A first-of-its-kind, federally funded clinical trial has shown it’s possible to identify breast cancer survivors who are at higher risk of their cancer coming back due to the presence of dormant cancer cells and to effectively treat these cells with repurposed, existing drugs.the research, led by scientists from the Abramson Cancer Center of the University of Pennsylvania and Penn’s Perelman School of Medicine was published today in Nature Medicine.
While breast cancer survival continues to improve thanks to advances in detection and treatment, relapse remains incurable. For the 30 percent of women and men who experience recurrence, current treatment options offer only continuous, indefinite management without a complete cure. Some breast cancers recur within a few years, while others, like ER+, can return decades later. Until now, ther was no way to identify survivors harboring these dormant cells – which lead to recurrence – in real time and intervene with a preventative treatment.
A randomized phase II clinical trial involving 51 breast cancer survivors demonstrated that existing drugs coudl clear dormant tumor cells in 80 percent of participants. the three-year survival rate without disease recurrence exceeded 90 percent in patients receiving one drug and reached 100 percent for those receiving both study drugs.
“The lingering fear of cancer returning is a meaningful burden for many breast cancer survivors after treatment ends,” said principal investigator Angela DeMichele, MD, MSCE, FASCO, the Mariann T. and Robert J. MacDonald Professor in breast Cancer Research. “Currently, we lack the ability to predict when or if someone’s cancer will return – this was the problem we aimed to solve. Our study suggests that monitoring and targeting dormant tumor cells to prevent recurrence is a promising strategy, and I hope it encourages further research in this area.”
Seizing a window of chance to wipe out cancer while it’s sleeping
The study builds on previous research revealing that dormant tumor cells can persist in some patients even after breast cancer treatment. These “sleeper cells,” also known as minimal residual disease (MRD), can reactivate years or decades later. Because they are not actively growing and can be scattered throughout the body, they ofen go undetected by standard imaging tests used to monitor for recurrence.
When these sleeper cells begin to expand and circulate in the bloodstream, they can lead to metastatic breast cancer. Patients with MRD are at higher risk of recurrence and have decreased overall survival.
Lewis Chodosh, MD, PhD, chair of cancer Biology and senior author of the study, previously identified the pathways that allow dormant tumor cells to survive for decades.
“Our research indicates that this dormant phase presents an opportunity to intervene and eliminate these cells before they become aggressive, metastatic disease,” Chodosh said. “Surprisingly, we found that certain drugs – which are ineffective against actively growing cancers – can be highly effective against these sleeper cells. this highlights the distinct biology of dormant tumor cells compared to active cancer cells.”
Preclinical experiments in mice showed that two FDA-approved drugs, targeting autophagy and mTOR signaling, effectively cleared MRD and prolonged survival without recurrence. Researchers found these mechanisms were key to maintaining the dormant state of the tumor cells.
Translating science into original clinical trials
DeMichele’s team initially enrolled breast cancer survivors who had completed treatment within the last five years and had clear scans into a screening study to detect dormant tumor cells in their bone marrow.
Patients found to have dormant tumor cells were then eligible for the Phase II CLEVER clinical trial, randomized to receive six cycles of either monotherapy with one of two study drugs, or combination therapy with both. Treatment cleared dormant tumor cells in most patients after six to 12 months. After a median follow-up of 42 months, only two patients on the study have experienced cancer recurrence.
“We aim to offer patients a better alternative then ‘wait and see’ after completing breast cancer treatment,” DeMichele said. “These results encourage us that we are on the right path.”
The team is currently enrolling patients in two larger, ongoing studies to confirm and expand on the CLEVER study’s findings: the Phase II ABBY clinical trial and the Phase II PALAVY clinical trial, available at several cancer centers nationwide. Patients interested in learning more about these or other breast cancer clinical trials at Penn Medicine should contact [email protected].
The research was funded by 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 philanthropic donations. DeMichele previously presented interim outcomes data from the study at the European Society for Medical Oncology (ESMO) Congress 2023.