Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer

J Clin Oncol. 2008 Apr 10;26(11):1789-96. doi: 10.1200/JCO.2007.14.8957. Epub 2008 Mar 17.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antibody-Dependent Cell Cytotoxicity / genetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Disease-Free Survival
  • Docetaxel
  • Female
  • Genotype
  • Humans
  • Middle Aged
  • Paclitaxel / administration & dosage
  • Polymorphism, Genetic*
  • Receptor, ErbB-2 / metabolism*
  • Receptors, IgG / genetics*
  • Receptors, IgG / metabolism
  • Signal Transduction
  • Taxoids / administration & dosage
  • Trastuzumab
  • Treatment Outcome


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Receptors, IgG
  • Taxoids
  • Docetaxel
  • Receptor, ErbB-2
  • Trastuzumab
  • Paclitaxel