Neoadjuvant Trastuzumab, Pertuzumab Plus Metronomic Vinorelbine for Elderly HER2-Positive Breast Cancer

A Multicenter, Prospective Clinical Study of Neoadjuvant Therapy With Trastuzumab Plus Pertuzumab Combined With Metronomic Vinorelbine Chemotherapy in Elderly Patients With Early-Stage HER2-Positive Breast Cancer

English Translation (Professional Medical Version) This study is a multicenter, prospective clinical trial designed to investigate the efficacy and safety of neoadjuvant therapy with trastuzumab plus pertuzumab combined with metronomic vinorelbine chemotherapy in elderly patients with HER2-positive breast cancer.

Eligible patients were aged ≥70 years, with histopathologically confirmed primary HER2-positive breast cancer, and met the indications for neoadjuvant therapy as stipulated in the clinical guidelines for the diagnosis and treatment of breast cancer.

A Simon two-stage design was employed in this study, with a planned total enrollment of 45 patients. In the first stage, 14 patients would be enrolled. If the number of observed responders was no more than 6, the trial would be terminated; otherwise, the trial would advance to the second stage, and the total sample size would be expanded to 45 patients.

The treatment regimen comprised 6 cycles of trastuzumab combined with pertuzumab (subcutaneous pertuzumab/trastuzumab fixed-dose combination was permitted as an alternative to intravenous formulations) plus metronomic vinorelbine therapy. Tumor response was assessed by imaging every 2 cycles. Patients with a confirmed response would complete all 6 cycles of treatment and undergo surgery per investigator assessment; postoperative pathological reports would be evaluated to determine the achievement of tpCR. For non-responders, the treatment regimen would be modified or surgery would be performed at the investigator's discretion.

Inclusion Criteria:

• Subjects voluntarily participate in this study and sign informed consent.
• Age ≥70 years at the time of informed consent signing.
• ECOG performance status (PS) 0-1; expected survival >3 months.
• Primary HER2-positive breast cancer confirmed by histopathology or cytology.
• Primary tumor diameter >2 cm, or axillary lymph node metastasis.
• Laboratory indicators conform to the following standards:

Absolute neutrophil count (ANC) ≥1.5×10⁹/L; Absolute lymphocyte count (LC) ≥0.5×10⁹/L; Platelet count (PLT) ≥100×10⁹/L; Hemoglobin (Hb) ≥90 g/L; White blood cell count (WBC) 3.0×10⁹/L ≤ WBC ≤15×10⁹/L. Serum biochemistry (no blood transfusion or albumin infusion within 7 days before screening): ALT and AST ≤2.5×ULN; ALT and AST ≤5×ULN in patients with hepatic metastases. ALP ≤2.5×ULN (≤5×ULN for patients with bone tumor metastasis). BUN and Cr ≤1.5×ULN, and creatinine clearance ≥60 mL/min (Cockcroft-Gault formula).

PT and APTT ≤1.5×ULN, INR ≤1.5×ULN (patients not receiving anticoagulation therapy).

Urine protein <2+. If urine protein ≥2+, 24-hour urinary protein quantification ≤1 g.

Thyroid-stimulating hormone (TSH) ≤ULN. Left ventricular ejection fraction (LVEF) ≥50%. Patients with abnormal TSH may be enrolled as long as T3 and T4 levels are normal.

Exclusion Criteria:

• Stage Ⅳ metastatic breast cancer, or patients who cannot undergo curative surgical resection after neoadjuvant therapy as assessed by investigators.
• Prior anti-tumor therapies including chemotherapy, endocrine therapy, anti-HER2 biological therapy, or previous breast surgery (excluding diagnostic biopsy for primary breast cancer).
• Other malignancies diagnosed within 3 years or concurrent malignant tumors at enrollment.
• The following cases are eligible: Other malignancies treated solely by surgery with continuous 5-year disease-free survival (DFS); cured cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder tumors (Ta: non-invasive tumor, Tis: carcinoma in situ, T1: basement membrane-invasive tumor).
• Major surgery, incisional biopsy or severe traumatic injury within 28 days before study treatment (excluding diagnostic biopsy of primary breast cancer).
• Persistent unhealed wounds or fractures.
• History of uncontrolled psychoactive drug abuse or psychiatric disorders.

Severe and/or uncontrolled underlying systemic diseases, including:

1. History of hypertensive crisis or hypertensive encephalopathy; uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg after antihypertensive treatment).

2. Confirmed heart failure or cardiac systolic dysfunction (LVEF <55%).

3. Grade ≥2 myocardial ischemia, myocardial infarction, arrhythmia (QTc ≥450 ms for males, QTc ≥470 ms for females), or grade ≥2 congestive heart failure (NYHA classification).

4. Angina pectoris requiring anti-anginal medication.

   • Comorbidities interfering with scheduled treatment, including severe pulmonary dysfunction, active pulmonary disease, or uncontrolled severe infection (≥Grade 2 per CTCAE 5.0).
   • Allergy to any investigational drug, active ingredients or pharmaceutical excipients.
   • Subjects with comorbidities that threaten safety or affect study completion, or those unsuitable for enrollment according to investigator judgment.