, 2008; 26(11): 1778 - 1780. [Full Text] [PDF]

				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]

				M. Peipp, T. Schneider-Merck, M. Dechant, T. Beyer, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. H. I. Parren, J. G. J. van de Winkel, and T. Valerius Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations J. Immunol., March 15, 2008; 180(6): 4338 - 4345. [Abstract] [Full Text] [PDF]