Efficacy and Safety of Trastuzumab Rezetecan Followed by CDK4/6 Inhibitors and Endocrine Therapy in HR+/HER2-Low/Ultra-Low Advanced Breast Cancer

Inclusion criteria

Participants must meet all of the following criteria:

• Female patients aged ≥18 years. 2. Pathologically confirmed HER2-low/ultra-low, HR-positive unresectable or metastatic breast cancer:

• HER2-low: IHC 1+ or IHC 2+/ISH-negative；HER2-ultra-low: IHC 0 with membranous staining (>0 but <1+). HR+: ≥10% tumor cells with ER/PR nuclear staining (verified by central pathology review).
• Disease stage: Recurrent/metastatic disease; locally recurrent cases must be deemed unresectable by investigators.

• Prior therapy:

• Disease progression after endocrine therapy (ET) + CDK4/6 inhibitor in the advanced/metastatic setting.
• Progression within 12 months of adjuvant ET + CDK4/6 inhibitor allowed.
• ≤1 line of prior ET and ≤1 line of chemotherapy for advanced disease. 4. Measurable disease per RECIST 1.1 (including lytic/mixed bone-only metastases).

• ECOG PS 0-1. 6. Adequate organ function (no transfusions/G-CSF within 2 weeks prior):

• Hematologic: ANC >1.5×10⁹/L; platelets >90×10⁹/L; Hb >90 g/L.
• Hepatic: Total bilirubin ≤ULN (≤2×ULN if Gilbert's syndrome). ALT/AST ≤1.5×ULN (≤5×ULN with liver metastases). Alkaline phosphatase ≤2.5×ULN.
• Renal: BUN/Cr ≤1.5×ULN.
• Cardiac: LVEF ≥50%;
• QTcF <470 ms. 7. Voluntary participation with signed informed consent.

Exclusion criteria

Participants will be excluded if they meet any of the following conditions:

• Prior anti-HER2 therapy at any stage (including HER2-ADCs such as T-DM1 or T-DXd).
• Significant cardiac disease, including:

• Heart failure or systolic dysfunction (LVEF <50%). 2) High-risk/treated angina or arrhythmias (e.g., Type II Mobitz II/third-degree AV block, ventricular tachycardia).

• Clinically significant valvular disease. 4) ECG-confirmed transmural myocardial infarction. 5) Uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg). 3. Interstitial lung disease (ILD)/pneumonitis:

• History of non-infectious ILD requiring steroids.
• Current ILD or suspected ILD that cannot be ruled out by imaging at screening. 4. Impaired drug absorption due to:

• Dysphagia, chronic diarrhea, intestinal obstruction, or other factors affecting oral medication intake.

• Uncontrolled third-space effusions (e.g., pleural/peritoneal effusions) not manageable by drainage.

• Pregnancy, lactation, or unwillingness to use effective contraception during and for 7 months post-treatment.

• Other exclusions:

• Severe comorbidities interfering with treatment (e.g., active HBV, pulmonary infections requiring therapy).
• Any condition deemed unsuitable by investigators.