Originally published as JCO Early Release 10.1200/JCO.2008.18.0463 on January 21 2009

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Impact of FcRIIa-FcRIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan

From the Departments of Pathology, Biology, Biostatistics, and Oncology, Centre Régional de Lutte Contre le Cancer Val d'Aurelle-Paul Lamarque, Montpellier; Digestive Oncology Unit, Department of Gastroenterology, Rouen University Hospital; Inserm U614, Faculty of Medicine; Department of Pathology, Rouen University Hospital; and the Department of Pathology, Centre Jean Perrin, Clermont-Ferrand, France.

Corresponding author: Frédéric Bibeau, MD, Département de Pathologie, Centre Régional de Lutte Contre le Cancer Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Parc Euromédecine, 34298 Montpellier Cedex 05 France; e-mail: fbibeau{at}valdorel.fnclcc.fr.

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 (FcRs) expressed by immune cells. ADCC is influenced by FcRIIa-H131R and FcRIIIa-V158F polymorphisms that are clinically relevant in follicular lymphoma and metastatic breast cancer treated with rituximab and trastuzumab, respectively. We investigated the association of FcR 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 FcRIIa and FcRIIIa 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 FcRIIa-131H/H and/or FcIIIa-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 FcR combined status were independent risk factors for PFS.

Conclusion Combined FcRIIa/FcRIIIa 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.

Presented in part at 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30 to June 3, 2008.

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

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