A new global Phase 3 trial, AFT-70 NAVIGATE, is set to test whether ultrasensitive Signatera circulating tumor DNA (molecular residual disease, MRD) monitoring can guide safer use of CDK4/6 inhibitors in ER-positive/HER2-negative early breast cancer. The design aims to reduce toxicity by escalating treatment only when MRD is detected. The trial pairs giredestrant with an MRD-response strategy: patients avoid additional exposure unless the blood-based signal indicates ongoing residual disease. This approach reflects a broader shift toward precision treatment intensity based on molecular dynamics rather than fixed-duration drug schedules. If the strategy works, it would offer a clinically actionable framework to balance efficacy and tolerability while preserving CDK4/6 inhibitor benefits for higher-risk patients.