Abstract
IntroductionThe 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.MethodsN9831 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.ResultsMedian 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.ConclusionsConcordance 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 registrationClinicaltrials.gov NCT00005970. Registered 5 July 2000.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0643-7) contains supplementary material, which is available to authorized users.
Highlights
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
Reliable testing methodology is critical and multiple discussions and publications related to this issue have been presented, addressing test reliability, and definition of “positivity,” and which tests may best help predict the efficacy of anti-HER2 therapies for patients; the optimal target: protein, RNA, or DNA, and type of detection assay [immunohistochemistry (IHC), reverse transcriptase polymerase chain reaction (RT-PCR), or fluorescence in situ hybridization (FISH)] for HER2 remains controversial [5,6,7,8,9,10,11,12,13,14,15,16]
Persistent problems with test accuracy were recently highlighted by both the North Central Cancer Treatment Group (NCCTG) and National Surgical Adjuvant Breast and Bowel Project (NSABP) National Cancer Institutesupported Cancer Cooperative Groups who demonstrated that approximately 3–7 % of breast cancers formerly assessed as HER2 positive in local laboratories were called HER2-normal [IHC
Summary
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. Persistent problems with test accuracy were recently highlighted by both the North Central Cancer Treatment Group (NCCTG) and National Surgical Adjuvant Breast and Bowel Project (NSABP) National Cancer Institutesupported Cancer Cooperative Groups who demonstrated that approximately 3–7 % of breast cancers formerly assessed as HER2 positive in local laboratories were called HER2-normal [IHC
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