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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.

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