Role of polymorphic fc gamma receptor II/III in the efficacy of cetuximab in KRAS-NRAS-BRAF-PI3K mutated.

477 Background: The immunoglobulin G1 (IgG1) monoclonal antibody (MoAb) cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumors. IgG1 may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by FcγR polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus cetuximab. Methods: Tumor tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester. UK). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays. Results: DCR was significantly higher in KRAS wild-type tumors (61% vs 39%, p=0.049). In EGFR downstream-mutated mCRC patients, those harbouring a FcγRIIa H/H genotype had a high...