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

Condition(s) studied

Investigational drug(s) / intervention(s)

Dalpiciclib + Aromatase Inhibitor with ctDNA-Guided Therapy: Patients 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: Patients 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.

Study 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.

Eligibility

Primary outcome measure(s)

• 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.

Trial sites (1)

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