Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
N Engl J Med. 2012 Feb 9;366(6):520-9. doi: 10.1056/NEJMoa1109653. Epub 2011 Dec 7.
BACKGROUND: Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity. METHODS: In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed. RESULTS: Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). CONCLUSIONS: Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).
背景：乳腺癌对内分泌治疗的耐药性与哺乳动物雷帕霉素靶蛋白（mTOR）细胞内信号通路的激活有关。在早期研究中，添加至内分泌治疗的 mTOR 抑制剂依维莫司显示出抗肿瘤活性。
方法：在这项 3 期、随机试验中，我们比较了依维莫司联合依西美坦与依西美坦联合安慰剂（按 2:1 的比例随机分配）在 724 例激素受体阳性、先前在辅助治疗或治疗晚期疾病时接受过非甾体芳香酶抑制剂治疗时发生复发或进展的晚期乳腺癌患者中的疗效。主要终点是无进展生存期。次要终点包括生存、缓解率和安全性。在观察到 359 例无进展生存事件后，由独立的数据和安全监测委员会进行了计划中的中期分析。
结果：两组患者的基线特征均衡。中位年龄为 62 岁，56%有内脏转移，84%为激素敏感型疾病。先前的治疗包括来曲唑或阿那曲唑（100%）、他莫昔芬（48%）、氟维司群（16%）和化疗（68%）。最常见的 3 级或 4 级不良事件为口腔炎（依维莫司联合依西美坦组 8%，安慰剂联合依西美坦组 1%）、贫血（6% vs. <1%）、呼吸困难（4% vs. 1%）、高血糖（4% vs. <1%）、疲劳（4% vs. 1%）和肺炎（3% vs. 0%）。根据当地研究者的评估，在中期分析时，依维莫司联合依西美坦组和安慰剂联合依西美坦组的中位无进展生存期分别为 6.9 个月和 2.8 个月（进展或死亡的风险比，0.43；95%置信区间[CI]，0.35 至 0.54；P<0.001）。根据中心评估，中位无进展生存期分别为 10.6 个月和 4.1 个月（风险比，0.36；95%CI，0.27 至 0.47；P<0.001）。
结论：依维莫司联合芳香酶抑制剂可改善先前接受非甾体芳香酶抑制剂治疗的激素受体阳性晚期乳腺癌患者的无进展生存期。（由诺华公司资助；BOLERO-2 临床试验.gov 编号，NCT008
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