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

Phase 2

Not yet recruiting

• Conditions: Hormone Receptor-Positive Breast Cancer; High-risk Breast Cancer; Early-Stage Breast Cancer; HER2-negative Breast Cancer; ctDNA Monitoring; Breast Cancer Early Stage Breast Cancer (Stage 1-3)
• Interventions: Drug: Taxane-Based Neoadjuvant Chemotherapy; Drug: Dalpiciclib + Aromatase Inhibitor with ctDNA-Guided Therapy

• Registration Number: NCT06970912
• Lead Sponsor: Peking University People's Hospital

Brief Summary

* 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.

Detailed 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

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.

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-06
• Study First Submitted QC: 2025-05-06
• Last Update Submitted: 2025-05-06
• Study First Posted: 2025-05-14
• Last Update Posted: 2025-05-14
• Study Start: 2025-06-01
• Primary Completion: 2029-12-31
• Study Completion: 2029-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 393

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:

  1. ER-positive and/or PR-positive defined as: ≥10% of tumor cells showing positive staining;
  2. 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:

  1. T1c-3N0M0 with high-risk factors (Grade 3, or Grade 2 with Ki67 ≥20%);
  2. 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:

  1. Absolute neutrophil count (ANC) ≥1,500/mm³ (1.5 × 10⁹/L) (without granulocyte colony-stimulating factor [G-CSF] treatment within 14 days);
  2. Platelet count (PLT) ≥100,000/mm³ (100 × 10⁹/L) (without corrective therapy within 7 days);
  3. Hemoglobin (Hb) ≥9 g/dL (90 g/L) (without corrective therapy within 7 days);
  4. Serum creatinine ≤1.5× upper limit of normal (ULN) or creatinine clearance ≥60 mL/min (without corrective therapy within 7 days);
  5. Total bilirubin (TBIL) ≤1.5×ULN (without corrective therapy within 7 days);
  6. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤1.5×ULN (without corrective therapy within 7 days);
  7. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Taxane Neoadjuvant Chemo ± Adjuvant Therapy	Taxane-Based Neoadjuvant Chemotherapy	Arm Description: This group receives neoadjuvant taxane-based chemotherapy (e.g., paclitaxel 80 mg/m² weekly or docetaxel 75-100 mg/m² triweekly for 4 cycles) before surgery. Post-surgery adjuvant chemotherapy (whether or not and how to adopt depend on the physician's choice) may be administered ± CDK4/6 inhibitors. The intervention aims to compare standard chemotherapy efficacy as a control. Intervention phases: * Neoadjuvant: Chemotherapy only * Adjuvant: Optional chemotherapy based on physician discretion ± （CDK4/6 inhibitors+endocrine therapy） Key endpoints: Pathological response 0/1 (RCB 0/1), safety profiles.
Dalpiciclib + AI with ctDNA-Driven Adjuvant	Dalpiciclib + Aromatase Inhibitor with ctDNA-Guided Therapy	Arm Description: Patients receive 4 cycles of neoadjuvant dalpiciclib (125 mg/day, 21 days on/7-off) combined with aromatase inhibitors (letrozole/anastrozole/exemestane). Post-surgery treatment is guided by ctDNA status: 1. ctDNA-negative at baseline and post-neoadjuvant, with post-op Ki67 ≤10% ：Continue dalpiciclib + endocrine therapy (ET) for 2 years. 2. ctDNA-positive → negative, or persistently ctDNA-negative with post-op Ki67 \>10% : Randomized 1:1 to: * Arm B1: Dalpiciclib + ET for 2 years. * Arm B2: Adjuvant chemotherapy (investigator's choice) → dalpiciclib + ET for 2 years. 3. Persistently ctDNA-positive or ctDNA-negative → positive: Adjuvant chemotherapy → dalpiciclib + ET for 2 years. Premenopausal women receive ovarian suppression with LHRH agonists.

Primary Outcome Measures

Name	Time	Method
ctDNA Clearance Rate after Neoadjuvant Therapy	From baseline to 4 weeks post-neoadjuvant therapy (pre-surgery)	Proportion of patients in Group B achieving conversion from detectable to undetectable ctDNA in plasma after 4 cycles of neoadjuvant Dalpiciclib + aromatase inhibitor. ctDNA analysis uses tumor-informed personalized panels (tracking 16 clonal variants via whole-exome sequencing), with clearance defined as ≥2 consecutive negative results at 1% variant allele frequency threshold.
3-Year Event-Free Survival (EFS)	From randomization to 36 months post-surgery	Time from randomization to first occurrence of locoregional/distant recurrence, contralateral breast cancer, secondary malignancy, or death from any cause. Assessed via imaging (CT/MRI), pathology, and clinical exams every 3 months for 3 years. Events are adjudicated by blinded independent review committee.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) by RECIST 1.1	Baseline to pre-surgery (week 16)	Proportion of patients with complete/partial response per RECIST 1.1 criteria during neoadjuvant phase, measured by MRI/CT. Target lesion size reduction ≥30% (partial) or disappearance (complete) required, confirmed by two consecutive assessments ≥4 weeks apart.
Correlation Between ctDNA Clearance and 3-Year EFS	From baseline to 36 months post-surgery	Exploratory analysis of the association between ctDNA clearance status (post-neoadjuvant) and 3-year EFS using Cox proportional hazards models. ctDNA dynamics (baseline, post-treatment) are analyzed as time-dependent covariates.
Incidence of Grade ≥3 Treatment-Related Adverse Events (TRAEs)	From first dose to 30 days after last treatment (up to 26 months)	Proportion of patients experiencing grade ≥3 adverse events (per NCI CTCAE v5.0) related to Dalpiciclib + AI or chemotherapy, including hematologic (neutropenia, anemia), hepatic (ALT/AST elevation), and cardiac (LVEF decline ≥10%) toxicities. Events are monitored every cycle during neoadjuvant therapy and quarterly during adjuvant phase.
Residual Cancer Burden (RCB) 0-1 Rate	At surgery (approximately 16 weeks after randomization)	Proportion of patients achieving RCB 0 (pathological complete response) or RCB-1 (minimal residual disease) in surgical specimens. RCB is calculated using standardized criteria (tumor bed area, cellularity, nodal involvement) by blinded central pathology review.
Complete Cell Cycle Arrest (CCCA) Rate (Ki67 ≤2.7%)	Post-neoadjuvant therapy (pre-surgery, week 16)	Percentage of patients with Ki67 ≤2.7% in post-neoadjuvant tumor biopsies, assessed via immunohistochemistry (IHC) with 3,3'-diaminobenzidine staining. Central laboratory quantification uses Aperio image analysis system (Leica Biosystems).

Trial Locations

Locations (1)

Peking University People's Hospital; 🇨🇳 Beijing, Beijing, China