Targeting Dormant Tumor Cells: A New Frontier in Preventing Breast Cancer Recurrence

For breast cancer patients, tecurrence continues to be one of the most daunting challenges. Despite the fact that early detection and the use of adjuvant therapy have significantly prolonged the survival of patients, the prognosis is often fatal for the around 30% of patients whose cancer returns.¹ A recently published randomized phase 2 trial now offers compelling evidence that directly targeting dormant disseminated tumor cells (DTCs) may represent a novel preventive strategy for recurrence.²

Following primary treatment (surgery ± systemic therapy), breast cancer cells may be left in a dormant state or minimal residual disease (MRD), which does not show up on standard imaging and treatment methods.¹ These dormant cells can survive in the body for years without causing any symptoms before emerging as overt metastatic disease.

Researchers at the Abramson Cancer Center of the Perelman School of Medicine (University of Pennsylvania) state that “the lingering fear of cancer returning is something that hangs over many breast cancer survivors after they celebrate the end of treatment”.¹ The ability to identify patients harboring DTCs and intervene therapeutically has until now been lacking.

The authors in the clinical study CLEVER (NCT03032406) published in Nature Medicine enrolled 51 breast cancer survivors (within 5 years of diagnosis) who had completed therapy and had detectable DTCs in bone marrow aspirates.² Patients were randomly assigned to receive hydroxychloroquine (HCQ), everolimus (EVE), or their combination.

The 3-year recurrence-free survival (RFS) rates were close to 100% in all treatment arms: 91.7% for HCQ, 92.9% for EVE, and 100% for the combination arm, over a median follow-up of 42 months.² In addition, the rates of DTC reduction were 80% for HCQ, 78% for EVE, and 87% for the combination group.² The main investigator, Angela DeMichele stated, “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”.¹

These findings represent a paradigm shift: instead of waiting for recurrence and treating metastatic disease, the aim is to intercept the disease at its dormant stage. That is especially relevant because the biology of dormant cells appears distinct from actively proliferating tumors, an observation supported by both preclinical and translational work.²

Mechanistic Insights: Autophagy and mTOR Pathways

The biology underlying tumor dormancy has been linked to survival mechanisms such as autophagy and mammalian target of rapamycin (mTOR) signaling. In mice, inhibition of autophagy (via HCQ or chloroquine) or mTOR (via rapamycin/everolimus) resulted in reduced residual tumor cell burden and prolonged RFS.² Complementing that, a recent study published in Breast Cancer Research demonstrated that dormant mammary tumor cells are uniquely dependent on autophagy for survival: genetic knockdown of ATG5 or ATG7, or pharmacologic chloroquine, significantly reduced recurrence by killing dormant cells.³ This suggests a vulnerability in the dormant state that can be therapeutically exploited.

Conclusion

The emerging strategy of targeting dormant tumor cells offers hope for transforming breast cancer management from reactive to proactive—moving beyond relapse treatment to relapse prevention. For pharmacy professionals integrated into oncology care teams, the implications are significant. Understanding the underlying biology, therapeutic opportunities, screening logistics, and safety considerations will be essential as this paradigm evolves. The promising results from the CLEVER trial mark a major step forward, and the proactive interception of breast cancer recurrence may soon become a clinical reality.

REFERENCES

1. Penn Medicine News. Pioneering Strategy May Keep Breast Cancer From Coming Back. University of Pennsylvania; Published September 2, 2025. Accessed October 30, 2025. https://www.pennmedicine.org/news/pioneering-strategy-may-keep-breast-cancer-from-coming-back

2. DeMichele A, Clark AS, Shea E, et al. Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial. Nat Med. 2025;31(10):3464-3474. doi:10.1038/s41591-025-03877-3

3. Dwyer S, Ruth J, Seidel HE, et al. Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy. Breast Cancer Res. 2024;26(1):143. doi:10.1186/s13058-024-01878-7