ctdna-guided de-escalation of adjuvant chemotherapy with dalpiciclib in hr-positive/her2-negative breast cancer

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)

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.

- 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.

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.

Keywords: hr-positive her2-negative breast cancer early-stage breast cancer dalpiciclib cdk4/6 inhibitor ctdna-guided therapy adjuvant chemotherapy de-escalation circulating tumor dna (ctdna) event-free survival (efs) chemotherapy sparing personalized therapy biomarker-guided therapy