Two immunoglobulin G fragment C receptor polymorphisms associated with clinical outcome of EGFR-expressing metastatic colorectal cancer patients treated with single agent cetuximab

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3028 Background: Cetuximab is a chimeric immunoglobulin G1 anti-EGFR monoclonal antibody with efficacy in metastatic colorectal cancer patients refractory to irinotican chemotherapy. Recent studies show that Antibody-dependent cellular cytotoxicity (ADCC) mediated through Fc receptors plays an important role in the antitumor effect of IgG1 antibody. There are three classes of FcγRs involved in the regulation of ADCC. FcγRIIa(CD32) and FcγRIIIa(CD16) activates and FcγRIIb inhibits activation. Clinical studies show FcγRIIIa 158 V/F polymorphism was associated with tumor response and progression-free survival in the follicular lymphoma patients treated with rituximab as first line treatment. Also, a H/R polymorphism at position 131 of FcγRIIa has been found to affects its affinity to human IgG and independently predict response to Rituximab. Since Cetuximab and Rituximab belong to the same chimeric IgG1 monoclonal antibody, we test hypothesis whether these two FcγR polymorphisms associated with clinical outcome in colorectal cancer patients treated with single agent Cetuximab. Methods: we tested both FcγRIIIa 158 V/F and FcγRIIa 131 H/R gene polymorphisms using PCR-RFLP method in genomic DNA extracted from peripheral blood from 39 EGFR-expressing metastatic colorectal cancer patients enrolled in a phase II single agent Cetuximab treatment clinical trial (IMCL-0144). Results: We found patients with FcγRIIa 131 HH or HR genotype show better time to progression and overall survival compare to patients with R/R genotype (p=0.037, p=0.22, respectively, log-rank test). Also, there is trend significance in tumor response when we compare patients with RR genotype and patients with HH or HR genotype (p=0.08, fisher’s exact test). FcγRIIIa 158 V/F also show trend significance in tumor response (p=0.067, fisher’s exact test). Conclusions: These data suggest Two Immunoglobulin G Fragment C Receptor polymorphismsFcγRIIIa158V/F andFcγRIIa 131 H/R may be potential molecular markers for clinical outcome of refractory metastatic colorectal caner patients treated with single agent EGFR inhibitor Cetuximab. Prospective studies are needed to confirm these preliminary findings. [Table: see text]