12月6-10日,，第34屆圣安東尼奧乳腺癌大會在美國德克薩斯州圣安東尼奧的Henry B. Gonzalez會議中心舉辦,。大會主題是“一個在乳腺癌中基礎(chǔ)科學和臨床醫(yī)生相互作用和交流的國際科學會議。”
德克薩斯大學M.D. Anderson 癌癥中心的Gabriel N. Hortobagyi博士在圣安東尼奧乳腺癌在研討會上報告了Ⅲ期BOLERO-2試驗的結(jié)果：對于既往激素治療后已出現(xiàn)疾病進展的絕經(jīng)后激素受體陽性（HR+）乳腺癌患者,，與依西美坦或安慰劑相比,，依維莫司+依西美坦聯(lián)合治療可使中位無進展生存期和臨床獲益率翻倍。上述結(jié)果同期發(fā)表在《新英格蘭醫(yī)學雜志》12月7日在線版上,。
Hortobagyi 博士在新聞發(fā)布會上發(fā)布聲明：“這是首次在大規(guī)模Ⅲ期試驗中證實,，對于已接受過內(nèi)分泌治療的患者，二聯(lián)治療的療效優(yōu)于單藥內(nèi)分泌治療,。” BOLERO-2的發(fā)現(xiàn)將改變目前難治性乳腺癌患者的標準治療方案,，即從序貫使用其他芳香酶抑制劑轉(zhuǎn)變?yōu)橥瑫r使用芳香酶抑制劑和雌激素信號通路抑制劑，例如聯(lián)用依西美坦和PI3激酶/AKT/mTOR通路抑制劑依維莫司,。
2009年6月~2011年1月,，研究者從24個國家189家醫(yī)療中心招募對非甾體芳香酶抑制劑耐藥的女性HR+乳腺癌患者，納入口服依維莫司治療乳腺癌試驗-2（BOLERO-2）,。其中485例患者隨機接受依維莫司+依西美坦聯(lián)合治療（聯(lián)合治療組）,，239例隨機接受依西美坦+安慰劑治療（依西美坦單藥組）?；颊叩钠骄挲g為62歲,，56%有內(nèi)臟受累，76%已發(fā)生骨轉(zhuǎn)移,。既往治療包括來曲唑或阿那曲唑（100%）,、他莫西芬（48%）、氟維司群（16%）和化療（68%）,。主要終點為無進展生存期。
結(jié)果顯示,，與依西美坦單藥組相比,，依維莫司+依西美坦聯(lián)合治療使中位無進展生存期由3.2個月增至7.4個月。不僅如此,，聯(lián)合治療還使臨床獲益率由25.5%上升至50.5%,，6個月時產(chǎn)生完全或部分應答或病情穩(wěn)定的患者增加1倍,。
但加用mTOR抑制劑在增強療效的同時，也伴隨著口炎,、貧血和呼吸困難等不良事件的增加,。最常見的3或4級不良事件為口炎（聯(lián)合治療組 vs. 依西美坦單藥組：8% vs. 1%）、貧血（6% vs. ＜1%）,、呼吸困難（4% vs. 1%）,、高血糖（4% vs. ＜1%）、疲乏（4% vs. 1%）和肺炎（3% vs. 0%）,。聯(lián)合治療組報告不良事件者的比例高出依西美坦單藥組1倍（23% vs. 12%）,，停用依維莫司的患者也遠多于停用安慰劑者（19% vs. 4%），并且有更多患者退出試驗（5% vs. 2%）,。在停用依西美坦的患者中,，聯(lián)合治療組停用另一藥物者（7% vs. 3%）和退出試驗者（7% vs. 2%）也更多。
主要研究者,、麻省總醫(yī)院癌癥中心的José Baselga博士認為,，聯(lián)合治療組不良事件增多的情況，與既往依維莫司和其他雷帕霉素類似物的相關(guān)報告相符,，包括口炎,、疲乏、無力,、腹瀉,、咳嗽、發(fā)熱和高血糖等,。聯(lián)合治療組患者治療時間較長可能是其停藥率較高的原因之一,，提示應重視依維莫司的安全性并加強不良反應監(jiān)測。
研究者總結(jié)稱：“我們的研究結(jié)果與另2項采用依維莫司和抗雌激素藥物治療HR+乳腺癌的研究結(jié)果一致,。鑒于這類患者的治療選擇有限,，我們對觀察到的收益感到滿意。”（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.)
