Immunoglobulin G Fragment C Receptor Polymorphisms and Clinical Efficacy of Trastuzumab-Based Therapy in Patients With HER-2/neu–Positive Metastatic Breast Cancer Antonino Musolino, Nadia Naldi, Beatrice Bortesi, Debora Pezzuolo, Marzia Capelletti, Gabriele Missale, Diletta Laccabue, Alessandro Zerbini, Roberta Camisa, Giancarlo Bisagni, Tauro Maria Neri, and Andrea Ardizzoni From the Medical Oncology Unit and Medical Genetics Unit; Laboratory of Viral Immunopathology, Department of Infectious Diseases and Hepatology, University Hospital of Parma, Parma; and the Department of Oncology, S. Maria Nuova Hospital, Reggio Emilia, Italy. Submitted October 15, 2007; accepted December 17, 2007; published online ahead of print at www.jco.org on March 17, 2008. Supported in part by the Cariparma Foundation (Fondazione Cassa di Risparmio di Parma, Parma, Italy). Terms in blue are defined in the glos- sary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Corresponding author: Antonino Musolino, MD, Medical Oncology Unit, University Hospital of Parma, via Gram- sci 14, 43100 Parma, Italy; e-mail: antoninomusolino@hotmail.com. © 2008 by American Society of Clinical Oncology 0732-183X/08/2611-1789/$20.00 DOI: 10.1200/JCO.2007.14.8957 A B S T R A C T Purpose The anti–HER-2/neu monoclonal antibody trastuzumab has been shown to engage both activatory (fragment C receptor [FcR]IIIa; FcRIIa) and inhibitory (FcRIIb) antibody receptors and FcR polymorphisms have been identified that may affect the antibody-dependent cell-mediated cytotoxicity (ADCC) of natural-killer cells/monocytes. In this study, we tested whether FcR polymorphisms are associated with clinical outcome of patients with breast cancer who re- ceived trastuzumab. Patients and Methods Fifty-four consecutive patients with HER-2/neu–amplified breast cancer receiving trastuzumab plus taxane for metastatic disease were evaluated for genotype for the FcRIIIa-158 valine(V)/ phenylalanine(F), FcRIIa-131 histidine(H)/arginine(R), and FcRIIb-232 isoleucine(I)/threonine(T) polymorphisms. Trastuzumab-mediated ADCC of patients’ peripheral blood mononuclear cells (PBMCs) was measured by chromium-51 release using a HER-2/neu– expressing human breast cancer cell line as a target. Controls comprised thirty-four patients treated with taxane alone. Results Our population was in Hardy-Weinberg equilibrium except for the FcRIIb polymorphism. The FcRIIIa-158 V/V genotype was significantly correlated with objective response rate (ORR) and progression-free survival (PFS). Also, there was trend significance in ORR and PFS for the FcRIIa-131 H/H genotype. The combination of the two favorable genotypes (VV and/or H/H) was independently associated with better ORR and PFS compared with the other combinations. The ADCC analysis showed that V/V and/or H/H PBMCs had a significantly higher trastuzumab- mediated cytotoxicity than PBMCs harboring different genotypes. Conclusion These data support for the first time the hypothesis that FcR-mediated ADCC plays an important role in the clinical effect of trastuzumab. Prospective studies are needed to confirm the role of FcR polymorphisms in predicting clinical outcome of patients with breast cancer treated with trastuzumab-based therapy. J Clin Oncol 26:1789-1796. © 2008 by American Society of Clinical Oncology INTRODUCTION The humanized anti-HER-2/neu immunoglobin G (IgG) 1 monoclonal antibody (mAb), trastuzumab, is an effective treatment for HER-2/neu–positive breast cancer. However, only 25% to 30% of patients with HER-2/neu–positive breast cancers will re- spond to this mAb and the exact mechanism of its antitumor effect is not clear. Direct antiproliferative and pro-apoptotic effects have been suggested by studies with trastuzumab in vitro on HER-2/neu– positive breast cancer cell lines. 1 Immune mecha- nisms, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity, may also be involved. This notion has been supported by several observations: trastu- zumab had a significantly reduced antitumor effect in IgG fragment C receptor (FcR) -deficient mice 2 ; HER-2/neu–positive breast cancer cell lines are sus- ceptible to ADCC and to complement-mediated cy- totoxicity in the presence of trastuzumab 3-5 ; and in vivo acitivity of trastuzumab has been correlated JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 26  NUMBER 11  APRIL 10 2008 © 2008 by American Society of Clinical Oncology 1789 Downloaded from jco.ascopubs.org on July 21, 2016. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.