\- 1. Scientific Background and Rationale： Breast cancer remains a leading cause of cancer-related morbidity and mortality globally, with hormone receptor-positive (HR+), HER2-negative (HER2-) subtypes accounting for approximately 70% of cases. While adjuvant chemotherapy is standard for high-risk early-stage HR+/HER2- breast cancer, it carries significant toxicity, and many patients may not derive clinical benefit. Emerging evidence suggests that circulating tumor DNA (ctDNA)-a minimally invasive biomarker reflecting residual disease-may guide personalized treatment de-escalation.
Preclinical and clinical studies demonstrate that ctDNA dynamics correlate with tumor burden and prognosis. In HR+ breast cancer, ctDNA clearance after neoadjuvant therapy is associated with improved survival, while persistent ctDNA post-treatment predicts recurrence. CDK4/6 inhibitors, such as Dalpiciclib, have revolutionized advanced HR+/HER2- breast cancer management by enhancing endocrine therapy efficacy. However, their role in early-stage disease, particularly in a ctDNA-guided de-escalation strategy, remains underexplored. This study addresses this gap by evaluating whether ctDNA-driven decision-making can safely reduce chemotherapy use while maintaining clinical outcomes.
* 2\. Study Objectives
1. Primary Objectives
Group B (Experimental Arm):
Assess ctDNA clearance rate (defined as conversion from detectable to undetectable ctDNA) after 4 cycles of neoadjuvant Dalpiciclib + aromatase inhibitor (AI).
Evaluate 3-year event-free survival (EFS), where events include local/distant recurrence, secondary malignancies, or death.
2. Secondary Objectives Compare safety profiles of Dalpiciclib + AI versus chemotherapy.
Evaluate tumor response metrics:
Pathological complete response (pCR) and residual cancer burden (RCB 0-1). Complete cell cycle arrest (CCCA; Ki67 ≤2.7%). Assess objective response rate (ORR) by RECIST 1.1.
3. Exploratory Objectives Correlate ctDNA clearance with long-term outcomes (e.g., EFS, overall survival).
Identify molecular signatures predictive of response to Dalpiciclib + AI.
* 3\. Study Design
1. Overview
This is a prospective, multicenter, randomized, open-label Phase II trial. Patients are stratified by clinical stage (I/II vs. III) and menopausal status, then randomized 1:4 to:
Group A (Control): 4 cycles of taxane-based neoadjuvant chemotherapy (N=79). Group B (Experimental): 4 cycles of neoadjuvant Dalpiciclib (125 mg/day, 21 days on/7 days off) + AI (N=314).
2. Post-Surgery Treatment Group A: Physicians may recommend adjuvant chemotherapy ± CDK4/6 inhibitors.
Group B:
ctDNA-negative post-neoadjuvant: Continue Dalpiciclib + AI for 2 years. ctDNA-positive post-neoadjuvant: Optional adjuvant chemotherapy followed by Dalpiciclib + AI.
* 4\. Study Population
1. key inclusion Criteria ①Women aged 18-75 with histologically confirmed HR+ (ER/PR ≥10%), HER2- early breast cancer.
* High-risk features:
T1c-T3N0M0 with grade 3 histology or grade 2 + Ki67 ≥20%. Any T with N+ and M0.
③ECOG performance status 0-1.
④Adequate organ function (hematologic, hepatic, renal, cardiac).
2. key exclusion Criteria
* Metastatic disease, bilateral breast cancer, or prior breast malignancy.
* Active infections, cardiovascular comorbidities, or concurrent malignancies.
* Pregnancy/lactation or refusal to use contraception.
* 5\. Interventions
1. Neoadjuvant Phase
Group A:
Taxane regimens (e.g., paclitaxel 80 mg/m² weekly, docetaxel 75-100 mg/m² every 3 weeks).
Group B:
Dalpiciclib (125 mg orally, days 1-21 of 28-day cycles) + AI (letrozole/anastrozole/exemestane).
2. Adjuvant Phase Group B ctDNA-negative: Dalpiciclib + AI for 2 years. Premenopausal patients receive ovarian suppression (LHRH agonists).
* 6\. Assessments and Follow-Up
1. ctDNA Analysis Baseline and Pre-Surgery: Tumor-informed personalized ctDNA panels (16 clonal variants via whole-exome sequencing).
2. Efficacy and Safety ①Tumor imaging (MRI/CT) every 2 cycles during neoadjuvant therapy.
②Pathological evaluation of surgical specimens (RCB classification).
③Safety monitoring: Adverse events (NCI CTCAE v5.0), ECG, lab tests (hematology, chemistry).
3. Follow-Up Schedule Treatment Phase: Clinic visits every 4 weeks (neoadjuvant) or 12 weeks (adjuvant).
Survival Follow-Up: Every 3 months post-treatment for recurrence and survival.
* 7\. Statistical Considerations
1. Sample Size Primary Endpoint 1 (ctDNA clearance): 215 patients (Group B) provide 80% power to detect a 10% improvement over historical controls (40% vs. 50%, α=0.025).
Primary Endpoint 2 (3-year EFS): 314 patients (Group B) provide 80% power to detect a 5% absolute improvement (85% vs. 90%, α=0.05).
Total enrollment: 393 (1:4 randomization).
2. Analysis Populations Intent-to-Treat (ITT): All randomized patients with ≥1 post-baseline assessment.
Safety Set (SS): Patients receiving ≥1 dose of study treatment.
3. Statistical Methods ctDNA clearance rate: Clopper-Pearson exact 95% CI. EFS: Kaplan-Meier estimates with log-rank tests. Subgroup analyses by stratification factors.
* 8\. Ethical and Regulatory Considerations
①Approved by institutional review boards at all participating centers.
②Written informed consent required before screening.
③SAEs reported to regulators within 24 hours.
④Independent Data Monitoring Committee (IDMC) oversees safety and futility.
* 9\. Innovation and Impact
This trial pioneers a ctDNA-guided de-escalation strategy in early HR+ breast cancer, addressing two critical unmet needs:
Reducing chemotherapy overuse in patients likely cured by targeted therapy. Validating ctDNA as a dynamic biomarker for real-time treatment adaptation. If successful, the study could establish a new paradigm for personalized adjuvant therapy, minimizing toxicity while maintaining survival outcomes.
