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

• 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.

• 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.

• 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).

• 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

• 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).

• 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).

• 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).

• Analysis Populations Intent-to-Treat (ITT): All randomized patients with ≥1 post-baseline assessment.

Safety Set (SS): Patients receiving ≥1 dose of study treatment.

• 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.

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-2N0M0 with high-risk factors (Grade 3, or Grade 2 with Ki67 ≥20%);
• T3N0M0;
• 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.