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Breast cancer recurrence remains a major clinical challenge: roughly 30 percent of patients whose initial treatments succeed will experience a return of the disease, contributing to an estimated 685,000 deaths globally each year. A recent translational study led by researchers at the University of Pennsylvania suggests a new preventative strategy that seeks out and eliminates dormant tumor cells (DTCs) that can survive initial therapy and later spark relapse.
Instead of relying solely on surveillance after primary treatment, the researchers tested active drug interventions aimed at the root causes of recurrence — cells that hide in the bone marrow and other tissues in a low‑activity state. This move from passive monitoring to targeted eradication could change post‑treatment care if larger trials confirm the initial results.
Study design and key findings
In preclinical mouse models and an early-phase human study, the team evaluated two drugs informed by recent molecular work on DTC biology: hydroxychloroquine, an established autoimmune medicine, and everolimus, an mTOR inhibitor already used in some cancer treatments. The researchers selected 51 people who had previously been treated for breast cancer and who tested positive for DTCs.
In human trials and animal tests (shown here), treatment reduced the risk of cancer returning. (DeMichele et al., Nat. Med., 2025)
Alone, each drug cleared as many as 80 percent of detectable dormant cells in some participants. When combined, the two agents removed 87 percent of dormant cells across the cohort. Clinically, the difference was notable: every participant who received the combination remained free of detectable recurrence at three years, while participants who received a single agent had a three‑year disease‑free rate of about 92–93 percent.
Mouse models recapitulated these effects and allowed investigators to probe mechanisms. The data indicate that DTCs have distinct biology compared with actively growing tumor cells, and that drugs ineffective against proliferating cancers can nonetheless disable or eliminate these so‑called sleeper cells.
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Biological context and safety considerations
Dormant tumor cells are cancer cells that have survived initial therapy and entered a reversible, nonproliferative state. They can persist for years in niches such as bone marrow, evading treatments that target cell division. Molecular studies have begun to reveal survival pathways used by DTCs, including autophagy and mTOR signaling — pathways that hydroxychloroquine and everolimus can influence.
While the early results are promising, safety and broader applicability must be established. Hydroxychloroquine carries risks including retinal toxicity with long‑term use; everolimus can suppress immune function and has metabolic side effects. Larger randomized trials are required to define optimal dosing, combinations, treatment duration, and patient selection criteria. Not every breast cancer survivor harbors DTCs, so accurate, reproducible assays for detecting these cells will be essential for targeting therapy to those most likely to benefit.
Implications for treatment and research
If replicated in larger cohorts, active targeting of DTCs could shift standard post‑treatment protocols from watchful waiting to proactive eradication of minimal residual disease. Reducing relapse rates would have direct impact on mortality, long‑term morbidity, and the psychological burden survivors carry. The findings also highlight the value of looking beyond rapidly dividing tumor populations to their dormant counterparts when developing anti‑recurrence strategies.
Next steps described by the authors include expanded clinical trials with more participants, exploration of alternative combinations that may be more effective or better tolerated, and refinement of molecular diagnostics to identify DTC‑positive patients reliably.
Expert Insight
Dr. Maya Patel, a clinical translational researcher unaffiliated with the study, commented: "This work is an important example of translating mechanistic insights about cancer dormancy into a testable therapeutic approach. The challenge now is demonstrating benefit across diverse patient populations and ensuring that treatments do more good than harm when given to people who may otherwise remain disease‑free." She added that improved DTC detection methods will be key to making such treatments practical in routine oncology care.
Conclusion
Targeting dormant tumor cells represents a promising new frontier in preventing breast cancer recurrence. Early human and animal data indicate that drugs like hydroxychloroquine and everolimus — particularly in combination — can substantially reduce detectable DTCs and lower short‑term relapse rates. Robust, larger randomized trials and improved diagnostics are needed to confirm efficacy, clarify safety, and determine how this approach could be integrated into standard post‑treatment management to reduce long‑term mortality from breast cancer.
Source: sciencealert
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