Noah Kornblum, Della F. Makower, and Joseph A. Sparano, Albert Einstein College of Medicine, Bronx; Paula Klein, Mount Sinai Beth Israel Comprehensive Cancer Center, New York, NY; Fengmin Zhao and Judith Manola, Dana-Farber Cancer Institute, Boston, MA; Bhuvaneswari Ramaswamy, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Adam Brufsky, University of Pittsburgh, Pittsburgh; Cristina I. Truica, Penn State Cancer Institute, Hershey; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Phillip J. Stella, Saint Joseph Mercy (Michigan Cancer Consortium), Ann Arbor, MI; Brian Burnette, Saint Vincent Hospital, Green Bay; Timothy R. Wassenaar, Pro Health Care, Waukesha, WI; Melinda Telli, Stanford University School of Medicine, Stanford, CA; Puneet Cheema, Metro-Minnesota Community Oncology Research Consortium, Saint Louis Park, MN; Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Gamini S. Soori, Missouri Valley Cancer Consortium, Omaha, NE; Barbara Haley, UT Southwestern Medical Center, Dallas, TX; and Kathy D. Miller, Indiana University School of Medicine, Indianapolis, IN.
J Clin Oncol. 2018 Jun 1;36(16):1556-1563. doi: 10.1200/JCO.2017.76.9331. Epub 2018 Apr 17.
Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.
目的
雷帕霉素靶蛋白抑制剂依维莫司通过 PI3K/AKT/哺乳动物雷帕霉素靶蛋白途径靶向异常信号传导，这是雌激素受体（ER）阳性乳腺癌对抗雌激素治疗产生耐药的机制。我们假设依维莫司联合选择性 ER 下调剂氟维司群在对芳香酶抑制剂（AI）治疗耐药的 ER 阳性转移性乳腺癌中比氟维司群单药更有效。
患者和方法
这是一项随机、双盲、安慰剂对照、Ⅱ期研究，纳入了 131 例绝经后 ER 阳性、人表皮生长因子受体 2 阴性、对 AI 耐药的转移性乳腺癌患者，随机分配至氟维司群（第 1 天和第 15 天，第 1 天，周期 2 及以后）联合依维莫司或安慰剂组。该研究设计有 90%的效能检测中位无进展生存期从 5.4 个月提高至 9.2 个月。次要终点包括客观缓解率和临床获益率（缓解或至少 24 周稳定疾病）。未使用预防性皮质类固醇漱口液。
结果
依维莫司联合氟维司群可将中位无进展生存期从 5.1 个月延长至 10.3 个月（风险比，0.61[95%CI，0.40 至 0.92]；分层对数秩检验 P =.02），表明主要试验终点达到。客观缓解率相似（18.2%比 12.3%；P =.47），但依维莫司组的临床获益率显著更高（63.6%比 41.5%；P =.01）。所有等级的不良事件在依维莫司组更常见，包括口腔黏膜炎（53%比 12%）、疲劳（42%比 22%）、皮疹（38%比 5%）、贫血（31%比 6%）、腹泻（23%比 8%）、高血糖（19%比 5%）、高甘油三酯血症（17%比 3%）和肺炎（17%比 0%），尽管 3 级至 4 级不良事件并不常见。
结论
依维莫司增强了氟维司群在 AI 耐药、ER 阳性转移性乳腺癌中的疗效。
