Originally published as JCO Early Release 10.1200/JCO.2007.14.8957 on March 17 2008

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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, 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

Corresponding author: Antonino Musolino, MD, Medical Oncology Unit, University Hospital of Parma, via Gramsci 14, 43100 Parma, Italy; e-mail: antoninomusolino{at}hotmail.com

Purpose The anti–HER-2/neu monoclonal antibody trastuzumab has been shown to engage both activatory (fragment C receptor [FcR]IIIa; FcRIIa) and inhibitory (FcRIIb) antibody receptors and FcR 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 FcR polymorphisms are associated with clinical outcome of patients with breast cancer who received 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 FcRIIIa-158 valine(V)/phenylalanine(F), FcRIIa-131 histidine(H)/arginine(R), and FcRIIb-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 FcRIIb polymorphism. The FcRIIIa-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 FcRIIa-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 FcR-mediated ADCC plays an important role in the clinical effect of trastuzumab. Prospective studies are needed to confirm the role of FcR polymorphisms in predicting clinical outcome of patients with breast cancer treated with trastuzumab-based therapy.

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 glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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