Abstract
BackgroundAnti-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 (FcγR) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of FcγRIIa and FcγRIIIa and clinical outcome in mCRC treated with anti-EGFR antibodies.MethodsSeventy-four consecutive patients with mCRC were analyzed. The genotypes for FcγRIIa-131 histidine (H)/arginine (R), FcγRIIIa-158 valine (V)/phenylanaline (F) polymorphisms were evaluated by directly sequencing. Multiplex allele-specific polymerase chain reaction was performed for FcγRIIIa-158 valine (V)/phenylanaline (F). Correlations between FcγR 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.ResultsFcγRIIIa 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 FcγRIIa polymorphisms. Furthermore, obtained results suggested that prognosis is particularly unfavorable for patients carrying the FcγRIIIa-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 FcγRIIa polymorphisms.ConclusionsIn mCRC patients the presence of FcγRIIIa-F can predict resistance to anti-EGFR therapy and unfavorable prognosis.
Highlights
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer
It was described that FcγRIIa-131H/H and FcγRIIIa-158F/F polymorphisms associated with better progression-free survival (PFS) in a series of EGFR-expressing metastatic colorectal cancer (mCRC) patients treated with single-agent cetuximab [14]
No prognostic ability was identified for FcγRIIa polymorphisms
Summary
Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). Monoclonal antibodies (mAbs) binding to the vascular endothelial growth factor (VEGF) (bevacizumab) or the epidermal growth factor receptor (EGFR) (cetuximab and panitumumab) have shown efficacy in the treatment of mCRC increasing the life expectancy of patients by more than 2 years [3]. Polymorphisms have been demonstrated on genes encoding for the activating receptors FcγRIIa (CD32, mainly expressed on macrophages) and FcγRIIIa (CD16, expressed on NK cells and macrophages) [9], affecting their affinity to human IgG: a histidine (H)/arginine (R) polymorphism at position 131 for FcγRIIa and a valine (V)/phenylalanine (F) polymorphism at position 158 for FcγRIIIa. Based on the different affinities, patients harboring FcγRIIa-131H/H and FcγRIIIa-4 158V/V genotypes would be expected to mediate a more efficient ADCC antitumor response.
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