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Analysis of Fcγ Receptor IIIa and IIa Polymorphisms: Lack of Correlation with Outcome in Trastuzumab-Treated Breast Cancer Patients
Open accessPublished version of a preprint
Abstract
PURPOSE: The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high-affinity SNPs are associated with disease-free survival (DFS) among patients with HER2-positive nonmetastatic breast cancer. EXPERIMENTAL DESIGN: Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was conducted using Sanger sequencing and Sequenom mass spectrometry. RESULTS: Patient samples (N = 1,189) were successfully genotyped for FCGR3A and 1,218 for FCGR2A. Compared with the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms than control arm (HR, 0.842; P = 0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR, 0.74; P = 0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs. V/F vs. F/F, P = 0.98; 131H/H vs. H/R vs. R/R, P = 0.76; 158V/V and/or 131H/H vs. others, P = 0.67). CONCLUSION: This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not show a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab.
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“We should note, however, that a large trial of trastuzumab-based adjuvant chemotherapy in patients with early HER2+ breast cancer did not show an association between FCGR3A and FCGR2A polymorphisms with patient outcome (Hurvitz et al., 2012)”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Hurvitz et al., 2012
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Metadata
- Authors
- Hurvitz, S. A., Betting, D. J., Stern, H. M., Quinaux, E., Stinson, J., Seshagiri, S., Zhao, Y., Buyse, M., Mackey, J., Driga, A., Damaraju, S., Sliwkowski, M. X., Robert, N. J., Valero, V., Crown, J., Falkson, C., Brufsky, A., Pienkowski, T., Eiermann, W., Martin, M., Bee, V., Marathe, O., Slamon, D. J., & Timmerman, J. M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Authors' Affiliations: 1University of California at Los Angeles, Los Angeles; 2Genentech, South San Francisco, California; 3International Drug Development Institute, Louvain-la-Neuve, Belgium; 4Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada; 5Virginia Cancer Specialists, US Oncology, Fairfax, Virginia; 6University of Texas MD Anderson Cancer Center, Houston, Texas; 7St. Vincent's Hospital, Dublin, Ireland; 8University of Alabama at Birmingham, Birmingham, Alabama; 9University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 10Cancer Center, Warsaw, Poland; 11Redcross Women's Hospital, Muenchen, Germany; 12Hospital Gregorio Maranon, Madrid, Spain; and 13Breast Cancer International Research Group (BCIRG), Paris, France
- Corresponding author
- Hurvitz, Sara A.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-06-14
- Volume
- 18
- Issue
- 12
- Pages
- 3478-3486
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3821872
- OpenAlex
- W2162904392
- Cited by
- 115
- References
- 27
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 10 · 2018: 6 · 2017: 11 · 2016: 14 · 2015: 16 · 2014: 13 · 2013: 9 · 2012: 5
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1ul1rr033176-01, UL1TR000124)
- National Cancer Institute (P30CA016042)
- National Center for Research Resources (UL1-RR-033176)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Oncology › Gastric Cancer Management and Outcomes
- Keywords
- FcγRIIIa, FCGR2A, single nucleotide polymorphisms, trastuzumab, HER2-positive breast cancer, disease-free survival, antibody-dependent cellular cytotoxicity, pharmacogenetics, adjuvant chemotherapy
- MeSH terms
- Trastuzumab, Adult, Aged, Breast Neoplasms, Female, Gene Frequency, Genotype, Humans, Middle Aged, Treatment Outcome, Receptors, IgG, Amino Acid Substitution, Polymorphism, Single Nucleotide, Young Adult, Antibodies, Monoclonal, Humanized
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