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
Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.
Genomic Health, Inc, 301 Penobscot Drive, Redwood City, CA, 94063, USA.
Breast Cancer Res. 2015 Oct 1;17(1):133. doi: 10.1186/s13058-015-0643-7.
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.
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.
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.
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.
Clinicaltrials.gov NCT00005970 . Registered 5 July 2000.
N9831试验通过蛋白质或基因分析证明了辅助性曲妥珠单抗对人表皮生长因子受体2（HER2）局部阳性肿瘤患者的疗效。我们使用21基因检测法来研究HER2信使核糖核酸（mRNA）基因定量表达与曲妥珠单抗获益之间的关联。
N9831试验在Ⅰ-Ⅲ期HER2阳性乳腺癌患者中测试了曲妥珠单抗联合化疗的效果。在该试验的两个治疗组中，一组采用多柔比星和环磷酰胺序贯紫杉醇（AC-T）方案，另一组采用多柔比星和环磷酰胺序贯紫杉醇联合曲妥珠单抗同步化疗（AC-TH）方案，通过21基因检测法（Oncotype DX®）测定复发评分（RS）和HER2 mRNA表达（阴性<10.7，临界值为10.7至<11.5，阳性≥11.5 log2表达单位）。采用Cox回归分析评估HER2表达与曲妥珠单抗在预防远处复发方面的获益之间的关联。
中位随访时间为7.4年。在1940例患者中，901例患者同意并提供了足够的组织样本。通过逆转录聚合酶链反应（RT-PCR）检测，130例（14%）患者的HER2为阴性，85例（9%）为临界值，686例（76%）为阳性。HER2评估结果之间的一致性为：RT-PCR与中心免疫组织化学（IHC）（>10%阳性细胞=阳性）为95%，RT-PCR与中心荧光原位杂交（FISH）（≥2.0=阳性）为91%，中心IHC与中心FISH为94%。在初步分析中，通过21基因检测法测得的HER2表达与曲妥珠单抗获益之间的关联略无统计学意义（非线性p=0.057）。在激素受体阳性患者（局部IHC）中，该关联具有统计学意义（p=0.002）。该关联呈非线性，在HER2表达水平较低和较高时估计获益最大。
中心IHC、FISH和RT-PCR对HER2的评估结果之间的一致性相似且较高。通过远处复发时间衡量的HER2 mRNA表达与曲妥珠单抗获益之间的关联无统计学意义。在IHC阳性或FISH阳性肿瘤患者中，无论mHER2水平如何，均观察到曲妥珠单抗具有一致的获益。在任何一项或所有中心检测结果为阴性的小部分患者中也观察到了获益趋势。
Clinicaltrials.gov NCT00005970。2000年7月5日注册。
