Phase 2 Signatera™ ctDNA MRD surveillance to time CDK4/6 inhibition (CDK4/6 cell-cycle blockade)

This prospective, single-arm, multicenter Phase 2 study from Natera tests whether ctDNA (molecular residual disease) using the tumor-informed Signatera Genome assay can guide when to start adjuvant CDK4/6 inhibitor therapy in intermediate-risk HR+/HER2− early breast cancer, rather than treating everyone up front. Participants undergo blood draws about every 3 months; ctDNA-positive patients initiate a CDK4/6 inhibitor (ribociclib from Novartis or abemaciclib from Eli Lilly) plus standard endocrine therapy, while ctDNA-negative patients continue endocrine therapy alone with ongoing surveillance and “triggered” CDK4/6 initiation if ctDNA later becomes detectable (with staging first to rule out overt metastasis). Ribociclib and abemaciclib inhibit CDK4/6 to prevent RB phosphorylation and arrest tumor cells in G1. Eligible disease is anatomic stage II after complete resection: N1, or N0 with T2/T3 plus higher-risk features (e.g., grade 2–3 and/or Ki-67 ≥20%, excluding grade 1). The commercial/scientific angle is de-escalation: today’s care for this population is surgery ± radiation, endocrine therapy for years, and selective use of adjuvant CDK4/6 inhibitors based on clinicopathologic risk; this trial asks if MRD-guided timing can preserve outcomes while reducing unnecessary toxicity and cost, benchmarking against historical NATALEE outcomes.