Dormant Breast Cancer Cells: New Trial Shows Promise for Preventing Recurrence

The specter of recurrence haunts many breast cancer survivors, even after successful treatment. Now, a first-of-its-kind clinical trial offers a glimmer of hope: the possibility of identifying and eliminating dormant cancer cells – those “sleeper cells” that can reactivate years, even decades, after initial remission. Research led by scientists at the Abramson Cancer Center of the University of Pennsylvania, and published in Nature Medicine, demonstrates that existing drugs can clear these cells in a significant number of patients, dramatically improving long-term survival rates.

The Challenge of Dormant Disease

Breast cancer survival rates have steadily improved thanks to advances in early detection and treatment. However, for the roughly 30 percent of patients who experience a relapse, the cancer is often incurable. The unpredictable nature of recurrence – some cancers returning within a few years, others decades later – has long frustrated clinicians and patients alike. Until recently, there was no reliable way to identify those at highest risk or to intervene before the cancer became active again. These dormant tumor cells, also known as minimal residual disease (MRD), are particularly insidious because they don’t show up on standard imaging tests. They can lie hidden throughout the body, waiting for the right conditions to reawaken and spread.

How the CLEVER Trial Worked

The study, a randomized phase II clinical trial involving 51 breast cancer survivors, focused on identifying and targeting these dormant cells. Participants, all of whom had completed treatment within the past five years and had clear scans, were screened for the presence of MRD in their bone marrow. Those found to harbor these cells were then enrolled in the CLEVER trial. Patients were randomly assigned to receive either monotherapy with one of two study drugs, or a combination of both. The drugs, already approved by the FDA for other conditions, target key mechanisms that allow dormant tumor cells to survive: autophagy and mTOR signaling.

Remarkably, the treatment successfully cleared dormant tumor cells in 80 percent of the study participants. After a median follow-up of 42 months, the three-year survival rate without disease recurrence was over 90 percent for those receiving one drug and a full 100 percent for those receiving both. Only two patients on the study have experienced a cancer recurrence to date. “We want to be able to provide patients a better option than ‘wait and see’ after they complete breast cancer treatment,” explains principal investigator Angela DeMichele, MD, MSCE, FASCO, the Mariann T. And Robert J. MacDonald Professor in Breast Cancer Research at Penn Medicine.

Unlocking the Secrets of Sleeper Cells

This research builds on years of work by Lewis Chodosh, MD, PhD, chair of Cancer Biology at Penn, who previously identified the pathways that enable dormant tumor cells to persist for extended periods. His team’s preclinical research, conducted in mice, demonstrated that these specific drugs – which are ineffective against actively growing cancers – could effectively eliminate MRD, leading to longer survival. “Our research shows that this sleeper phase represents an opportunity to intervene and eradicate the dormant tumor cells before they have the chance to approach back as aggressive, metastatic disease,” Chodosh said. The Abramson Cancer Center has develop into a leading hub for this type of research, supported by funding from the National Cancer Institute and other organizations.

What Does This Mean for Patients?

The findings suggest a paradigm shift in breast cancer treatment. Instead of simply monitoring for recurrence, clinicians may soon be able to proactively identify and eliminate the seeds of future disease. However, it’s crucial to understand the limitations of this study. The CLEVER trial was a phase II trial, meaning it was designed to assess the safety and preliminary efficacy of the treatment. Larger, phase III trials are needed to confirm these results and to determine the optimal duration and dosage of treatment. The study population was relatively small, and the long-term effects of the treatment remain unknown.

It’s also vital to note that not all breast cancers are created equal. The study included patients with various subtypes of breast cancer, but the effectiveness of the treatment may vary depending on the specific characteristics of the tumor. The researchers are currently investigating whether this approach is equally effective for all subtypes, including particularly aggressive forms like triple-negative breast cancer. The Abramson Cancer Center is also an international leader in breast cancer immunotherapy, including pioneering work in CAR T-cell therapy.

Ongoing Research and Future Directions

The team at Penn Medicine is already enrolling patients in two larger, ongoing studies – the Phase II ABBY and PALAVY clinical trials – to validate and expand upon the findings of the CLEVER trial. These trials are available at multiple cancer centers across the country. Patients interested in learning more about these trials or other breast cancer clinical trials at Penn Medicine can contact the clinical trials team directly.

The ultimate goal is to develop a personalized approach to breast cancer treatment, where patients are routinely screened for MRD after completing initial therapy and receive targeted treatment to eliminate any remaining dormant cells. This could potentially prevent recurrence altogether, transforming breast cancer from a life-threatening disease into a manageable condition. The research also highlights the importance of continued investment in basic science research to unravel the complex biology of cancer and identify new therapeutic targets.