A groundbreaking clinical trial has demonstrated for the first time that dormant breast cancer cells can be successfully identified and eliminated using repurposed existing drugs, offering new hope for preventing cancer recurrence in survivors. The federally funded study, led by researchers from the University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine, achieved an 80% success rate in clearing these "sleeper cells" from participants.
The research, published in Nature Medicine, represents a paradigm shift in breast cancer survivorship care. Currently, approximately 30% of breast cancer patients experience relapse, which remains incurable and requires continuous, indefinite treatment that cannot completely eliminate the cancer.
Targeting Cancer's Hidden Threat
The study focused on minimal residual disease (MRD), consisting of dormant tumor cells that persist after initial treatment. These cells, scattered throughout the body, remain undetectable by standard imaging tests used to monitor for breast cancer recurrence.
"These so-called 'sleeper cells' can reactivate years or even decades later," according to Penn Medicine researchers. "Because they can be scattered throughout the body, they do not show up on standard imaging tests that are used to watch for breast cancer recurrence."
Lewis Chodosh, MD, PhD, chair of Cancer Biology and senior author of the study, explained the unique vulnerability of these dormant cells: "Surprisingly, we've found that certain drugs that don't work against actively growing cancers can be very effective against these sleeper cells. This tells us that the biology of dormant tumor cells is very different from active cancer cells."
Clinical Trial Design and Results
The Phase II CLEVER clinical trial enrolled 51 breast cancer survivors who had completed treatment within the past five years and showed clear scans. Participants first underwent screening to detect dormant tumor cells in their bone marrow. Those with detectable MRD were randomized to receive six cycles of treatment with either hydroxychloroquine, everolimus, or a combination of both drugs.
The results exceeded expectations. The drugs successfully cleared dormant tumor cells in 80% of study participants. More significantly, the three-year survival rate without disease recurrence was above 90% in patients who received single-drug therapy and reached 100% in patients who received combination therapy.
After a median follow-up period of 42 months, only two of the 51 participants experienced cancer recurrence, demonstrating the potential of this approach to transform outcomes for breast cancer survivors.
Scientific Foundation and Mechanism
The clinical success builds on extensive preclinical research that identified the biological pathways allowing dormant tumor cells to survive for decades. Chodosh's team conducted experiments in mice showing that the two FDA-approved drugs could effectively clear MRD, resulting in longer survival without cancer recurrence.
The drugs target autophagy and mTOR signaling pathways, which researchers identified as key mechanisms enabling tumor cells to remain dormant. This discovery explains why treatments effective against actively growing cancers may fail against dormant cells, requiring a different therapeutic approach.
Clinical Impact and Future Directions
Principal investigator Angela DeMichele, MD, MSCE, FASCO, emphasized the significance for patient care: "The lingering fear of cancer returning is something that hangs over many breast cancer survivors after they celebrate the end of treatment. Right now, we just don't know when or if someone's cancer will come back-that's the problem we set out to solve."
The research addresses a critical unmet need in breast cancer care. While some breast cancers like triple negative and HER2+ typically recur within a few years, others like ER+ can recur decades later. Until now, no method existed to identify survivors harboring dormant cells in real time and intervene to prevent incurable relapse.
DeMichele added: "We want to be able to give patients a better option than 'wait and see' after they complete breast cancer treatment. We're encouraged by these results that we're on the right track."
Expanding Research Program
Building on these promising results, the research team is already enrolling patients in two larger ongoing studies: the Phase II ABBY clinical trial and the Phase II PALAVY clinical trial, available at multiple cancer centers nationwide. These studies aim to confirm and extend the CLEVER study findings.
The research received funding from the National Cancer Institute and Department of Defense, with additional support from the V Foundation, Breast Cancer Research Foundation, and other philanthropic organizations. DeMichele previously presented interim outcomes data at the European Society for Medical Oncology Congress 2023.
