New Trial Shows Repurposed Drugs Can Prevent Breast Cancer Recurrence

In a first of its kind clinical trial, Penn Medicine researchers identified breast cancer survivors who harbored dormant tumor cells and then cleared those cells using existing drugs. The randomized Phase II CLEVER study, published in Nature Medicine, showed hydroxychloroquine, everolimus, or both reduced minimal residual disease in about 80 percent of participants, with three year recurrence free survival ranging from 91 to 100 percent. It is early, it is cautious, but it is proof of concept that relapse might be prevented rather than simply watched.

Breast cancer relapse remains incurable once it occurs. About 30 percent of patients will see their cancer return, sometimes within a few years for triple negative or HER2 positive disease, or decades later for estrogen receptor positive subtypes. Until now, clinicians have not been able to identify survivors with dormant cells in real time or intervene with a therapy designed specifically to eliminate them.

“The lingering fear of cancer returning is something that hangs over many breast cancer survivors after they celebrate the end of treatment,” said Angela DeMichele, principal investigator at Penn. “Our study shows that preventing recurrence by monitoring and targeting dormant tumor cells is a strategy that holds real promise.”

Targeting Sleeper Cells

These so called sleeper cells, or minimal residual disease, are invisible on scans and can persist silently in bone marrow and other tissues. Once reactivated, they seed metastasis. Lewis Chodosh, senior author of the study, previously mapped the pathways that allow dormant cells to survive for decades. His lab’s preclinical experiments in mice showed that drugs which failed against fast growing tumors could succeed against cells in the dormant state, particularly by targeting autophagy and mTOR signaling.

“Surprisingly, we’ve found that certain drugs that don’t work against actively growing cancers can be very effective against these sleeper cells,” Chodosh said. “This tells us that the biology of dormant tumor cells is very different from active cancer cells.”

Proof in Patients

The CLEVER trial enrolled 51 breast cancer survivors who had completed treatment within the last five years and had no evidence of active disease on scans. Bone marrow aspiration revealed dormant tumor cells in each participant. Patients were then randomized to receive hydroxychloroquine, everolimus, or the combination for six cycles. Most cleared their dormant cells within six to twelve months. After a median follow up of 42 months, only two patients experienced recurrence.

Three year recurrence free survival was 91.7 percent with hydroxychloroquine, 92.9 percent with everolimus, and 100 percent with the combination. The approach was generally tolerable, with only one patient discontinuing for a grade 3 adverse event.

From Concept to Care

The Penn team is already extending this strategy through two additional Phase II trials, ABBY and PALAVY, now recruiting at multiple cancer centers across the United States. These studies will test variations of the approach, including sequential and combination regimens, to validate whether clearing dormant disease translates into lasting prevention of recurrence. If confirmed, this shift could replace “wait and see” surveillance with targeted intervention.

For millions of breast cancer survivors, the value is not only clinical but psychological. Fear of relapse shadows every follow up visit. A treatment designed to erase that fear at its biological root would represent a new chapter in survivorship.

Journal: Nature Medicine
DOI: 10.1038/s41591-025-03877-3