Therapeutic Targeting of Minimal Residual Disease to Prevent Late Recurrence in Hormone-Receptor Positive Breast Cancer: Challenges and New Approaches.

While the majority of breast cancers are diagnosed at a curable stage, approximately 20% of women will experience recurrence at a distant site during their lifetime. These metastatic recurrences are incurable with current therapeutic approaches. Over the past decade, the biologic mechanisms underlying these recurrences have been elucidated, establishing the existence of minimal residual disease in the form of circulating micrometastases and dormant disease, primarily in the bone marrow. Numerous technologies are now available to detect minimal residual disease (MRD) after breast cancer treatment, but it is yet unknown how to best target and eradicate these cells, and whether clearance of detectable disease prior to the formation of overt metastases can prevent ultimate progression and death. Clinical trials to test this hypothesis are challenging due to the rare nature of MRD in the blood and bone marrow, resulting in the need to screen a large number of survivors to identify those for study. Use of prognostic molecular tools may be able to direct screening to those patients most likely to harbor MRD, but the relationship between these predictors and MRD detection is as yet undefined. Further challenges include the lack of a definitive assay for MRD with established clinical utility, difficulty in selecting potential interventions due to limitations in understanding the biology of MRD, and the emotional impact of detecting MRD in patients who have completed definitive treatment and have no evidence of overt metastatic disease. This review provides a roadmap for tackling these challenges in the design and implementation of interventional clinical trials aimed at eliminating MRD and ultimately preventing metastatic disease to improve survival from this disease, with a specific focus on late recurrences in ER+ breast cancer.