美国全国乳腺癌肠癌术后辅助治疗研究协作组（NSABP）前瞻研究B-20的回顾分析表明，当21基因检测（Oncotype DX）乳腺癌复发评分≥31时，他莫昔芬＋化疗与单用他莫昔芬相比，淋巴结阴性雌激素受体阳性乳腺癌的远处复发风险显著减少。不过，HER2基因表达水平作为21基因检测乳腺癌复发评分的组成部分，与复发评分成正比，由于B-20研究入组时HER2基因检测尚未普及，如果入组时剔除HER2阳性患者，那么对于21基因检测乳腺癌复发评分预测效果的质疑油然而生。
2018年11月14日，美国乳腺癌研究基金会和英国《自然》旗下《乳腺癌》在线发表NSABP、弗吉尼亚联邦大学、匹兹堡大学、佛罗里达大学、奥兰多医疗、基因组医疗、阿勒格尼医疗、韩国延世大学的研究报告，剔除HER2阳性患者后，对21基因B-20研究进行了探索性二次分析。
该二次分析通过逆转录聚合酶链反应（RT-PCR）将HER2定量≥11.5单位的HER2阳性患者剔除后，采用B-20研究临界值（<18、18-30、≥31）以及TAILORx研究临界值（<11、11-25、>25）患者进行分组重新分析，终点仍为无远处复发间隔时间。通过生存曲线法推算无远处复发分布，并且通过对数秩检验进行比较。通过多因素比例风险回归模型，推算不同复发评分的化疗获益。
结果发现，复发评分<18、18-30、≥31的患者组，HER2阳性率分别为1.7、6.7%、41%。剔除HER2阳性患者后，导致远处复发事件减少，所有HER2阴性患者的化疗获益失去统计学意义（对数秩P=0.06），但是化疗显著获益仍可见于复发评分较高的HER2阴性患者：
复发评分≥31：化疗的远处复发风险减少82%（风险比：0.18，95%置信区间：0.07～0.47）
复发评分>25：化疗的远处复发风险减少72%（风险比：0.28，95%置信区间：0.12～0.64）
其他复发评分：化疗的远处复发风险减少不显著
因此，该二次分析结果表明，通过RT-PCR表达水平剔除HER2阳性患者后，对于B-20研究复发评分≥31、TAILORx研究复发评分>25的患者，化疗＋他莫昔芬与单用他莫昔芬相比，远处复发风险仍然显著减少。
NPJ Breast Cancer. 2018 Nov 14. [Epub ahead of print]
21-Gene assay as predictor of chemotherapy benefit in HER2-negative breast cancer.
Charles E. Geyer Jr., Gong Tang, Eleftherios P. Mamounas, Priya Rastogi, Soonmyung Paik, Steven Shak, Frederick L. Baehner, Michael Crager, D. Lawrence Wickerham, Joseph P. Costantino, Norman Wolmark.
NRG Oncology/NSABP, Pittsburgh, PA, USA; Virginia Commonwealth University, Richmond, VA, USA; The University of Pittsburgh, Pittsburgh, PA, USA; Orlando Health UF Health Cancer Center, Orlando, FL, USA; Yonsei University, Seoul, Korea; Genomic Health, Inc., Redwood, CA, USA; Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA.
The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was ≥31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded. We report an exploratory reanalysis of the B-20, 21-gene study following exclusion of such patients. Patients were considered HER2 positive if quantitative RT-PCR for HER2 was ≥11.5 units, and excluded from re-analyses performed using the original cutoffs: <18, 18-30, ≥31, and the TAILORx cutoffs: <11, 11-25, >25. The endpoint remained distant recurrence-free interval (DRFI) as in the original study. Distribution was estimated via the Kaplan-Meier method and compared via log-rank test. Multivariate Cox proportional hazards models estimated chemotherapy benefit in each group. In the RS < 18 and 18-30 groups, 1.7 and 6.7% were HER2 positive. In the RS ≥ 31 group, 41% were HER2 positive. Exclusion resulted in fewer events, with loss of significance for benefit from chemotherapy in the overall HER2-negative cohort (log-rank P = 0.06), but substantial benefit from chemotherapy remained in the RS ≥ 31 cohort (HR = 0.18; 95% CI: 0.07-0.47) and the RS > 25 cohort (HR = 0.28; 95% CI: 0.12-0.64). No benefit from chemotherapy was evident in the other RS groups. Following exclusion of HER2-positive patients based on RT-PCR expression, substantial benefit of chemotherapy remained for RS ≥ 31 as originally employed, and with RS > 25 employed in TAILORx.
DOI: 10.1038/s41523-018-0090-6
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