TPS626 Background: Dalpiciclib is a CDK4/6 inhibitor that has shown promising efficacy and safety when in combination with endocrine in the treatment of advanced HR+ HER2- breast cancer. Building on preliminary findings from our previous study (Geng, 2023SABCS PO2-02-05), we aim to evaluate the efficacy and safety of dalpiciclib combined with letrozole versus standard chemotherapy as neoadjuvant treatment in patients with high-risk early breast cancer (EBC). Methods: This is a prospective, multicenter, randomized phase II non-inferiority trial. Main eligibility criteria include: female patients ≥18 years, ECOG performance status of 0-1, histologically confirmed invasive breast cancer, clinical stage T1c-T2, cN1–2 or T3-4, cN0-2, ER≥50%, HER2-negative, and Ki67 ≤ 20%. Participants are randomized 1:1 to receive either 24-week experimental intervention (oral dalpiciclib 150mg once daily for 3 weeks on, 1 week off and oral letrozole 2.5 mg/day) or 24-week standard intervention (intravenous epirubicin 100 mg/m² and intravenous cyclophosphamide 500 mg/m² on day 1 for three 3-week cycles, followed by intravenous docetaxel 100 mg/m2 on day 1 for three 3-week cycles). The primary endpoint is the objective response rate (ORR) assessed by RECIST v1.1. Secondary endpoints include patient-reported outcomes (EORTC QLQ-C30, EORTC QLQ-BR23), residual cancer burden 0–I rate, preoperative endocrine prognostic index score 0 rate, pathological complete response rate , 2-year invasive disease-free survival rate, and safety. Exploratory endpoints include biomarker analysis. The hypothesis is that the experimental group will not be inferior to control group. Assuming an ORR of 70% for both groups, a sample size of 65 patients per group is required to achieve 80% power to detect a non-inferiority margin of up to 20% at a two-sided significance level of 5%. A total of 130 patients are needed (65 per group). Considering a dropout rate of 10% per group, the total sample size is approximately 144 patients. The trial was registered at ClinicalTrials.gov (NCT06107673) and is actively recruiting. Clinical trial information: NCT06107673 .