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- Title
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.
- Authors
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.
- Abstract
<bold>Introduction: </bold>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.<bold>Methods: </bold>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 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence.<bold>Results: </bold>Median follow-up was 7.4 years. 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.<bold>Conclusions: </bold>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.<bold>Trial Registration: </bold>Clinicaltrials.gov NCT00005970 . Registered 5 July 2000.
- Subjects
BREAST cancer treatment; EPIDERMAL growth factor receptor genetics; TRASTUZUMAB; REVERSE transcriptase polymerase chain reaction; GENE expression; IMMUNOLOGICAL adjuvants; ANTINEOPLASTIC agents; BREAST tumors; CANCER relapse; CELL receptors; CLINICAL trials; DRUG resistance in cancer cells; POLYMERASE chain reaction; PROGNOSIS; RESEARCH funding; TREATMENT effectiveness; PROPORTIONAL hazards models; PHARMACODYNAMICS; PREVENTION
- Publication
Breast Cancer Research, 2015, Vol 17, Issue 1, p1
- ISSN
1465-5411
- Publication type
journal article
- DOI
10.1186/s13058-015-0643-7