Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial.

Clinically, DTCs are independently associated with breast cancer recurrence and death.

临床上，DTCs与乳腺癌复发和死亡独立相关。

Preclinical studies in mouse models identified autophagy and mammalian target of rapamycin (mTOR) signaling as critical mechanisms of tumor dormancy and escape.

在小鼠模型中的临床前研究确定了自噬和哺乳动物雷帕霉素靶蛋白(mTOR)信号通路是肿瘤休眠和逃避免疫监视的关键机制。

We subsequently tested the effects of transient versus chronic inhibition of autophagy with chloroquine or hydroxychloroquine (HCQ) and mTOR signaling with rapamycin (RAPA) or everolimus (EVE) on residual tumor cell (RTC) burden and recurrence-free survival (RFS).

随后，我们测试了短期与长期抑制自噬（使用氯喹或羟氯喹）和mTOR信号通路（使用雷帕霉素或依维莫司）对残余肿瘤细胞(RTC)负荷和无复发生存(RFS)的影响。

In mice harboring dormant RTCs, inhibition of mTOR alone or in combination with autophagy inhibition decreased RTC burden and improved RFS in a duration-dependent manner.

在携带休眠性RTC的小鼠中，单独抑制mTOR或与自噬抑制联合使用，均能以持续时间依赖的方式减少RTC负荷并改善无复发生存期（RFS）。

RTC number was strongly and inversely correlated with RFS, suggesting that RTC reduction mediated an improvement in RFS.

RTC数量与无复发生存期（RFS）之间存在强烈的负相关性，这表明RTC的减少介导了RFS的改善。

To translate findings clinically, we performed a randomized phase 2 trial (CLEVER) of HCQ, EVE or their combination in breast cancer survivors within 5 years of diagnosis who had detectable DTCs on bone marrow aspirate.

为了将研究结果转化为临床应用，我们进行了一项随机II期临床试验（CLEVER），在诊断后5年内乳腺癌幸存者中，对骨髓穿刺可检测到的循环肿瘤细胞（DTCs）患者，使用羟氯喹（HCQ）、依维莫司（EVE）或它们的联合治疗。

Primary endpoints were feasibility and safety; secondary endpoints included DTC reduction/clearance and RFS.

主要终点是可行性和安全性；次要终点包括DTCs的减少/清除和无复发生存期（RFS）。

In total, 51 DTC+ patients initiated HCQ (n = 15), EVE (n = 15) or HCQ + EVE (n = 21).

共有51名DTC+患者开始接受HCQ（n = 15），EVE（n = 15）或HCQ + EVE（n = 21）治疗。

Treatment was feasible and tolerable; only one patient discontinued early for grade 3 toxicity.

治疗是可行且可耐受的；只有一名患者因3级毒性提前中断治疗。

At 42 months median follow-up, landmark 3-year RFS for HCQ, EVE and HCQ + EVE was 91.7%, 92.9% and 100%, respectively, and was greater in those who cleared DTCs versus those who did not (hazard ratio(HR) = 0.21 (95% confidence interval0.01-3.4)).

在中位随访42个月时，羟氯喹(HCQ)、依维莫司(EVE)和HCQ + EVE的3年无复发生存(RFS)分别为91.7%、92.9%和100%，在清除循环肿瘤细胞(DTCs)的患者中大于未清除的患者（风险比(HR) = 0.21 (95%置信区间0.01-3.4)）

Posterior probabilities were 98-99.9% that three cycles of HCQ, EVE or HCQ + EVE led to reduced or undetectable DTCs compared to observation alone, with estimated DTC reductions of 80%, 78% and 87%, respectively.

与单独观察相比，三周期HCQ、EVE或HCQ + EVE导致DTCs减少或不可检测的后验概率为98-99.9%，估计DTCs分别减少80%、78%和87%。

These findings provide proof-of-concept that targeting dormant RTCs with HCQ, EVE or their combination in breast cancer survivors or mouse models depletes minimal residual disease, warranting a definitive human randomized controlled trial. ClinicalTrials.gov registration: NCT03032406 .

这些发现提供了概念验证，即使用HCQ、EVE或它们的组合针对乳腺癌幸存者或小鼠模型中的休眠RTC，可以耗尽微小残留病变，这证明了进行一项明确的人类随机对照试验是必要的。ClinicalTrials.gov注册号：NCT03032406。