Dormant Tumor Cells and The Systemic Nature of Breast Cancer

Abstract

Introduction: Emerging evidence indicates that breast cancer may behave as a systemic disease from its earliest stages, challenging the view that metastasis is purely a late event. Disseminated tumor cells (DTCs) have been found in distant organs—including bone marrow, liver, and lungs—even before the primary tumor is clinically detectable. These cells can lie dormant for years and later reactivate to seed metastases. Yet the research is fragmented: some studies measure DTCs, others probe the biology of dormancy, and others track outcomes, with few pulling these strands together for stage I–II disease. This review integrates these lines of evidence to clarify how early DTCs, dormancy programs, and relapse risk intersect, and to assess whether breast cancer acts systemically from the start.

Methods: We conducted a narrative review of peer-reviewed studies (2020–2025) on disseminated tumor cells and dormancy in stage I–II breast cancer. Eligible articles were screened using predefined criteria, and findings were synthesized qualitatively. No new sequencing, retrospective database analyses, or statistical pooling were performed; all results derive from published sources.

Anticipated Results: We anticipate that the literature will show that roughly one-third of early-stage patients have detectable DTCs, with higher rates in HER2-positive and ER-positive disease, and that dormancy-related gene programs are linked to increased relapse risk and shorter metastasis-free survival.

Discussion: Evidence indicates that breast cancer can behave systemically from the earliest stages. DTCs are detected in a notable fraction of stage I–II cases, especially HER2-positive and ER-positive, and dormancy programs (e.g., ZFP281, NR2F1; MAP3K4–p38 modulation) help explain late relapse beyond primary-tumor size.

Conclusion: The evidence supports that systemic dissemination can begin at the earliest stages of breast cancer and that tumor dormancy plays a key role in long-term disease progression. Recognizing DTCs as clinically significant in early-stage patients underscores the need for therapies targeting dormancy-associated pathways to suppress reactivation or eliminate dormant cells, with the goal of reducing relapse and improving patient outcomes.