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

Abstract

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.

Late Recurrence Following Early Breast Cancer

“…Given the potential of these scientific advances, plus the large unmet clinical need, the National Cancer Institute sponsored a Clinical Trials Planning Meeting in May 2019, from which evolved REFINE-BrCa (Refining Adjuvant Therapy Through Identification and Escalation), a collaboration across National Clinical Trials Network group members who are developing clinical trials to address these key questions about breast cancer late recurrence. 15…”

Can a Late Interception by Circulating Tumor DNA Deliver a Win in Estrogen Receptor–Positive Early Breast Cancer?

“…With an increasing body of evidence pointing to the possibility that MRD might identify and stratify patients' personal recurrence risk, a new generation of prospective studies is essential to address the critical gaps in our understanding. 13 Is the risk conferred by having detectable ctDNA without scan-confirmed measurable disease a modifiable risk? A simple first step is to determine whether lead time over radiographic metastatic disease exists through dedicated prospective studies since surveillance systemic imaging is not standard in breast cancer follow-up.…”

Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer

“…Before there is a known effective intervention for MRD-positive patients without scan-detectable disease, MRD testing may contribute to unintentional harm if incorporated into routine clinical practice. 35 Our institution is studying patient understanding of and attitudes toward late recurrence in a survey study on Patient-reported Outcomes in Women with ER+/PR+ breast cancer (POWER). Additionally, many patients with early-stage HR+ breast cancer in the late adjuvant setting ultimately die of non–breast cancer causes including cardiovascular, cerebrovascular, and neurodegenerative diseases.…”