Breast cancer recurrence remains a major concern for survivors, with dormant tumor cells—also called “sleeper cells” or minimal residual disease (MRD)—often evading detection for years. A recent clinical trial led by the University of Pennsylvania offers a promising new approach: detecting these hidden cells and eliminating them with repurposed, existing drugs, potentially preventing recurrence and improving survival rates.

The Challenge of Dormant Cancer Cells

Even after successful treatment, approximately 30% of breast cancer patients face relapse. Dormant tumor cells can persist in the body long after initial therapy, reactivating years or even decades later. These cells are not visible on standard imaging and are resistant to conventional treatments targeting actively dividing cancer cells.

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

The CLEVER Phase II Clinical Trial

The Phase II CLEVER trial enrolled 51 breast cancer survivors who had completed treatment within five years. Participants were screened for dormant tumor cells in their bone marrow, and those who tested positive were randomized to receive one of two existing drugs or a combination of both.

Key findings include:

• 80% of participants cleared dormant tumor cells after six to twelve months of treatment.
• Three-year disease-free survival exceeded 90% for those on monotherapy, and reached 100% for combination therapy recipients.
• Only two patients experienced recurrence after a median follow-up of 42 months.

The drugs used target autophagy and mTOR signaling, pathways critical for dormant cell survival. Preclinical experiments in mice confirmed that these therapies could effectively eliminate MRD, providing the biological rationale for clinical application.

Scientific and Clinical Implications

This study represents a paradigm shift in breast cancer management:

• Proactive intervention: Instead of the traditional “wait and see” approach, clinicians can identify high-risk survivors and intervene before recurrence occurs.
• Repurposed therapeutics: Drugs previously ineffective against active cancer cells can successfully eradicate dormant cells due to their unique biology.
• Extended survival and reduced relapse risk: Targeting MRD may significantly improve long-term outcomes, especially for high-risk subtypes like triple-negative or HER2+ breast cancers.

Future Directions

Building on the CLEVER trial, the research team is expanding studies with Phase II ABBY and PALAVY trials to confirm efficacy and explore broader applications. This approach could become a standard component of post-treatment monitoring and intervention for breast cancer survivors.

“Our research shows that this sleeper phase represents an opportunity to intervene and eradicate the dormant tumor cells before they have the chance to come back as aggressive, metastatic disease,” said Dr. Lewis Chodosh, senior author of the study.

Conclusion

The University of Pennsylvania study offers hope for a future where breast cancer recurrence is no longer a lingering threat. By combining detection of dormant tumor cells with targeted intervention using repurposed drugs, clinicians can significantly reduce relapse risk and enhance long-term survival. This research underscores the importance of integrating laboratory discoveries into clinical care, opening new avenues for molecular biologists, clinicians, and biotech researchers seeking proactive cancer treatment strategies.

Source

• DeMichele A., Chodosh L.A., et al. “Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial.” Nature Medicine, 2025. DOI: 10.1038/s41591-025-03877-3

• University of Pennsylvania School of Medicine. ScienceDaily, September 3, 2025. https://www.sciencedaily.com/releases/2025/09/250902085143.htm