Fc gamma receptor IIIa polymorphisms in advanced colorectal cancer patients correlated with response to anti-EGFR antibodies and clinical outcome

Background: Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). One of the mechanism is the antibody-dependent cell-mediated cytotoxicity (ADCC) in which Fc region of the antibody binds to the Fc gamma receptors (Fc gamma R) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of Fc gamma RIIa and Fc gamma RIIIa and clinical outcome in mCRC treated with anti-EGFR antibodies. Methods: Seventy-four consecutive patients with mCRC were analyzed. The genotypes for Fc gamma RIIa-131 histidine (H)/arginine (R), Fc gamma RIIIa-158 valine (V)/phenylanaline (F) polymorphisms were evaluated by directly sequencing. Multiplex allele-specific polymerase chain reaction was performed for Fc gamma RIIIa-158 valine (V)/phenylanaline (F). Correlations between Fc gamma R polymorphisms, baseline patient and tumor features were studied by contingency tables and the chi-square test. The Kaplan-Meier product limit method was applied to the progression-free survival (PFS) curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on PFS. Results: Fc gamma RIIIa polymorphisms were significantly associated with response to anti-EGFR-based therapy in 49 patients with kras wt tumors (p=0.035). There was not association with response for Fc gamma RIIa polymorphisms. Furthermore, obtained results suggested that prognosis is particularly unfavorable for patients carrying the Fc gamma RIIIa-158F/F genotype (median PFS V/V, V/F, F/F: 18.2 vs 17.3 vs 9.4 months). No prognostic ability was identified for Fc gamma RIIa polymorphisms. Conclusions: In mCRC patients the presence of Fc gamma RIIIa-F can predict resistance to anti-EGFR therapy and unfavorable prognosis.