【原】抗雌激素耐药乳腺癌的靶向治疗

　　编者按：雌激素受体阳性乳腺癌的标准治疗方法为抗雌激素疗法，其耐药机制之一为PI3K→AKT→mTOR通路信号转化传导异常。依维莫司为哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，可以靶向治疗抗雌激素疗法耐药的雌激素受体阳性乳腺癌。那么，对于芳香酶抑制剂耐药的雌激素受体阳性转移性乳腺癌，依维莫司＋氟维司群（选择性雌激素受体抑制剂）与氟维司群单药相比，是否更有效？

　　2018年4月17日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表爱因斯坦医学院、纽约西奈山医院贝斯以色列综合癌症中心、哈佛大学达纳法伯癌症研究所、俄亥俄州立大学综合癌症中心、匹兹堡大学、宾夕法尼亚州立大学癌症研究所、天普大学福克斯蔡斯癌症中心、密歇根癌症联盟圣约瑟夫默西医院、格林贝圣文森特医院、沃科夏医院、斯坦福大学医学院、明尼苏达都会社区肿瘤研究联盟、约翰霍普金斯大学西德尼坎摩尔综合癌症中心、密苏里山谷癌症联盟、德克萨斯大学西南医学中心、印第安纳大学医学院的随机II期研究（PrE0102），报告了氟维司群＋依维莫司或安慰剂治疗激素受体阳性、人表皮生长因子受体2（HER2）阴性转移性乳腺癌芳香酶抑制剂耐药绝经后女性的结果。

　　该随机双盲安慰剂对照II期研究于2013年5月～2015年11月入组雌激素受体阳性HER2阴性芳香酶抑制剂耐药转移性乳腺癌绝经后女性131例，随机分配接受氟维司群＋依维莫司或安慰剂。主要终点为中位无进展生存。次要终点包括客观缓解率和临床获益率（缓解或疾病稳定至少24周）。未使用皮质类固醇漱口液预防口腔黏膜炎。

　　结果发现，依维莫司＋氟维司群与安慰剂＋氟维司群相比：

• 无进展生存较长（10.3比5.1个月，风险比：0.61，95%置信区间：0.40～0.92，分层对数秩P=0.02），达到主要研究终点。

• 客观缓解率相似（18.2%比12.3%，P=0.47）

• 临床获益率较高（63.6%比41.5%，P=0.01）

　　依维莫司＋氟维司群与安慰剂＋氟维司群相比，不良事件发生率较高，主要为1～2级事件：

• 口腔黏膜炎（53%比12%）

• 疲乏（42%比22%）

• 皮疹（38%比5%）

• 贫血（31%比6%）

• 腹泻（23%比8%）

• 高血糖（19%比5%）

• 高血脂（17%比3%）

• 肺炎（17%比0%）

　　因此，对于芳香酶抑制剂耐药的雌激素受体阳性转移性乳腺癌，依维莫司可以提高氟维司群的疗效。

　　对此，旧金山加利福尼亚大学综合癌症中心的霍普·雨果教授接受访谈时发表评论：扩大激素受体阳性晚期乳腺癌靶向治疗范围。

Extending the Reach of Targeted Therapy for Hormone-Receptor-Positive Advanced Breast Cancer By Hope S. Rugo

J Clin Oncol. 2018 Apr 17. [Epub ahead of print]

Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102.

Kornblum N, Zhao F, Manola J, Klein P, Ramaswamy B, Brufsky A, Stella PJ, Burnette B, Telli M, Makower DF, Cheema P, Truica CI, Wolff AC, Soori GS, Haley B, Wassenaar TR, Goldstein LJ, Miller KD, Sparano JA.

Albert Einstein College of Medicine, Bronx; Mount Sinai Beth Israel Comprehensive Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; The Ohio State University Comprehensive Cancer Center, Columbus, OH; University of Pittsburgh, Pittsburgh; Penn State Cancer Institute, Hershey; Fox Chase Cancer Center, Philadelphia, PA; Saint Joseph Mercy (Michigan Cancer Consortium), Ann Arbor, MI; Saint Vincent Hospital, Green Bay; Pro Health Care, Waukesha, WI; Stanford University School of Medicine, Stanford, CA; Metro-Minnesota Community Oncology Research Consortium, Saint Louis Park, MN; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Missouri Valley Cancer Consortium, Omaha, NE; UT Southwestern Medical Center, Dallas, TX; Indiana University School of Medicine, Indianapolis, IN.

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.

PMID: 29664714

DOI: 10.1200/JCO.2017.76.9331