Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients

Abstract

Purpose: 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 FCGR3A and FCGR2A 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.

Experimental design: 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.

Results: Patient samples (N = 1,189) were successfully genotyped for FCGR3A and 1,218 for FCGR2A. 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; P = 0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR, 0.74; P = 0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs. V/F vs. F/F, P = 0.98; 131H/H vs. H/R vs. R/R, P = 0.76; 158V/V and/or 131H/H vs. others, P = 0.67).

Conclusion: This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not show a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab.

©2012 AACR.

Figures

Figure 1

Consort Diagram for Adjuvant Cohort

Figure 2

Kaplan Meier estimates of disease free survival (DFS) in trastuzumab treated patients within the adjuvant cohort according to FcγR polymorphisms. (A) FCGR3A 158 V/F genotype, P=0.98 (V/V vs V/F vs F/F) (B) FCGR2A 131 H/R genotype, P=0.76 (H/H vs H/R vs R/R). (C) FcγRIIIa and FcγRIIa polymorphisms. Others represents patients with neither FCGR3A 158 V/V nor FCGR2A 131 H/H genotype, P=0.67 (H/H and/or V/V vs others).

Figure 3

Kaplan-Meier estimates of disease free survival in trastuzumab (AC-TH/TCH combined) versus no trastuzumab (AC-T) treated patients, by FcγR genotype. (A) V/V (P=0.13) (B) V/F (P=0.422) (C) F/F (P=0.81) (D) H/H (P=0.35) (E) H/R (P=0.985) (F) R/R (P=0.58)