Data from Analysis of Fcγ Receptor IIIa and IIa Polymorphisms: Lack of Correlation with Outcome in Trastuzumab-Treated Breast Cancer Patients

Abstract

<div>Abstract<p><b>Purpose:</b> The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in <i>FCGR3A</i> and <i>FCGR2A</i> genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high-affinity SNPs are associated with disease-free survival (DFS) among patients with HER2-positive nonmetastatic breast cancer.</p><p><b>Experimental Design:</b> Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was conducted using Sanger sequencing and Sequenom mass spectrometry.</p><p><b>Results:</b> Patient samples (N = 1,189) were successfully genotyped for <i>FCGR3A</i> and 1,218 for <i>FCGR2A</i>. Compared with the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms than control arm (HR, 0.842; <i>P</i> = 0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR, 0.74; <i>P</i> = 0.036). No correlation between DFS and <i>FCGR3A/2A</i> genotypes was seen for trastuzumab-treated patients (158V/V vs. V/F vs. F/F, <i>P</i> = 0.98; 131H/H vs. H/R vs. R/R, <i>P</i> = 0.76; 158V/V and/or 131H/H vs. others, <i>P</i> = 0.67).</p><p><b>Conclusion:</b> This analysis evaluating the association between <i>FCGR3A/2A</i> genotypes and trastuzumab efficacy in HER2-positive breast cancer did not show a correlation between <i>FCGR3A</i>-V/F and <i>FCGR2A</i>-H/R SNPs and DFS in patients treated with trastuzumab. <i>Clin Cancer Res; 18(12); 3478–86. ©2012 AACR</i>.</p></div>