A new global Phase 3 trial, AFT-70 NAVIGATE, will test whether ultrasensitive circulating-tumor DNA monitoring using Signatera MRD can safely guide therapy decisions in ER-positive/HER2-negative early breast cancer and spare patients from unnecessary exposure to CDK4/6 inhibitors. The study design pairs giredestrant with an escalation framework driven by MRD detection. Patients would receive molecular monitoring and treatment escalation only when MRD is detected, targeting reduced toxicity without compromising outcomes. For the field, the key issue is whether blood-based MRD can operationalize de-escalation beyond imaging and standard pathology. The trial also highlights how companies are trying to convert genomics-driven risk stratification into dosing decisions with measurable patient-impact endpoints. NAVIGATE’s start underscores a growing shift toward marker-guided oncology pathways intended to reduce overtreatment, particularly where chronic therapy side effects can erode adherence and quality of life.