Overview
- 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 ：
- 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).
- 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.
Description
\- 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
- 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
- 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
- key inclusion Criteria ①Women aged 18-75 with histologically confirmed HR+ (ER/PR ≥10%), HER2- early breast cancer.
- High-risk features:
- key inclusion Criteria ①Women aged 18-75 with histologically confirmed HR+ (ER/PR ≥10%), HER2- early breast cancer.
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
- 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
- ctDNA Analysis Baseline and Pre-Surgery: Tumor-informed personalized ctDNA panels (16 clonal variants via whole-exome sequencing).
- 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
- 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.
Eligibility
Inclusion Criteria:
- Female breast cancer patients aged ≥18 years and ≤75 years, either postmenopausal or premenopausal/perimenopausal;
- Pathologically confirmed hormone receptor-positive (HR+), HER2-negative invasive breast cancer:
- ER-positive and/or PR-positive defined as: ≥10% of tumor cells showing positive staining;
- HER2-negative defined as: standard immunohistochemistry (IHC) result of 0/1+; or IHC 2+ with negative in situ hybridization (ISH) (confirmed by the central pathology laboratory);
- At least one evaluable lesion per RECIST 1.1, with clinical staging meeting:
- T1c-3N0M0 with high-risk factors (Grade 3, or Grade 2 with Ki67 ≥20%);
- Any TN+M0;
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;
- Willing to participate in the study and voluntarily sign informed consent;
- Agree to undergo ctDNA testing during treatment;
- Adequate organ and bone marrow function defined as:
- Absolute neutrophil count (ANC) ≥1,500/mm³ (1.5 × 10⁹/L) (without granulocyte colony-stimulating factor \[G-CSF\] treatment within 14 days);
- Platelet count (PLT) ≥100,000/mm³ (100 × 10⁹/L) (without corrective therapy within 7 days);
- Hemoglobin (Hb) ≥9 g/dL (90 g/L) (without corrective therapy within 7 days);
- Serum creatinine ≤1.5× upper limit of normal (ULN) or creatinine clearance ≥60 mL/min (without corrective therapy within 7 days);
- Total bilirubin (TBIL) ≤1.5×ULN (without corrective therapy within 7 days);
- Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤1.5×ULN (without corrective therapy within 7 days);
- Cardiac function: left ventricular ejection fraction (LVEF) ≥55%; QTc interval corrected by Fridericia's formula (QTcF) \<470 msec on 12-lead ECG;
- Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization and agree to use non-hormonal contraception from informed consent signing until 2 months after the last treatment.
Exclusion Criteria:
- HER2-positive breast cancer confirmed by current pathological diagnosis;
- Inflammatory breast cancer;
- Stage IV (metastatic) breast cancer;
- Bilateral breast cancer;
- Prior history of breast cancer (including ductal carcinoma in situ or invasive breast cancer);
- Any prior antitumor therapy for the current breast cancer, including systemic therapies (endocrine, chemotherapy, immunotherapy, biological therapy) or local therapies (radiotherapy, vascular embolization, axillary lymph node biopsy);
- Diagnosis of any malignancy within 5 years prior to randomization, except cured cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin;
- History of severe pulmonary diseases (e.g., interstitial pneumonia);
- HIV infection, acquired immunodeficiency syndrome (AIDS), active hepatitis B (HBV DNA ≥500 IU/mL), hepatitis C (HCV antibody-positive with HCV RNA above the lower limit of detection), or co-infection with HBV and HCV;
- Within 6 months prior to randomization: myocardial infarction, severe/unstable angina, NYHA Class ≥II heart failure, ≥Grade 2 persistent arrhythmia (per NCI CTCAE v5.0), atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident (including transient ischemic attack), or symptomatic pulmonary embolism;
- Severe active infection within 4 weeks prior to randomization (requiring intravenous antibiotics, antifungals, or antivirals) or unexplained fever \>38.5°C during screening/before first dose;
- Known allergy to any component of the study drugs;
- Current participation in another interventional drug clinical study;
- Pregnancy or lactation;
- Refusal to comply with follow-up;
- Other severe physical/mental illnesses or laboratory abnormalities that may increase study risk, interfere with results, or render the patient unsuitable per investigator judgment.