Finding and targeting dormant tumor cells to prevent breast cancer recurrence

While breast cancer survival continues to improve, thanks to advances in detection and treatment, when breast cancer recurs – or returns after initial treatment – it is incurable. Currently, there is no way to predict who is most likely to experience a breast cancer recurrence, and for the 30 percent of women and men who do relapse, continuous and indefinite treatment is the only option for attempting to slow the cancer growth.

A research team from the Perelman School of Medicine at the University of Pennsylvania and the Abramson Cancer Center has received a $10 million grant from the Department of Defense (BC221382) to combat these challenges, by finding and targeting dormant tumor cells before they can cause a recurrence of the disease. Today, the team also reported the results of a phase II clinical trial that showed – for the first time – it is possible to detect and treat dormant tumor cells in breast cancer survivors, offering a proof-of-concept for the strategy of preventing breast cancer recurrence.

Dormant tumor cells were successfully cleared from more than 80 percent of patients across all three arms of the study, principal investigator Angela DeMichele, MD, MSCE, FASCO, the Alan and Jill Miller Professor in Breast Cancer Excellence, reported today at the European Society for Medical Oncology (ESMO) Congress 2023. The new grant will support continued surveillance of patients who participated in the study, as well as several other studies led by the 2-PREVENT Breast Cancer Translational Center of Excellence, which DeMichele co-directs with Lewis Chodosh, MD, PhD, chair of Cancer Biology and partnering PI on the grant, at Penn Medicine's Abramson Cancer Center.

Recurrence is a lifelong issue and problem for breast cancer survivors because it can happen decades after their initial treatment. This grant will allow us to extend the research we've already started and continue to answer questions about what happens to people years down the line. We want to get away from 'watchful waiting' and move toward 'active surveillance' by learning how we can intervene to prevent relapse of breast cancer."

Angela DeMichele, MD, MSCE, FASCO, the Alan and Jill Miller Professor in Breast Cancer Excellence

After breast cancer treatment, dormant tumor cells continue to lay in wait in some patients. These so-called "sleeper cells," also referred to as minimal residual disease (MRD), can reactivate years or even decades later. Once the 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.

"The dormant/latency phase is an opportune window to intervene because we've found that these dormant cells are sensitive to drugs that don't work against actively growing cancer cells," Chodosh said. "Contrary to current thinking, drugs that are not effective against metastatic disease may be highly effective when used during the dormant phase of disease."

Chodosh's lab led previous work to identify the pathways that allow dormant tumor cells to survive in patients for decades and showed, in preclinical studies, that drugs targeting those pathways could eliminate dormant tumor cells. DeMichele's team translated that research into the Phase II CLEVER study (NCT03032406), which tested several existing, FDA-approved drugs in patients who were previously treated for breast cancer and found to have MRD, but otherwise considered "cancer free."

The breast cancer survivors in the study had all completed their cancer treatment within the last five years at the time of study enrollment and were randomized to receive one of three drug therapy regimens. Nearly half of the patients in the study had triple-negative breast cancer, which has a historic recurrence rate of 30 percent within the first five years. After four years of follow up on the study, none of the triple-negative breast cancer patients who were treated on the study have had a breast cancer recurrence. Only two of 51 patients on the study have experienced a breast cancer recurrence to date.

The grant funding will support the continued monitoring of more than 200 patients who enrolled in CLEVER and three other studies. The research team hopes to evaluate a more sensitive test for dormant tumor cells and develop the optimal testing strategy for MRD, determine the long-term benefits of the study treatments, and learn more about how dormant cancer cells evade the immune system. In addition, the team will use patient-reported outcome (PRO) surveys to better understand patients' perspectives on this type of active surveillance approach, including the psychological and emotional ramifications for survivors, as what some individuals find empowering may be anxiety-producing for others who want to move past their breast cancer diagnosis and treatment.

"We have a lot more work to do to prove that this approach can prevent breast cancer recurrence, but these results are encouraging and show that it's feasible to safely detect and therapeutically target dormant disseminated tumor cells," DeMichele said. "With the help of this grant funding, we want to be able to get to a point where we can effectively test patients for dormant cells after treatment and either reassure them that they're likely cured, because they don't have dormant cells, or if they do have dormant cells, provide them with an effective treatment to stop their cancer from returning."

Two additional clinical trials are currently ongoing to confirm and extend the results of the CLEVER study: the Phase II ABBY clinical trial (NCT04523857) and the Phase II PALAVY clinical trial (NCT04841148).