10 december 2025: Bron:  2025 Oct;31(10):3464-3474

Uit de resultaten van de fase II studie CLEVER blijkt everolimus (Afinitor) gecombineerd met hydroxychloroquine uitstekende ziektevrije overleving en overall overlevingsresultaten te geven bij borstkankerpatiënten met aantoonbaar gemeten slapende tumorcellen in hun beenmerg en wervels. Ook wanneer de twee medicijnen alleen werden gegeven waren de resultaten uitstekend. Na een mediane follow-up van 42 maanden was de 3-jaars recidiefvrije overleving voor hydroxychloroquine alleen 91,7 procent, everolimus (Afinitor) alleen 92,9 procent en hydroxychloroquine plus everolimus (Afinitor) samen 100 procent. 

Hoewel de CLEVER studie over kleine groep patiënten ging; N = 15 voor hydroxychloroquine alleen, N = 15 voor everolimus (Afinitor) alleen en 21 deelnemende patiënten voor hydroxychloroquine plus everolimus (Afinitor) samen, zijn dit wel uitstekende resultaten en worden snel studies opgezet met grotere aantallen borstkankerpatiënten. 

Hier het abstract van de studie:

Abstract

Breast cancer recurrence may arise from dormant disseminated tumor cells (DTCs) that persist in bone marrow and other sites. Clinically, DTCs are independently associated with breast cancer recurrence and death. Preclinical studies in mouse models identified autophagy and mammalian target of rapamycin (mTOR) signaling as critical mechanisms of tumor dormancy and escape. 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). 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. RTC number was strongly and inversely correlated with RFS, suggesting that RTC reduction mediated an improvement in RFS. 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. Primary endpoints were feasibility and safety; secondary endpoints included DTC reduction/clearance and RFS. In total, 51 DTC+ patients initiated HCQ (n = 15), EVE (n = 15) or HCQ + EVE (n = 21). Treatment was feasible and tolerable; only one patient discontinued early for grade 3 toxicity. 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 interval 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. 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 .

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Conflict of interest statement

Competing interests: A.D. has received institutional research funding from Novartis, Genentech, Pfizer and NeoGenomics. L.A.C. has received institutional research funding from Novartis, AstraZeneca and Merck Research Laboratories, and has served as an expert consultant to Teva Pharmaceuticals, Eisai, Sanofi, Takeda Pharmaceuticals, Eli Lilly, Whittaker, Clark and Daniels, Wyeth, Imerys, Becton Dickinson, Sterigenics and the U.S. Department of Justice in litigation. The other authors declare no competing interests.

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borstkanker, everolimus, Afinitor, slapende tumorcellen, CLEVER fase II studie, ziektevrije overleving, overall overleving, 3-jaars meting, hydroxychloroquine


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