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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.
J Clin Oncol. 2008 Apr 10; 26(11):1789-96.JC

Abstract

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.

Authors+Show Affiliations

Medical Oncology Unit, University Hospital of Parma, via Gramsci 14, 43100 Parma, Italy. antoninomusolino@hotmail.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18347005

Citation

Musolino, Antonino, et al. "Immunoglobulin G Fragment C Receptor Polymorphisms and Clinical Efficacy of Trastuzumab-based Therapy in Patients With HER-2/neu-positive Metastatic Breast Cancer." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 26, no. 11, 2008, pp. 1789-96.
Musolino A, Naldi N, Bortesi B, et al. 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;26(11):1789-96.
Musolino, A., Naldi, N., Bortesi, B., Pezzuolo, D., Capelletti, M., Missale, G., Laccabue, D., Zerbini, A., Camisa, R., Bisagni, G., Neri, T. M., & Ardizzoni, A. (2008). Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 26(11), 1789-96. https://doi.org/10.1200/JCO.2007.14.8957
Musolino A, et al. 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. PubMed PMID: 18347005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. AU - Musolino,Antonino, AU - Naldi,Nadia, AU - Bortesi,Beatrice, AU - Pezzuolo,Debora, AU - Capelletti,Marzia, AU - Missale,Gabriele, AU - Laccabue,Diletta, AU - Zerbini,Alessandro, AU - Camisa,Roberta, AU - Bisagni,Giancarlo, AU - Neri,Tauro Maria, AU - Ardizzoni,Andrea, Y1 - 2008/03/17/ PY - 2008/3/19/pubmed PY - 2008/5/6/medline PY - 2008/3/19/entrez SP - 1789 EP - 96 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J. Clin. Oncol. VL - 26 IS - 11 N2 - 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. SN - 1527-7755 UR - https://www.unboundmedicine.com/medline/citation/18347005/Immunoglobulin_G_fragment_C_receptor_polymorphisms_and_clinical_efficacy_of_trastuzumab_based_therapy_in_patients_with_HER_2/neu_positive_metastatic_breast_cancer_ L2 - http://ascopubs.org/doi/full/10.1200/JCO.2007.14.8957?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -