Trastuzumab Rezetecan Followed by Pyrotinib, Fulvestrant, and Dalpiciclib in HR-Positive, HER2-Positive Advanced Breast Cancer

Prior treatment

• No prior trastuzumab, chemotherapy, or endocrine therapy.
• Considered by the investigator to be a candidate for chemotherapy.
• Inability to swallow, chronic diarrhea, or bowel obstruction that may affect drug administration or absorption.
• More than one prior line of endocrine therapy, chemotherapy, or targeted therapy for metastatic disease.
• Concurrent other anticancer therapy.
• Any severe concomitant disease that, in the investigator's judgment, would compromise patient safety or study completion.

Other illness

• Other malignancy within the past 5 years, except curatively treated cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin.
• Known allergy to any component of the study drugs; history of immunodeficiency, including HIV positivity, HCV, active hepatitis B, or other acquired/congenital immunodeficiency; history of organ transplantation.
• History of neurological or psychiatric disorders, including epilepsy or dementia.
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for the study.

Lab values

• Severe cardiac disease or condition, including but not limited to: heart failure or systolic dysfunction (LVEF ≤50%), uncontrolled hypertension, significant ventricular arrhythmia, high-grade atrioventricular block, angina requiring anti-anginal therapy, clinically significant valvular disease, or ECG evidence of acute myocardial infarction.

Other

• Central nervous system metastases.
• Visceral crisis.
• Pregnancy or lactation, or a positive pregnancy test at baseline in women of childbearing potential.

• Adult female patients aged 18 to 80 years with metastatic breast cancer confirmed by pathology or imaging, not amenable to curative surgery or radiotherapy.
• Pathologically confirmed estrogen receptor (ER) and/or progesterone receptor (PR) positive (≥10% tumor cells by immunohistochemistry) and HER2-positive (IHC 3+ or FISH-positive).
• Disease progression during or within 1 year after neoadjuvant/adjuvant trastuzumab, or prior trastuzumab-based therapy for metastatic disease.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and estimated life expectancy ≥3 months.
• Prior treatment-related toxicity resolved to Grade ≤1 per NCI CTCAE v4.03 (except alopecia or other toxicity deemed by the investigator not to pose a safety risk).
• Adequate bone marrow function within 1 week before enrollment: white blood cell count ≥3.0×10⁹/L, absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥100×10⁹/L.
• Adequate hepatic, renal, and cardiac function within 1 week before enrollment: total bilirubin ≤1.5×ULN; ALT/AST ≤2.5×ULN (≤5×ULN in patients with liver metastases); serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL/min; left ventricular ejection fraction ≥55%; QTcF ≤470 ms.
• Patient understands the study procedures, voluntarily agrees to participate, and provides written informed consent.