CDK4/6 Inhibitors Combined With Endocrine Therapy for Neoadjuvant Treatment of Breast Cancer: ctDNA-Guided Personalized Therapy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 158
- 试验地点
- 1
- 主要终点
- ctDNA Clearance Rate after Neoadjuvant Therapy
研究概览
简要总结
Exploring the dynamics of ctDNA following neoadjuvant therapy with CDK4/6 inhibitors combined with endocrine treatment, and its potential to guide de-escalation of adjuvant chemotherapy
详细描述
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.
Study Objectives Primary Objectives: Assess ctDNA clearance rate (defined as conversion from detectable to undetectable ctDNA) after 4 cycles of neoadjuvant CDK4/6i + endocrine therapy.
Secondary Objectives Evaluate 3-year event-free survival (EFS), where events include local/distant recurrence, secondary malignancies, or death.
Compare safety profiles of CDK4/6i + endocrine therapy versus chemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •1.Female breast cancer patients aged ≥18 years and ≤75 years, either postmenopausal or premenopausal/perimenopausal; 2.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%);
- •Any TN+M0; 4.Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1; 5.Willing to participate in the study and voluntarily sign informed consent; 6.Agree to undergo ctDNA testing during treatment; 7.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.
排除标准
- •1.Bilateral breast cancer; 2.Prior history of breast cancer (including ductal carcinoma in situ or invasive breast cancer); 3.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); 4.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; 5.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; 7.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; 8.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; 9.Known allergy to any component of the study drugs; 10.Current participation in another interventional drug clinical study; 11.Pregnancy or lactation; 12.Refusal to comply with follow-up; 13.Other severe physical/mental illnesses or laboratory abnormalities that may increase study risk, interfere with results, or render the patient unsuitable per investigator judgment.
研究组 & 干预措施
CDK4/6 inhibitor with endocrine therapy
Patients receive 4 cycles of neoadjuvant CDK4/6 inhibitor with endocrine therapy. Post-surgery treatment is guided by ctDNA status:
ctDNA-negative at baseline and post-neoadjuvant, with post-op Ki67 ≤10% ：Continue CDK4/6 inhibitor with endocrine therapy for 2-3 years.
ctDNA-positive → negative, or persistently ctDNA-negative with post-op Ki67 >10% :
Randomized 1:1 to:
Arm 1: CDK4/6 inhibitor with endocrine therapy for 2-3 years. Arm 2: Adjuvant chemotherapy (investigator's choice) → CDK4/6 inhibitor with endocrine therapy for 2-3 years.
（3）Persistently ctDNA-positive or ctDNA-negative → positive: Adjuvant chemotherapy → CDK4/6 inhibitor with endocrine therapy for 2-3 years.
Premenopausal women receive ovarian suppression with LHRH agonists.
干预措施: CDK4/6 inhibitor with endocrine therapy (Drug)
结局指标
主要结局
ctDNA Clearance Rate after Neoadjuvant Therapy
时间窗: From baseline to 4 weeks post-neoadjuvant therapy (pre-surgery)
Proportion of patients achieving conversion from detectable to undetectable ctDNA in plasma after 4 cycles of neoadjuvant CDK4/6i+endocronetherapy. 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.
次要结局
- 3-Year Event-Free Survival (EFS)(From neoadjuvant therapy to 36 months post-surgery)
- Residual Cancer Burden (RCB) 0-1 Rate(At surgery (approximately 16 weeks since neoadjuvant therapy))
- Objective Response Rate (ORR) by RECIST 1.1(Baseline to pre-surgery (week 16))
- Complete Cell Cycle Arrest (CCCA) Rate (Ki67 ≤2.7%)(Post-neoadjuvant therapy (pre-surgery, week 16))
- Incidence of Grade ≥3 Treatment-Related Adverse Events (TRAEs)(From first dose to 30 days after last treatment)
研究者
Shu Wang
director of breast center
Peking University People's Hospital