* 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.
Female breast cancer patients aged ≥18 years and ≤75 years, either postmenopausal or premenopausal/perimenopausal;
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);
T1c-2N0M0 with high-risk factors (Grade 3, or Grade 2 with Ki67 ≥20%);
HER2-positive breast cancer confirmed by current pathological diagnosis;
Inflammatory breast cancer;
Stage IV (metastatic) breast cancer;
Bilateral breast cancer;
Parallel
Dalpiciclib + Aromatase Inhibitor with ctDNA-Guided Therapy
DrugPatients receive 4 cycles of neoadjuvant dalpiciclib (125 mg orally, days 1-21 of 28-day cycles) combined with an aromatase inhibitor (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: Mandatory adjuvant chemotherapy → dalpiciclib + ET for 2 years. Premenopausal women undergo ovarian suppression with LHRH agonists.
Taxane-Based Neoadjuvant Chemotherapy
DrugPatients receive 4 cycles of taxane-based neoadjuvant chemotherapy (e.g., paclitaxel 80 mg/m² weekly or docetaxel 75-100 mg/m² triweekly) before surgery. Post-surgery adjuvant chemotherapy (physician's choice) may be administered. This arm serves as the control group for comparing standard chemotherapy efficacy.
ctDNA Clearance Rate after Neoadjuvant Therapy
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)
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.
Incidence of Grade ≥3 Treatment-Related Adverse Events (TRAEs)
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
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%)
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).
Objective Response Rate (ORR) by RECIST 1.1
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.
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