Immunoglobulin G fragment C gamma receptor (FcGR) polymorphisms and efficacy of single-agent trastuzumab in patients treated with metastatic breast cancer.

Abstract

#6073 Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) may be involved in antitumor effect of therapeutic monoclonal antibodies and their effector functions are induced following the interactions of IgG with FcGR. Studies have shown that FcGRIIIa-V158F and FcGRIIa-H131R polymorphisms may predict response to retuximab, cetuximab in patients with follicular lymphoma, colorectal cancer, and recently, trastuzumab-combined chemotherapy in breast cancer patients (J Clin Oncol 25; 1789, 2008). We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic breast cancer patients treated with single-agent trastuzumab treatment.
 Patients and Methods: Patients with HER2-positive (HercepTest (3+) or (2+) with gene amplification either in primary or metastatic site) metastatic breast cancer were enrolled onto this prospective study. Eligible patients were hormone receptor negative or endocrine therapy resistant, and had received no prior chemotherapy for metastatic disease. Study patients received single agent trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg per week until disease progression. The first clinical response was assessed at 8 week. FcGRIIIA-V158F and FcGRIIA-H131R genotypes were assessed from genomic DNA extracted from peripheral blood samples. The present study has been approved by the institutional review boards of National Cancer Center and Shikoku Cancer Center Hospital and all registered patients have given written consent to participate in this study.
 Results: To date, 33 patients have been enrolled. The frequency of FcGRIIIa-V158F genotypes were V/V 48%, V/F45%, F/F 6%, and that of FcGRIIA-H131R genotypes were H/H 59%, H/R38%, R/R 3% , respectively. 8-wk response could be evaluated in 29 patients (CR 1, PR 4, SD 13, PD 11). Clinical benefit was observed in 13 patients (CR 1, PR 6, SD>6months 6). FcGRIIIa-158V/V genotype was significantly correlated with 8-wk response (p=.017) and clinical benefit (p=0.02) of single-agent trastuzumab, while there was no significant difference in clinical response to trastuzumab by FcGRIIA-H131R polymorphism.
 Conclusion: Although still preliminary, these data support the previous finding that FcGRIIIa-V158F polymorphisms play an important role in the clinical activity of trastuzumab. Updated results will be presented at the 31st annual San Antonio Breast Cancer Symposium. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6073.

The role of pharmacogenetics in selection of breast cancer treatment

“…The Fc gamma RIIIa-158 V/V genotype was signifi cantly correlated with objective response rate and PFS, possibly due to higher trastuzumab-mediated cytotoxicity [53]. Similarly, the Fc gamma RIIIa-158V/V genotype was signifi cantly correlated with 8-week response and clinical benefi t in a single-arm study of single-agent trastuzumab in patients with metastatic breast cancer (n = 33) [54]. Larger studies are needed to further examine pharmacogenetic associations in trastuzumab and other agents that target HER-2.…”

“…Increased toxicity [48], reduced PFS and TTP in MBC [49] Bevacizumab VEGF Drug target -2578AA, -1154AA Improved OS [51] -634CC, -1498TT Less toxicity [51] Trastuzumab Fc gamma R Drug target -158VV Improved response rate and PFS in MBC [53,54] DFS-disease-free survival; DME-drug metabolizing enzymes; EFS-event-free survival; MBC-metastatic breast cancer; OS-overall survival; PFS-progression-free survival; RFS-relapse-free survival; RFT-relapse-free time; TTP-time to progression.…”

Predicting responses to chemotherapy in breast cancer: from bench to bedside

“…Antibody-dependent cell-mediated cytotoxicity (ADCC) of natural killer cells/monocytes may be involved in the antitumor effects of trastuzumab as their effector functions are induced following the interactions of IgG with fragment C receptor (FCGR). In addition, FCGR polymorphisms play an important role in the clinical effects of trastuzumab [19,20].…”