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The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831

Perez, EA and Baehner, FL and Butler, SM and Thompson, EA and Dueck, AC and Jamshidian, F and Cherbavaz, D and Yoshizawa, C and Shak, S and Kaufman, PA and Davidson, NE and Gralow, J and Asmann, YW and Ballman, KV (2015) The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831. Breast Cancer Research, 17 (1). ISSN 1465-5411

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Abstract

© 2015 Perez et al. Introduction: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. Methods: N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative <10.7, equivocal 10.7 to <11.5, and positive ≥11.5 log<inf>2</inf> expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence. Results: Median follow-up was 7.4years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14%), equivocal in 85 (9%), and positive in 686 (76%) patients. Concordance between HER2 assessments was 95% for RT-PCR versus central immunohistochemistry (IHC) (>10% positive cells = positive), 91% for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94% for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. Trial registration: Clinicaltrials.gov NCT00005970. Registered 5 July 2000.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Perez, EA
Baehner, FL
Butler, SM
Thompson, EA
Dueck, AC
Jamshidian, F
Cherbavaz, D
Yoshizawa, C
Shak, S
Kaufman, PA
Davidson, NEned23@pitt.eduNED23
Gralow, J
Asmann, YW
Ballman, KV
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 1 October 2015
Date Type: Publication
Journal or Publication Title: Breast Cancer Research
Volume: 17
Number: 1
DOI or Unique Handle: 10.1186/s13058-015-0643-7
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
ISSN: 1465-5411
Date Deposited: 05 Aug 2016 17:29
Last Modified: 04 Feb 2019 15:59
URI: http://d-scholarship.pitt.edu/id/eprint/29139

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