By Billy Candra 
A pivotal, federally funded clinical trial has unveiled a revolutionary approach to breast cancer management, demonstrating the feasibility of identifying survivors at heightened risk of relapse due to the persistence of dormant cancer cells and subsequently eradicating these elusive cells using existing, repurposed drugs. This landmark research, spearheaded by an interdisciplinary team of scientists from the Abramson Cancer Center at the University of Pennsylvania and Penn’s Perelman School of Medicine, has been published today in the esteemed journal Nature Medicine, marking a significant leap forward in the fight against one of the most insidious aspects of cancer: recurrence.
The specter of recurrence looms large for many breast cancer survivors, despite advancements in early detection and primary treatment modalities that have steadily improved overall survival rates. While the five-year survival rate for localized breast cancer now exceeds 99%, and even regional disease boasts an 86% five-year survival, the grim reality is that when breast cancer relapses, particularly after it has metastasized, it often becomes incurable. For the estimated 30 percent of women and men who experience a relapse, the current standard of care typically involves continuous, indefinite treatment aimed at managing the disease, but rarely achieving complete eradication. This enduring challenge underscores the urgent need for strategies that can proactively prevent recurrence rather than merely react to it.
Breast cancer is a heterogeneous disease, with different subtypes exhibiting distinct patterns of recurrence. Aggressive forms, such as triple-negative breast cancer (TNBC) and HER2-positive (HER2+) breast cancer, are known for their propensity to recur within a few years of initial treatment. In contrast, estrogen receptor-positive (ER+) breast cancer, while often having a more favorable prognosis initially, can famously return decades later, a phenomenon that has long baffled clinicians and patients alike. Until now, the medical community lacked a reliable, real-time method to pinpoint which breast cancer survivors harbored these dormant cells—often referred to as minimal residual disease (MRD) or "sleeper cells"—that are the root cause of late-stage recurrence. Furthermore, there was no proven therapeutic intervention capable of eliminating them before they reawaken and trigger an incurable relapse.
A Glimmer of Hope: Clinical Trial Success
The current study, a randomized phase II clinical trial, enrolled 51 breast cancer survivors who had completed their initial treatment and had clear scans, but were found to have dormant tumor cells in their bone marrow. The results are highly encouraging: existing, repurposed drugs successfully cleared dormant tumor cells from an impressive 80 percent of the study participants. The clinical benefit was profound, with a three-year survival rate without any disease recurrence reported to be above 90 percent in patients who received one study drug, and an astonishing 100 percent for patients who received a combination of both study drugs. These figures represent a potential paradigm shift in how breast cancer survivorship is managed.
Dr. Angela DeMichele, MD, MSCE, FASCO, the principal investigator and the Mariann T. and Robert J. MacDonald Professor in Breast Cancer Research, articulated the emotional weight of this breakthrough. "The lingering fear of cancer returning is something that hangs over many breast cancer survivors after they celebrate the end of treatment," Dr. DeMichele stated. "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." Her sentiments resonate deeply with the millions of individuals globally who have faced a breast cancer diagnosis.
Unmasking the ‘Sleeper Cells’: The Science of Dormancy
The foundation of this groundbreaking study rests upon years of preceding research into the enigmatic nature of dormant tumor cells. These "sleeper cells," or minimal residual disease (MRD), are cancer cells that survive initial treatments but do not actively divide or grow. Instead, they enter a quiescent state, capable of lying in wait within the body for extended periods—sometimes years, even decades—before reactivating. A critical challenge with these cells is their invisibility to standard diagnostic tools. Because they are not actively proliferating or forming detectable masses, they do not show up on conventional imaging tests such as mammograms, CT scans, or PET scans, which are designed to detect metabolically active cancer.
The danger posed by these dormant cells is immense. Once they begin to reactivate and expand, they can escape their initial confinement and circulate in the bloodstream, leading to the development of metastatic breast cancer—the primary cause of breast cancer-related mortality. Patients identified with MRD are known to have a significantly higher likelihood of experiencing breast cancer recurrence and, consequently, a decreased overall survival rate. The ability to detect and neutralize these cells before they unleash their destructive potential represents a monumental therapeutic opportunity.
Dr. Lewis Chodosh, MD, PhD, Chair of Cancer Biology and senior author of the study, has been at the forefront of this research for years, leading prior investigations that painstakingly identified the specific cellular pathways enabling 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," Dr. Chodosh explained. He highlighted a surprising and crucial finding: "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." This distinction is paramount, as it suggests that treatment strategies for dormant cells must fundamentally differ from those for active tumors.
In the preclinical phase of the latest research, Dr. Chodosh’s team conducted a meticulous series of experiments using mouse models to decipher the intricate underlying mechanisms of dormancy and test potential interventions. Their investigations revealed that two distinct drugs, already approved by the FDA for treating other medical conditions, could effectively clear MRD in mice. These drugs target autophagy and mTOR signaling, cellular processes that the researchers identified as key mechanisms allowing tumor cells to maintain their dormant state. By disrupting these pathways, the drugs effectively stripped the "sleeper cells" of their ability to remain quiescent and ultimately led to their elimination, resulting in significantly longer survival without cancer recurrence in the animal models.
