Polimorfismi del recettore del frammento costante delle immunoglobuline G ed efficacia clinica del trattamento con Trastuzumab in pazienti affette da carcinoma mammario metastatico HER-2 positivo

Background: The anti-HER-2/neu monoclonal antibody Trastuzumab has been shown to engage both activatory (FcγRIIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors and FcγR 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 FcγR polymorphisms are associated with clinical outcome of breast cancer patients who received trastuzumab. Methods: Fifty-four consecutive HER-2/neu-amplified breast cancer patients receiving trastuzumab plus taxane for metastatic disease were genotypized for the FcγRIIIa-158 valine(V)/phenylalanine(F), FcγRIIa-131 histidine(H)/arginine(R), and FcγRIIb-232 isoleucine(I)/threonine(T) polymorphisms. Trastuzumab-mediated ADCC of patients’ peripheral blood mononuclear cells (PBMCs) was measured by 51Cr 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 FcγRIIb polymorphism. The FcγRIIIa-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 FcγRIIa-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. Conclusions: These data support for the first time the hypothesis that FcγR-mediated ADCC plays an important role in the clinical effect of trastuzumab. Prospective studies are needed to confirm the role of FcγR polymorphisms in predicting clinical outcome of breast cancer patients treated with trastuzumab-based therapy.