TY - JOUR
T1 - Therapeutic Targeting of Minimal Residual Disease to Prevent Late Recurrence in Hormone-Receptor Positive Breast Cancer
T2 - Challenges and New Approaches
AU - Cescon, David W.
AU - Kalinsky, Kevin
AU - Parsons, Heather A.
AU - Smith, Karen Lisa
AU - Spears, Patricia A.
AU - Thomas, Alexandra
AU - Zhao, Fengmin
AU - DeMichele, Angela
N1 - Funding Information:
The authors gratefully acknowledge Dr. Mitchell Elliott (University of Toronto) for assistance with the figure design, created with BioRender.com
Publisher Copyright:
Copyright © 2022 Cescon, Kalinsky, Parsons, Smith, Spears, Thomas, Zhao and DeMichele.
PY - 2022/2/10
Y1 - 2022/2/10
N2 - 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.
AB - 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.
KW - CTC = circulating tumor cell
KW - adjuvant therapy
KW - breast cancer
KW - ctDNA = circulating tumor DNA
KW - minimal residual disease (MRD)
KW - molecular residual disease
KW - tumor dormancy
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U2 - 10.3389/fonc.2021.667397
DO - 10.3389/fonc.2021.667397
M3 - Review article
C2 - 35223447
AN - SCOPUS:85125204918
SN - 2234-943X
VL - 11
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 667397
ER -