Analysis of Fcγ Receptor IIA & IIIA Polymorphisms: Correlation with Outcome in Trastuzumab-Treated HER2/Neu Amplified Early and Metastatic Breast Cancer Patients.
Authors: Hurvitz S. , Betting D. , Stern H. , Quinaux E. , Stinson J. , Seshagiri S. , Zhao Y. , Buyse M. , Mackey J. , Robert N. , Valero V. , Crown J. , Driga A. , Bee V. , Slamon D. , Timmerman J. 
Published: December 2010

Abstract
Background: The mechanisms of action of the HER2-targeted antibody (Ab) trastuzumab remain incompletely understood. While disruption of constitutive HER2 signaling is believed to be the dominant anti-tumor mechanism, Ab-dependent cellular cytotoxicity (ADCC) via interactions with Fc receptors (FcR) on host leukocytes has been postulated to contribute to anti-tumor effects. Single nucleotide polymorphisms (SNPs) in FcγRIIIa 158 valine (V)/phenylalanine (F) (158V/F) and FcγRIIa 131histidine (H)/arginine (R) (131H/R) affect binding of Abs to FcR such that 158V/V and 131H/H bind Abs with the highest affinity. In previous reports, these 2 FcR genotypes were associated with more favorable outcomes. 158V/V correlated with response rate and progression free survival (PFS) in 54 patients (pts) with MBC treated (tx'd) with chemotherapy (chemo) plus trastuzumab (Musolino, J. Clin. Oncol. 2008). More recently, 131H/H was associated with pathologic complete response rate in 19 pts who received chemo + trastuzumab and with prolonged PFS in 36 pts with MBC tx'd with trastuzumab alone (Tamura, J Clin Oncol 27:15s, 2009). The current analysis was designed to determine whether these 2 SNPs are associated with disease free survival (DFS) in a large cohort of HER2+ early stage breast cancer pts receiving adjuvant chemo +/- trastuzumab; as well as whether they are associated with PFS in a cohort of HER2+ MBC pts receiving trastuzumab-based therapy.Methods: Genomic DNA was prepared from serum/blood samples from &gt;1300 pts enrolled in a trial of adjuvant trastuzumab-based chemo (BCIRG-006), and from another 52 pts who were tx'd with trastuzumab-based therapy for MBC. 158V/F & 131H/R SNP genotyping was performed using allele-specific PCR and confirmed by direct Sanger sequencing and mass spectrometry. DFS and PFS were calculated by Kaplan-Meier and compared using the log-rank test.Results: Among 1286 pt samples from BCIRG006 analyzed to date (414 tx'd with chemo alone, 872 tx'd with trastuzumab and chemo) 1199 have been successfully genotyped for FcγRIIIa and 1233 for FcγRIIa. In pts who received chemo alone (AC-T), no correlation was seen between FcγRIIIa158 genotype and DFS (p=0.92) and/or FcγRIIa131 genotype and DFS (p=0.91). No correlation between DFS and FcR genotype was seen for trastuzumab-tx'd pts (158 VV vs. VF vs. FF, p=0.96; 131 HH vs. HR vs. RR, p=0.97; 158 V/V and/or 131H/H vs. others, p=0.97). No correlation was seen between DFS & FcR genotype when the 2 trastuzumab-based regimens were analyzed separately (AC-TH: 158 VV vs VF vs FF p=0.90; 131 HH vs HR vs RR, p=0.63 and TCH: 158 VV vs VF vs FF, p=0.99; 131 HH vs HR vs RR, p=0.76). In the MBC cohort, there was also no difference in PFS when comparing 158V/V and/or 131H/H vs. others (p=0.47).Conclusions: The largest analysis to evaluate the association between FcR genotypes and trastuzumab efficacy in HER2+ breast cancer failed to confirm results from previously published smaller studies. In contrast to those studies, we find no statistically significant correlation between FcR SNPs and DFS in early breast cancer tx'd with adjuvant chemo +/- trastuzumab and no correlation between FcR SNPs and PFS for pts with trastuzumab-tx'd, HER2+ MBC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 64.