Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study
Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study
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DOI：
10.1200/jco.2011.39.0708
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发表时间：
2012-08-01
影响因子：
45.3
通讯作者：
Pujade-Lauraine, Eric
中科院分区：
文献类型：
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作者：
Bachelot, Thomas;Bourgier, Celine;Pujade-Lauraine, Eric
目的
信号转导通路之间的相互作用可能导致转移性乳腺癌（mBC）的激素耐药。依维莫司是一种口服的哺乳动物雷帕霉素靶蛋白抑制剂，在内分泌耐药模型中恢复了敏感性，并在早期mBC临床试验中显示出抗癌活性。本分析评估了依维莫司联合他莫昔芬在芳香化酶抑制剂（AIs）耐药的mBC患者中的疗效和安全性。
患者与方法
这项开放标签的Ⅱ期研究将绝经后激素受体阳性、人表皮生长因子受体2阴性、AI耐药的mBC女性随机分配至他莫昔芬20mg/天联合依维莫司10mg/天组（n = 54）或他莫昔芬20mg/天单药组（n = 57）。随机分组根据原发性和继发性激素耐药进行分层。主要终点是临床获益率（CBR），定义为在6个月时所有完全缓解、部分缓解或病情稳定患者的百分比。未计划在两组之间进行正式的统计学比较。
结果
他莫昔芬联合依维莫司组6个月的CBR为61%（95%置信区间，47% - 74%），他莫昔芬单药组为42%（95%置信区间，29% - 56%）。疾病进展时间（TTP）从他莫昔芬单药组的4.5个月增加到他莫昔芬联合依维莫司组的8.6个月，联合用药使进展风险降低了46%（风险比[HR]，0.54；95%置信区间，0.36 - 0.81）。与他莫昔芬单药相比，他莫昔芬联合依维莫司使死亡风险降低了55%（HR，0.45；95%置信区间，0.24 - 0.81）。与他莫昔芬联合依维莫司相关的主要毒性反应是疲劳（72%对他莫昔芬单药组的53%）、口腔炎（56%对7%）、皮疹（44%对7%）、厌食（43%对18%）和腹泻（39%对11%）。
结论
本研究表明，在绝经后AI耐药的mBC女性中，与他莫昔芬单药相比，他莫昔芬联合依维莫司提高了CBR、TTP和总生存期。
PurposeCross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs).Patients and MethodsThis open-label, phase II study randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned.ResultsThe 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% ( 95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%).ConclusionThis study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.