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

Edith A. Perez, Frederick L. Baehner, Steven M. Butler, E. Aubrey Thompson, Amylou C. Dueck, Farid Jamshidian, Diana Cherbavaz, Carl Yoshizawa, Steven Shak, Peter A. Kaufman, Nancy E. Davidson, Julie Gralow, Yan W. Asmann, Karla V. Ballman

Research output: Contribution to journalArticle

Abstract

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 2 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.

Original languageEnglish (US)
Article number133
JournalBreast Cancer Research
Volume17
Issue number1
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

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erbB-1 Genes
Reverse Transcriptase Polymerase Chain Reaction
Gene Expression
Genes
Fluorescence In Situ Hybridization
Immunohistochemistry
Paclitaxel
Recurrence
Doxorubicin
Cyclophosphamide
Messenger RNA
human ERBB2 protein
Trastuzumab
Drug Therapy
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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, Edith A.; Baehner, Frederick L.; Butler, Steven M.; Thompson, E. Aubrey; Dueck, Amylou C.; Jamshidian, Farid; Cherbavaz, Diana; Yoshizawa, Carl; Shak, Steven; Kaufman, Peter A.; Davidson, Nancy E.; Gralow, Julie; Asmann, Yan W.; Ballman, Karla V.

In: Breast Cancer Research, Vol. 17, No. 1, 133, 01.10.2015.

Research output: Contribution to journalArticle

Perez, EA, Baehner, FL, Butler, SM, Thompson, EA, Dueck, AC, Jamshidian, F, Cherbavaz, D, Yoshizawa, C, Shak, S, Kaufman, PA, Davidson, NE, Gralow, J, Asmann, YW & 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, vol. 17, no. 1, 133. https://doi.org/10.1186/s13058-015-0643-7
Perez, Edith A. ; Baehner, Frederick L. ; Butler, Steven M. ; Thompson, E. Aubrey ; Dueck, Amylou C. ; Jamshidian, Farid ; Cherbavaz, Diana ; Yoshizawa, Carl ; Shak, Steven ; Kaufman, Peter A. ; Davidson, Nancy E. ; Gralow, Julie ; Asmann, Yan W. ; Ballman, Karla V. / 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. In: Breast Cancer Research. 2015 ; Vol. 17, No. 1.
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abstract = "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{\circledR}) (negative 2 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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T1 - 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

AU - Perez, Edith A.

AU - Baehner, Frederick L.

AU - Butler, Steven M.

AU - Thompson, E. Aubrey

AU - Dueck, Amylou C.

AU - Jamshidian, Farid

AU - Cherbavaz, Diana

AU - Yoshizawa, Carl

AU - Shak, Steven

AU - Kaufman, Peter A.

AU - Davidson, Nancy E.

AU - Gralow, Julie

AU - Asmann, Yan W.

AU - Ballman, Karla V.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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 2 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.

AB - 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 2 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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