Researchers have discovered that dormant breast cancer cells can be detected and wiped out with existing drugs, dramatically lowering the risk of relapse. The breakthrough brings new hope to survivors haunted by the fear of recurrence.
Breakthrough Trial Targets Dormant Breast Cancer Cells
A landmark federally funded clinical trial has provided the first real evidence that doctors can pinpoint breast cancer survivors at higher risk of relapse by detecting dormant cancer cells, and that these hidden cells can be successfully treated using already available drugs. The work, led by researchers at the Abramson Cancer Center of the University of Pennsylvania and Penn’s Perelman School of Medicine, appears in the journal Nature Medicine.
Although survival rates for breast cancer continue to improve thanks to better screening and therapies, the disease remains incurable once it comes back after initial treatment. About 30 percent of women and men experience a relapse, leaving them dependent on ongoing treatment that cannot completely remove the cancer. Some forms, such as triple negative and HER2+, often reappear within a few years, while ER+ cases can resurface even decades later. Until now, doctors had no way to identify which survivors carried dormant cells that fuel recurrence or to step in with a therapy that could prevent it.
The Hidden Threat of Cancer Relapse
In the randomized phase II trial, 51 breast cancer survivors were tested with existing drugs, which successfully cleared dormant tumor cells in 80 percent of participants. After three years, the survival rate without any return of disease exceeded 90 percent among patients given a single drug and reached 100 percent for those who received both medications.
“The lingering fear of cancer returning is something that hangs over many breast cancer survivors after they celebrate the end of treatment,” said principal investigator Angela DeMichele, MD, MSCE, FASCO, the Mariann T. and Robert J. MacDonald Professor in Breast Cancer Research. “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. Our study shows that preventing recurrence by monitoring and targeting dormant tumor cells is a strategy that holds real promise, and I hope it ignites more research in this area.”
Survivors’ Hope: Preventing Recurrence Before It Starts
The study builds on previous research that showed how dormant tumor cells continue to lay in wait in some patients after breast cancer treatment. These so-called “sleeper cells,” also referred to as minimal residual disease (MRD), can reactivate years or even decades later. Because they are not “active” cancer cells and can be scattered throughout the body, they do not show up on standard imaging tests that are used to watch for breast cancer recurrence.
Once the sleeper cells begin to expand and circulate in the bloodstream, it can lead to the spread of metastatic breast cancer. Patients who have MRD are more likely to experience breast cancer recurrence and have decreased overall survival.
Why Dormant Cells Escape Detection
Lewis Chodosh, MD, PhD, chair of Cancer Biology and senior author of the study, previously led research to identify the pathways that allow dormant tumor cells to survive in patients for decades.
“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,” Chodosh said. “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.”
In the preclinical part of the latest research publication, Chodosh’s team conducted a series of experiments in mice to better understand the underlying mechanisms. They showed that two different drugs—approved by the FDA to treat other conditions—could effectively clear MRD in mice, resulting in longer survival without cancer recurrence. The drugs target autophagy and mTOR signaling, which the researchers found were key mechanisms to allow the tumor cells to remain dormant.
How FDA-Approved Drugs Target Dormant Cells
DeMichele’s team first enrolled breast cancer survivors who had completed treatment within the last five years and had clear scans into a screening study that looked for dormant tumor cells in participant’s bone marrow.
If dormant tumor cells were found, patients were then eligible to enroll in the Phase II CLEVER clinical trial, which randomized patients to receive six cycles of either monotherapy with one of two study drugs, or combination therapy with both drugs. The treatment cleared dormant tumor cells in most patients after six to 12 months. After a median follow-up time of 42 months, only two patients on the study have experienced a cancer recurrence.
The CLEVER Trial: Promising Early Results
“We want to be able to give patients a better option than ‘wait and see’ after they complete breast cancer treatment,” DeMichele said. “We’re encouraged by these results that we’re on the right track.”
The team is already enrolling patients in two larger, ongoing studies to confirm and extend the results of the CLEVER study: the Phase II ABBY clinical trial and the Phase II PALAVY clinical trial, available at several cancer centers across the country. Patients interested in learning more about these or other breast cancer clinical trials at Penn Medicine should contact [email protected].
Reference: “Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial” by Angela DeMichele, Amy S. Clark, Emily Shea, Lauren J. Bayne, Christopher J. Sterner, Killian Rohn, Samantha Dwyer, Tien-chi Pan, Isoris Nivar, Yan Chen, Paul Wileyto, Lindsay R. Berry, Shannon Deluca, Jessica Savage, Igor Makhlin, Dhruv K. Pant, Heather Martin, Adetutu Egunsola, Nathan Mears, Brooke L. Goodspeed, Elizabeth M. Chislock, Jewell Graves, Jianping Wang, Natalie Shih, George K. Belka, Don Berry, Anupma Nayak, Michael Feldman and Lewis A. Chodosh, 2 September 2025, Nature Medicine.
DOI: 10.1038/s41591-025-03877-3
The research was made possible with funding from the National Cancer Institute (R01CA208273) and Department of Defense (BC160784), with additional support from the V Foundation, Breast Cancer Research Foundation, QVC “Shoes on Sale,” Avon Foundation, Raynier Institute & Foundation, and generous philanthropic donations. DeMichele previously reported interim outcomes data from the study at the European Society for Medical Oncology (ESMO) Congress 2023.
Never miss a breakthrough: Join the SciTechDaily newsletter.