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针对休眠瘤细胞预防乳腺癌复发:一个随机的第二阶段试验

Angela DeMichele^1,2,3, Amy S Clark^4,5,6, Emily Shea^6,7

¹Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. angela.demichele@pennmedicine.upenn.edu.

Nature medicine

|September 2, 2025

概括

用氧化 (HCQ) 和Everelimus (EVE) 向休眠的乳腺癌细胞显示出有希望的结果,降低了残留瘤负担并改善了无复发的生存率. 这种组合治疗为幸存者预防乳腺癌复发提供了潜在的新策略.

科学领域:

癌症学
癌症生物学
药理学

背景情况:

乳腺癌复发通常与骨髓和其他部位的休眠扩散瘤细胞 (DTC) 有关.
自和哺乳动物的拉巴胺素 (mTOR) 信号传递是瘤休眠和逃逸的关键机制.
针对这些途径可以减少残留瘤细胞 (RTC) 的负担并防止复发.

研究的目的:

在临床前模型中评估抑制自 (使用HCQ) 和/ 或mTOR (使用EVE) 降低RTC负担和改善无复发存活率的有效性.
评估HCQ,EVE或其组合在乳腺癌幸存者的可行性,安全性和有效性.

主要方法:

在小鼠模型中进行的临床前研究测试了自和mTOR信号的暂时与慢性抑制.
一个随机的第二阶段临床试验 (CLEVER) 招募了乳腺癌幸存者和可检测的DTC.
患者接受HCQ,EVE或组合治疗;主要终点是可行性和安全性;次要终点包括DTC降低和RFS.

主要成果:

在小鼠中,单独抑制mTOR或与自抑制一起降低了RTC负担,并以持续时间依赖的方式改善了RFS.
临床试验发现HCQ,EVE及其组合是可行的和可以容忍的.
在3年的随访中,所有手臂的RFS高 (91. 7-100%),并且在清除DTC的患者中显著改善 (HR=0. 21).
估计的DTC降低是相当大的:HCQ降低了80%,EVE降低了78%,组合降低了87%.

结论:

在临床前模型和乳腺癌幸存者中,使用HCQ和/或EVE针对休眠的RTC有效地减少了最小的残留疾病.
组合治疗显示了显著的DTC降低和高RFS,为进一步的研究提供了概念证明.
这些发现支持最终的随机对照试验,以证实这种治疗策略的有效性.

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