12月6-10日，第34届圣安东尼奥乳腺癌大会在美国德克萨斯州圣安东尼奥的Henry B. Gonzalez会议中心举办。大会主题是“一个在乳腺癌中基础科学和临床医生相互作用和交流的国际科学会议。”
德克萨斯大学M.D. Anderson 癌症中心的Gabriel N. Hortobagyi博士在圣安东尼奥乳腺癌在研讨会上报告了Ⅲ期BOLERO-2试验的结果：对于既往激素治疗后已出现疾病进展的绝经后激素受体阳性（HR+）乳腺癌患者，与依西美坦或安慰剂相比，依维莫司+依西美坦联合治疗可使中位无进展生存期和临床获益率翻倍。上述结果同期发表在《新英格兰医学杂志》12月7日在线版上。
Hortobagyi 博士在新闻发布会上发布声明：“这是首次在大规模Ⅲ期试验中证实，对于已接受过内分泌治疗的患者，二联治疗的疗效优于单药内分泌治疗。” BOLERO-2的发现将改变目前难治性乳腺癌患者的标准治疗方案，即从序贯使用其他芳香酶抑制剂转变为同时使用芳香酶抑制剂和雌激素信号通路抑制剂，例如联用依西美坦和PI3激酶/AKT/mTOR通路抑制剂依维莫司。
2009年6月~2011年1月，研究者从24个国家189家医疗中心招募对非甾体芳香酶抑制剂耐药的女性HR+乳腺癌患者，纳入口服依维莫司治疗乳腺癌试验-2（BOLERO-2）。其中485例患者随机接受依维莫司+依西美坦联合治疗（联合治疗组），239例随机接受依西美坦+安慰剂治疗（依西美坦单药组）。患者的平均年龄为62岁，56%有内脏受累，76%已发生骨转移。既往治疗包括来曲唑或阿那曲唑（100%）、他莫西芬（48%）、氟维司群（16%）和化疗（68%）。主要终点为无进展生存期。
结果显示，与依西美坦单药组相比，依维莫司+依西美坦联合治疗使中位无进展生存期由3.2个月增至7.4个月。不仅如此，联合治疗还使临床获益率由25.5%上升至50.5%，6个月时产生完全或部分应答或病情稳定的患者增加1倍。
但加用mTOR抑制剂在增强疗效的同时，也伴随着口炎、贫血和呼吸困难等不良事件的增加。最常见的3或4级不良事件为口炎（联合治疗组 vs. 依西美坦单药组：8% vs. 1%）、贫血（6% vs. ＜1%）、呼吸困难（4% vs. 1%）、高血糖（4% vs. ＜1%）、疲乏（4% vs. 1%）和肺炎（3% vs. 0%）。联合治疗组报告不良事件者的比例高出依西美坦单药组1倍（23% vs. 12%），停用依维莫司的患者也远多于停用安慰剂者（19% vs. 4%），并且有更多患者退出试验（5% vs. 2%）。在停用依西美坦的患者中，联合治疗组停用另一药物者（7% vs. 3%）和退出试验者（7% vs. 2%）也更多。
主要研究者、麻省总医院癌症中心的José Baselga博士认为，联合治疗组不良事件增多的情况，与既往依维莫司和其他雷帕霉素类似物的相关报告相符，包括口炎、疲乏、无力、腹泻、咳嗽、发热和高血糖等。联合治疗组患者治疗时间较长可能是其停药率较高的原因之一，提示应重视依维莫司的安全性并加强不良反应监测。
研究者总结称：“我们的研究结果与另2项采用依维莫司和抗雌激素药物治疗HR+乳腺癌的研究结果一致。鉴于这类患者的治疗选择有限，我们对观察到的收益感到满意。”（生物谷bioon.com）
doi:10.1056/NEJMoa1109653
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Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer
José Baselga, M.D., Ph.D., Mario Campone, M.D., Ph.D., Martine Piccart, M.D., Ph.D., Howard A. Burris, III, M.D., Hope S. Rugo, M.D., Tarek Sahmoud, M.D., Ph.D., Shinzaburo Noguchi, M.D., Michael Gnant, M.D., Kathleen I. Pritchard, M.D., Fabienne Lebrun, M.D., J. Thaddeus Beck, M.D., Yoshinori Ito, M.D., Denise Yardley, M.D.,et al.
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.)
