A Phase II Study to Evaluate the Efficacy and Safety of Anti-HER2 Triple-targeted Drugs Combined With CDK4/6 Inhibitors in Neoadjuvant Therapy for ER-positive HER2-positive Breast Cancer Patients.

In patients with ER-positive and HER2-positive breast cancer, the therapeutic potential of combining trastuzumab, pertuzumab, and pyrotinib-representing a triple-targeted anti-HER2 strategy-alongside intensified endocrine therapy( with CDK4/6 inhibitors )has not yet been established. To further enhance treatment efficacy, minimize reliance on chemotherapy, and identify the optimal neoadjuvant approach for this patient population, we have designed a single-arm, phase II clinical trial. This study aims to evaluate the efficacy and safety of a novel regimen integrating CDK4/6 inhibitors intensified endocrine therapy and dual HER2-targeted monoclonal antibodies plus the tyrosine kinase inhibitor pyrotinib.

Inclusion criteria

• Women aged 18 to 70 years with breast cancer eligible for neoadjuvant therapy
• Clinically staged as II-III
• Histologically confirmed unilateral invasive breast cancer with HER2 positivity, defined as HER2 immunohistochemistry 3+ or in situ hybridization (FISH)-confirmed amplification
• Estrogen receptor (ER) expression ≥10% by immunohistochemistry
• Postmenopausal status
• Premenopausal or perimenopausal patients must undergo surgical oophorectomy or receive ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Left ventricular ejection fraction (LVEF) ≥50% and corrected QT interval (QTc) ≤470 ms
• Adequate major organ function, as evidenced by the following laboratory parameters:

(1) Hematologic function: hemoglobin (Hb) ≥90 g/L (without transfusion within 14 days), absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet count (PLT) ≥100×10⁹/L; (2) Hepatic and renal function: total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN, serum creatinine ≤1×ULN, and calculated creatinine clearance >50 mL/min using the Cockcroft-Gault formula 10) Willingness to participate in the study, provision of signed informed consent, and demonstrated ability to comply with study procedures and follow-up visits

Exclusion criteria

• HER2-negative disease, defined as immunohistochemistry (IHC) score of 0 or 1+; or IHC 2+ without amplification by fluorescence in situ hybridization (FISH)
• Prior receipt of neoadjuvant therapy or any systemic or non-surgical local treatment, including chemotherapy, targeted therapy, radiotherapy, or endocrine therapy
• History of another malignancy, except for adequately treated basal cell carcinoma of the skin or cervical carcinoma in situ
• Inflammatory breast cancer, bilateral breast cancer, or presence of distant metastases
• Pregnant or breastfeeding women, or women of childbearing potential who are unwilling or unable to use effective contraception during the study period
• Concurrent participation in another interventional clinical trial
• Significant organ dysfunction, including cardiac, pulmonary, hepatic, or renal impairment; left ventricular ejection fraction (LVEF) <50% on echocardiography; history of major cardiovascular or cerebrovascular events within 6 months prior to enrollment (e.g., unstable angina, chronic heart failure, myocardial infarction, or stroke); uncontrolled hypertension (>150/90 mmHg); or poorly controlled diabetes mellitus
• Current use of strong CYP3A4 inhibitors or inducers, including:

• Strong inhibitors: boceprevir, clarithromycin, conivaptan, delavirdine, indinavir, itraconazole, ketoconazole, ritonavir, mibefradil, miconazole, trazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, grapefruit, grapefruit juice, or grapefruit-containing products
• Strong inducers: carbamazepine, phenytoin, primidone, rifampicin, and St. John's wort
• Active, severe, or uncontrolled infection, or fever of unknown origin during the screening period
• History of substance abuse involving psychotropic agents with ongoing dependence, or history of significant psychiatric disorder that may impair compliance or safety
• Deemed unsuitable for study participation by the treating investigator