ctDNA-Guided De-Escalation of Adjuvant Chemotherapy With Dalpiciclib in HR-Positive/HER2-Negative Breast Cancer

Breast Cancer Early Stage Breast Cancer (Stage 1-3), ctDNA Monitoring, Early-Stage Breast Cancer, HER2-negative Breast Cancer, High-risk Breast Cancer, Hormone Receptor-Positive Breast Cancer

HR-positive HER2-negative breast cancer, Early-stage breast cancer, Dalpiciclib, CDK4/6 inhibitor, ctDNA-guided therapy, Adjuvant chemotherapy de-escalation, Circulating tumor DNA (ctDNA), Event-free survival (EFS), Chemotherapy sparing, Personalized therapy, Biomarker-guided therapy

* This is a Phase II, multicenter, randomized clinical trial evaluating a ctDNA-guided approach to de-escalate adjuvant chemotherapy in patients with hormone receptor (HR)-positive, HER2-negative early-stage breast cancer. The study aims to determine if combining the CDK4/6 inhibitor Dalpiciclib with endocrine therapy can reduce the need for chemotherapy while maintaining clinical benefits. * Key Details ： 1. Participants: 393 women (aged 18-75) with early-stage HR+/HER2- breast cancer at high risk of recurrence (e.g., tumor size ≥2 cm, lymph node involvement, or high-grade tumors). 2. Design: Patients are randomized 1:4 to two groups: Group A (Chemotherapy) : Receives 4 cycles of taxane-based chemotherapy before surgery. Group B (Experimental) : Receives Dalpiciclib + aromatase inhibitor (AI) for 4 cycles pre-surgery. Post-surgery, treatment is adjusted based on ctDNA results. 3. Primary Goals ： Assess ctDNA clearance rate (conversion from detectable to undetectable ctDNA) after neoadjuvant therapy in Group B. Evaluate 3-year event-free survival (EFS) in Group B (e.g., freedom from cancer recurrence, progression, or death). Secondary Goals ： Safety of Dalpiciclib + endocrine therapy. Tumor response rates (e.g., complete cell cycle arrest, pathological remission). Correlation between ctDNA clearance and long-term outcomes. * Why This Matters ： Current guidelines recommend chemotherapy for high-risk HR+ breast cancer, but it often causes significant side effects. This study explores a personalized approach using ctDNA-a blood-based biomarker-to identify patients who may safely avoid chemotherapy without compromising survival. If successful, it could shift clinical practice toward less toxic, targeted therapies for eligible patients.

\- 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. ②High-risk features: T1c-T2N0M0 with grade 3 histology or grade 2 + Ki67 ≥20%. T3N0M0. Any T with N+ and M0. * ECOG performance status 0-1. ④Adequate organ function (hematologic, hepatic, renal, cardiac). （2）key exclusion Criteria ①Metastatic disease, bilateral breast cancer, or prior breast malignancy. ②Active 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.

China