Translating Scientific Discovery into Clinical Reality: The CLEVER Trial
The success in preclinical models paved the way for the translation of these scientific insights into human clinical trials. Dr. DeMichele’s team initiated a two-stage process. First, breast cancer survivors who had completed their primary treatment within the last five years and had clear imaging scans were enrolled in a screening study. The objective was to identify the presence of dormant tumor cells, specifically in the participant’s bone marrow, a known sanctuary site for these elusive cells. This diagnostic step was crucial, as it allowed researchers to identify the high-risk cohort that would benefit most from the intervention.
Patients who were found to harbor dormant tumor cells were then deemed eligible for enrollment in the Phase II CLEVER clinical trial. This trial was designed as a randomized study, assigning eligible patients to receive six cycles of either monotherapy with one of the two study drugs, or combination therapy utilizing both drugs. The treatment regimen proved remarkably effective: dormant tumor cells were cleared from the majority of patients within six to twelve months. Following a median follow-up period of 42 months (3.5 years), only two patients in the entire study cohort experienced a cancer recurrence, a testament to the potential efficacy of this preventative strategy.
"We want to be able to give patients a better option than ‘wait and see’ after they complete breast cancer treatment," Dr. DeMichele stated, emphasizing the profound psychological and physical burden that the uncertainty of recurrence places on survivors. "We’re encouraged by these results that we’re on the right track."
Broader Implications and the Road Ahead
The findings from the CLEVER trial carry immense implications for the future of breast cancer care. This study represents a paradigm shift from a reactive treatment model—where interventions primarily occur after cancer has recurred and often metastasized—to a proactive, preventative strategy. By targeting dormant cells, researchers are aiming to eradicate the disease at its earliest, most vulnerable stage, before it can ever become a life-threatening metastatic cancer.
The use of repurposed, existing FDA-approved drugs is another significant aspect of this research. Drug development is notoriously time-consuming and expensive. By identifying new uses for established medications, this approach can dramatically accelerate the timeline for bringing new therapies to patients, potentially bypassing years of preclinical and early-phase clinical trials typically required for novel compounds. The financial implications are also considerable, as repurposed drugs generally cost less to develop and produce.
While the results are exceptionally promising, the researchers are not resting on their laurels. They are already actively enrolling patients in two larger, ongoing studies designed to confirm and extend the results observed in the CLEVER study. These include the Phase II ABBY clinical trial and the Phase II PALAVY clinical trial, both of which are available at several leading cancer centers across the country. These multi-center trials are critical for validating the initial findings in a broader patient population, assessing long-term efficacy and safety, and determining the optimal treatment protocols. The expansion to multiple sites also ensures that more patients can potentially benefit from these cutting-edge trials. Patients interested in learning more about these or other breast cancer clinical trials at Penn Medicine are encouraged to contact [email protected].
Chronology of a Breakthrough
The journey to this publication in Nature Medicine is a testament to sustained scientific inquiry and collaborative effort.
- Early 2000s – Present: Dr. Lewis Chodosh’s laboratory conducts foundational research into the mechanisms of cancer cell dormancy, identifying key pathways like autophagy and mTOR signaling crucial for the survival of "sleeper cells."
- Mid-2010s: Preclinical studies, primarily in mouse models, validate the concept of targeting these dormancy pathways with repurposed, FDA-approved drugs, demonstrating their ability to clear minimal residual disease and prevent recurrence.
- Late 2010s: The concept of the CLEVER clinical trial is developed, focusing on breast cancer survivors and the detection of dormant cells in bone marrow.
- Circa 2019-2020: Patient enrollment begins for the screening study to identify survivors with dormant cells, followed by enrollment in the randomized Phase II CLEVER clinical trial.
- 2020-2023: The CLEVER trial proceeds, with patients receiving monotherapy or combination therapy. Data collection and analysis commence.
- September 2023: Dr. DeMichele presents interim outcomes data from the CLEVER study at the prestigious European Society for Medical Oncology (ESMO) Congress, garnering significant attention from the global oncology community.
- Today (Date of Publication): The full research findings are published in Nature Medicine, making the detailed results available to the broader scientific and medical communities.
- Ongoing: The Phase II ABBY and PALAVY clinical trials continue to enroll patients, aiming to build upon and confirm the promising results of the CLEVER study.
This research was made possible through substantial and diverse funding, highlighting the collaborative effort required for such a significant breakthrough. Key financial support came from the National Cancer Institute (R01CA208273) and the Department of Defense (BC160784), reflecting a national strategic interest in combating breast cancer recurrence. Additional crucial support was provided by philanthropic organizations and foundations, including the V Foundation, the Breast Cancer Research Foundation, QVC "Shoes on Sale," the Avon Foundation, the Raynier Institute & Foundation, and numerous generous individual philanthropic donations. This multifaceted support underscores the broad recognition of the critical need to address the challenge of breast cancer recurrence.
The successful identification and targeted treatment of dormant cancer cells mark a monumental stride towards a future where breast cancer survivors can truly live without the pervasive fear of relapse. This Penn Medicine-led study not only offers a beacon of hope but also lays a robust foundation for an entirely new era of preventative oncology.