Résumé : Circulating tumor DNA (ctDNA) is a promising biomarker in early hormone receptor (HR) + , HER2-negative breast cancer. We assessed ctDNA with the RaDaR assay in NeoRHEA (NCT03065621), a single-arm, phase II neoadjuvant palbociclib plus endocrine therapy trial over 4 months (4 × 28-day cycles). Plasma samples were drawn pre-treatment, after cycle 1, pre-surgery, and 1 month post-surgery. Baseline ctDNA was detected in 55%, fell to 5% during treatment, and was undetectable in all patients by 1-month post-surgery. Baseline detection was higher in grade 3 tumors, lower in multifocal/multicentric disease, and higher in residual cancer burden (RCB) 3. MYC gains/amplifications were enriched in ultrasound (US) responders, while PIK3CA gains were enriched in US non-responders; FAT1 losses were enriched in RCB 3. Baseline ctDNA predicted poor response to this regimen, supporting ctDNA as a biomarker to guide treatment in HR + /HER2-negative disease. Trial registration: EU Clinical Trials Register (EudraCT 2016-000879-24; registered 15 February 2017).