Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 27, Issue 7, Pages 1122-1129Publisher
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2008.18.0463
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Purpose The antiepidermal growth factor receptor antibody cetuximab shows activity in irinotecan-refractory metastatic colorectal cancer (mCRC), mainly in wild-type KRAS tumors. Cetuximab may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC) in which antibody Fc portion interacts with Fc receptors (Fc gamma Rs) expressed by immune cells. ADCC is influenced by Fc gamma RIIa-H131R and Fc gamma RIIIa-V158F polymorphisms that are clinically relevant in follicular lymphoma and metastatic breast cancer treated with rituximab and trastuzumab, respectively. We investigated the association of Fc gamma R polymorphisms and KRAS mutation with the outcome of irinotecan-refractory mCRC patients treated with cetuximab plus irinotecan. Patients and Methods Tumor and normal tissues from 69 patients were screened for KRAS mutations using a sensitive multiplex assay and genotyped for Fc gamma RIIa and Fc gamma RIIIa polymorphisms by direct sequencing and multiplex allele-specific polymerase chain reaction, respectively. The results were correlated with response and progression-free survival (PFS). Results KRAS mutations were associated with lower response rate (4% v 27% in nonmutated patients; P = .021) and shorter PFS (3.0 v 5.3 months; P = .021). Patients with Fc gamma RIIa-131H/H and/or Fc gamma IIIa-158V/V genotypes had longer PFS than 131R and 158F carriers (5.5 v 3.0 months; P = .005). The difference remained significant for mutated-KRAS patients. By multivariate analysis, KRAS mutation and Fc gamma R combined status were independent risk factors for PFS. Conclusion Combined Fc gamma RIIa/Fc gamma RIIIa polymorphisms are prognostic factors for disease progression in mCRC patients treated with cetuximab plus irinotecan. As these polymorphisms are also clinically relevant in mutated-KRAS mCRC, an important role of ADCC in cetuximab efficacy is presumed. J Clin Oncol 27: 1122-1129. (C) 2009 by American Society of Clinical Oncology
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