Dormant tumor cells targeted to reduce breast cancer relapse

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, when breast cancer relapses-or returns after initial treatment-it is still incurable. For the 30 percent of women and men who do relapse, the only option is continuous and indefinite treatment which cannot eliminate the cancer completely. Some breast cancers, like triple negative and HER2+, recur within a few years, and others like ER+ can recur decades later. Until now, there has not been a way to identify those breast cancer survivors who harbor the dormant cells that lead to recurrence in real time and to intervene with a treatment that can prevent incurable relapse.

In a randomized phase II clinical trial with 51 breast cancer survivors, existing drugs were able to clear dormant tumor cells from 80 percent of the study participants. The three-year survival rate without any disease recurrence was above 90 percent in patients who received one drug and 100 percent for patients who received both study drugs.

The lingering fear of cancer returning is something that hangs over many breast cancer survivors after they celebrate the end of treatment. 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."

Angela DeMichele, MD, MSCE, FASCO, principal investigator, the Mariann T. and Robert J. MacDonald Professor in Breast Cancer Research

Seizing a window of opportunity to wipe out cancer while it's sleeping

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.

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.

Translating science into original clinical trials

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.

"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].

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.