From residual risk to precision intervention: the evolving role of minimal residual disease in breast cancer management

Breast cancer mortality is driven predominantly by metastasis, which affects 20-30% of patients with early-stage disease despite guideline-directed therapies. Because conventional imaging modalities currently lack sensitivity to identify residual disease, molecular-level monitoring must be developed. Circulating tumor DNA (ctDNA) profiling currently enables transformative minimal residual disease (MRD) detection and can quantify tumor burden at low variant allele frequencies. This review provides a comprehensive overview of MRD in breast cancer, including its definition, detection technologies, positivity thresholds, pathophysiology, clinical applications in adjuvant and neoadjuvant settings, ongoing clinical trials, challenges, and future directions. ctDNA-defined MRD has potential as a precision tool for adaptive therapy, and might facilitate post-adjuvant interception, whereby targeted therapies are administered to eradicate micro-metastases before radiographic recurrence. Persistent challenges include MRD assay standardization, subtype-specific MRD thresholds, tumor heterogeneity, and positioning MRD as a potentially valuable tool for precision management in breast cancer.