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

By A. Musolino, N. Naldi, B. Bortesi, D. Pezzuolo, M. Capelletti, G. Missale, D. Laccabue, A. Zerbini, R. Camisa, G. Bisagni and 2 more. Journal of Clinical Oncology, 2008

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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.

Subfields: Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/b4a166ed747e8932b8ece9ede797a386c924e9a0

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Citations in the corpus

Antibodies and cancer therapy: versatile platforms for cancer immunotherapy (2010, background): “More recent findings show that polymorphisms in genes encoding FcγRs are associated with clinical responses to other antibodies, including trastuzuma”
Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. (2009, background): “Activation of ADCC has been described as a major mechanism of action of trastuzumab (13, 14, 38) and the present study confirms that this is also a property of pertuzumab.”
Novel anticancer targets: revisiting ERBB2 and discovering ERBB3 (2009, background): “As a result of antibody binding to the ERBB2 extracellular domain, trastuzumab causes antibody-dependent cell-mediated cytotoxicity (ADCC”
Antibody therapy of cancer (2012, background): “ADCC has been demonstrated to have a major role in antibody efficacy, and there is evidence that FcγRIIa-131H polymorphisms have a favourable effect on response rates for cetuximab in colorectal cancer, trastuzumab in breast cancer and rituximab in follicular lymphom”
Treatment of HER2-positive breast cancer: current status and future perspectives (2012, background): “The genotype of the FcγRIIIa-158 correlates with response and progression-free survival (PFS) in patients receiving trastuzumab-based therapy for metastatic breast cancer, suggesting that ADCC is important in the antitumor activity of trastuzumab”
ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics (2014, background): “Polymorphisms in the gene encoding FcgRIII in humans were associated with resistance to trastuzumab in patients with metastatic HER2+ breast cancer (Musolino et al., 2008).”
A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. (2008, background): “For example, it has recently been reported that specific polymorphisms in FcgRIIIa and FcgRIIa that mediate greater efficiency of FcgR engagement are associated with improved outcome on trastuzumab (37).”
Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “…or monocytes due to certain FcgRIII polymorphisms have also been associated with the outcome of trastuzumab treatment in HER2-positive breast cancer (Musolino et al., 2008) and similarly in cetuximab treatment of head and neck squamous cell carcinoma cell lines (López-Albaitero et al., 2009).”