Molecular residual disease (MRD) testing: advancing clinical decision-making in breast cancer.

Abstract

Circulating tumor DNA (ctDNA) is emerging as a clinically meaningful biomarker across multiple solid tumors, including breast cancer. Advances in personalized, tumor-informed whole-genome sequencing have enabled highly sensitive detection of ctDNA, allowing for more precise assessment of tumor burden. Across treatment settings, ctDNA testing has demonstrated consistent prognostic value in patients with breast cancer. In the neoadjuvant setting, ctDNA status is strongly prognostic at baseline and following completion of therapy. After definitive surgery, detection of molecular residual disease (MRD) by ctDNA testing is associated with a marked increased risk of recurrence, with positive predictive values approaching 100% and a lead time of approximately 13.5 months over conventional approaches. These data support the potential role of ctDNA testing as an adjunct to current surveillance strategies, with the aim of identifying recurrence before the onset of significant clinical symptoms. Although ctDNA results are not yet used to guide treatment modification outside of established standards of care, the field is advancing rapidly. Multiple ongoing prospective, interventional trials are evaluating MRDguided therapeutic strategies, and emerging evidence suggests that ctDNA may ultimately help individualize adjuvant therapy-either by identifying patients who may safely de-escalate treatment or by signaling when escalation could be beneficial. In the metastatic setting, ctDNA testing can complement radiographic assessment by providing an additional measure of treatment response, particularly in patients with nonmeasurable or difficult-to-visualize disease. Across all settings, ctDNA testing is most informative when performed longitudinally, enabling assessment of dynamic changes over time. Although baseline ctDNA testing provides valuable prognostic information, its absence at this time point or at diagnosis does not limit the utility of ctDNA assessment at subsequent time points.