Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Frontier Science Foundation- Hellas, Athens, Greece3University of Athens, Athens, Greece.
JAMA Oncol. 2016 Aug 1;2(8):1040-7. doi: 10.1001/jamaoncol.2016.0339.
A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown.
To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial.
DESIGN, SETTING, AND PARTICIPANTS: The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2).
Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines.
Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models.
Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03; OS ITT Pvalue for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS Pvalue for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab.
Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (≥2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven.
clinicaltrials.gov Identifier: NCT00045032.
一些研究表明，抗人表皮生长因子受体-2（目前称为 ERBB2，但在本研究中称为 HER2）药物的反应因雌激素受体（ER）水平状态而异。其临床相关性尚不清楚。
根据 HERceptin 辅助（HERA）试验中 ER 和 HER2 的定量水平，确定曲妥珠单抗的获益幅度。
设计、地点和参与者：HERA 试验是一项国际、多中心、随机试验，纳入了 5099 例早期 HER2 阳性乳腺癌患者，2001 年至 2005 年期间随机分为接受或不接受曲妥珠单抗治疗，在辅助化疗后。这是 HERA 研究的二次分析。为 3037 例（59.6%）随机接受观察和曲妥珠单抗（1 年或 2 年）（队列 1）的患者提供了局部 ER 免疫组织化学（IHC）分析、HER2 荧光原位杂交（FISH）比值和拷贝数结果。为 615 例（12.1%）患者（队列 2）提供了 ESR1 和 HER2 基因的转录水平。
患者随机接受无曲妥珠单抗或 1 年或 2 年的曲妥珠单抗治疗。根据当地指南，为激素受体阳性疾病的患者提供内分泌治疗。
无病生存（DFS）和总生存（OS）是意向治疗人群（ITT）的主要和次要终点。还进行了调整交叉（删失和逆概率加权[IPW]）的分析。使用预定义的截止值评估治疗、ER 状态和 HER2 扩增之间的相互作用，在 Cox 比例风险回归模型中进行。
中位随访时间为 8 年。FISH 和 HER2 拷贝数水平在 ER 阴性患者中显著升高（P<0.001）。在队列 1 中，对于 DFS 和 OS，除了 ER 阳性/HER2 低 FISH 比值（≥2 至<5）组外（DFS：3 路 ITT 交互作用 P 值为 0.07；删失为 0.02；IPW 为 0.03；OS ITT 交互作用 P 值为 0.007；删失为 0.04；IPW 为 0.03），所有 ER、IHC 和 FISH 水平均发现治疗效果显著。在队列 2 中，与队列 1 一致，也观察到 ESR1 基因对两个终点的显著预测作用（DFS 交互作用 P 值为 0.06；OS 为 0.02），表明 ESR1 水平较高的乳腺癌患者从曲妥珠单抗治疗中获益较少。
HER2 阳性乳腺癌患者，IHC 分析为 ER 阳性且 FISH 比值（≥2 至<5）较低，或 ESR1 水平较高，在接受化疗后接受辅助曲妥珠单抗治疗的获益显著降低。这些数据可能解释了 HER2 阳性、ER 阳性乳腺癌中对抗 HER2 药物反应的异质性，因为一些可能比 HER2 驱动的更具腔细胞样。
clinicaltrials.gov 标识符：NCT00045032。
