Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3
Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3
复制标题
DOI：
10.1200/jco.2015.63.9161
复制
发表时间：
2016-06-20
影响因子：
45.3
通讯作者：
Slamon, Dennis
中科院分区：
文献类型：
--
作者：
Andre, Fabrice;Hurvitz, Sara;Slamon, Dennis
目的最近的两项III期临床试验，BOLERO-1和BOLERO-3（口服依维莫司的乳腺癌试验），评价了在曲妥珠单抗和化疗中加入依维莫司治疗人表皮生长因子受体2过度表达的晚期乳腺癌。目前的分析旨在确定生物标志物，以预测依维莫司treatment.MethodsArchival肿瘤样本中的患者在BOLERO-1和BOLERO-3进行了分析，使用下一代测序，免疫组化，和桑格sequencing.ResultsBiomarker数据为549例。分别在30%和16%的BOLERO-1样本和32%和12%的BOLERO-3样本中报告了PIK 3CA激活突变和PTEN丢失。在47%的BOLERO-1和41%的BOLERO-3样品中，PI 3 K途径过度活跃（PIK 3CA突变和/或PTEN丢失和/或AKT 1突变）。在这两项研究中，在根据PI 3 K通路状态定义的患者亚组中一致观察到依维莫司的不同无进展生存期（PFS）获益。当分析两项研究的合并数据集时，依维莫司与PIK 3CA突变患者的进展风险降低相关（风险比[HR]，0.67; 95% CI，0.45 - 1.00），PTEN丢失（HR，0.54; 95%CI，0.31至0.96），或PI 3 K通路过度活跃（HR，0.67; 95%CI，0.48至0.93）。野生型PIK 3CA患者（HR，1.10; 95% CI，0.83至1.46），正常PTEN（HR，1.00; 95% CI，0.80 - 1.26）或正常PI 3 K通路活性（HR，1.19; 95%CI，0.87至1.62）并没有从依维莫司中获得PFS益处。提示患有PIK 3CA突变、PTEN缺失或PI 3 K通路过度活跃的肿瘤的人表皮生长因子受体2阳性晚期乳腺癌患者可从依维莫司获得PFS获益。(C)2016年美国临床肿瘤学会
PurposeTwo recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2-overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment.MethodsArchival tumor samples from patients in BOLERO-1 and BOLERO-3 were analyzed using next-generation sequencing, immunohistochemistry, and Sanger sequencing.ResultsBiomarker data were available for 549 patients. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 samples and in 32% and 12% of BOLERO-3 samples, respectively. PI3K pathway was hyperactive (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) in 47% of BOLERO-1 and 41% of BOLERO-3 samples. In both studies, differential progression-free survival (PFS) benefits of everolimus were consistently observed in patient subgroups defined by their PI3K pathway status. When analyzing combined data sets of both studies, everolimus was associated with a decreased hazard of progression in patients with PIK3CA mutations (hazard ratio [HR], 0.67; 95% CI, 0.45 to 1.00), PTEN loss (HR, 0.54; 95% CI, 0.31 to 0.96), or hyperactive PI3K pathway (HR, 0.67; 95% CI, 0.48 to 0.93). Patients with wild-type PIK3CA (HR, 1.10; 95% CI, 0.83 to 1.46), normal PTEN (HR, 1.00; 95% CI, 0.80 to 1.26), or normal PI3K pathway activity (HR, 1.19; 95% CI, 0.87 to 1.62) did not derive PFS benefit from everolimus.ConclusionThis analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2-positive advanced breast cancer having tumors with PIK3CA mutations, PTEN loss, or hyperactive PI3K pathway could derive PFS benefit from everolimus. (C) 2016 by American Society of Clinical Oncology