ctDNA-guided reduction of chemotherapy using dalpiciclib plus endocrine therapy in high-risk HR+/HER2- early breast cancer

A Prospective, Multicenter, Randomized, Open-Label Phase II Study of ctDNA-Guided De-Escalation of Adjuvant Chemotherapy With Dalpiciclib in HR-Positive/HER2-Negative Breast Cancer

This trial tests whether giving the CDK4/6 drug dalpiciclib with endocrine therapy and using ctDNA results can let some women with early high-risk HR+/HER2- breast cancer skip or reduce chemotherapy.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 393 (estimated)
• Ages: 18 Years to 75 Years
• Sex: Female
• Sponsor: Peking University People's Hospital (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 1 site (Beijing, Beijing Municipality)
• Trial ID: NCT06970912 on ClinicalTrials.gov

What this trial studies

This Phase II randomized trial enrolls about 393 women with high-risk early HR+/HER2- breast cancer and randomizes them 1:4 to receive either standard taxane-based neoadjuvant chemotherapy or neoadjuvant dalpiciclib plus an aromatase inhibitor for four cycles before surgery. ctDNA is measured during and after neoadjuvant therapy and guides post-surgical treatment decisions, with the experimental arm's primary endpoint being ctDNA clearance after four cycles. Patients who clear ctDNA may have chemotherapy de-escalated, while those with persistent ctDNA may receive intensified therapy. The goal is to test whether this ctDNA-guided approach maintains cancer control while reducing exposure to chemotherapy.

Who should consider this trial

Good fit: Ideal candidates are women aged 18–75 with early-stage, hormone receptor–positive, HER2-negative breast cancer deemed high-risk (large tumor, node-positive, or high grade) who agree to ctDNA testing.

Not a fit: Patients with other breast cancer subtypes (HER2-positive or triple-negative), low-risk tumors, or those who cannot undergo serial ctDNA testing or follow-up visits are unlikely to benefit from this approach.

Why it matters

Potential benefit: If successful, this approach could allow many patients to avoid or reduce toxic chemotherapy while keeping similar cancer control.

How similar studies have performed: CDK4/6 inhibitors have improved outcomes in advanced HR+/HER2- breast cancer and ctDNA has shown promise as a marker of residual disease, but ctDNA-guided chemotherapy de-escalation with a CDK4/6 inhibitor in early disease remains largely untested.

Eligibility criteria

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.

Where this trial is running

Beijing, Beijing Municipality

• Peking University People's Hospital — Beijing, Beijing Municipality, China (Recruiting)

Study contacts

• Principal investigator: shu wang, doctor — Peking University People's Hospital
• Study coordinator: yuan peng, doctor

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; HR-positive HER2-negative breast cancer; Early-stage breast cancer