Dormancy in Breast Cancer

Abstract

The pattern of delayed recurrence in a subset of breast cancer patients has long been explained by a model that incorporates a variable period of cellular or tumor mass dormancy prior to disease relapse. In this review, we critically evaluate existing data to develop a framework for inferring the existence of dormancy in clinical contexts of breast cancer. We integrate these clinical data with rapidly evolving mechanistic insights into breast cancer dormancy derived from a broad array of genetically engineered mouse models as well as experimental models of metastasis. Finally, we propose actionable interventions and discuss ongoing clinical trials that translate the wealth of knowledge gained in the laboratory to the long-term clinical management of patients at a high risk of developing recurrence.

Figure 1.

Sites and mechanisms of dormancy induction. (A) Cells from pre-neoplastic lesions or primary tumors can undergo dormancy at the primary site or at secondary metastatic locations. (B) Dormancy can be induced following therapy directed at the primary tumor and/or by the microenvironment in the process of dissemination. Several core regulators are likely to be conserved independently of the mechanism of dormancy induction.

Figure 2.

Cross talk between tumor cells and the tumor microenvironment regulates dormancy. In addition to epithelial cells present in the target organ, stromal and immune cells, as well as the extracellular matrix (ECM), can regulate whether the tumor cells remain dormant or reactivate to give rise to recurrences. (NK) Natural killer.

Figure 3.

Proposed scheme for the application of dormancy-oriented therapies in the clinic. Breast cancer patients who undergo primary tumor-oriented therapy can be screened for their risk of developing recurrences by gene expression profiling of their primary tumor samples and/or monitoring for the presence of minimal residual disease (MRD) (e.g., disseminated tumor cells [DTCs]). High-risk patients who are DTC-positive can be enrolled into trials that either induce/maintain dormancy, or those that eradicate dormant DTCs. Patients classified as low risk based on their DTC status can be monitored long term for DTC presence as well as levels of niche-derived pro-dormancy cues. (RA) Retinoic acid.