This multicenter, prospective phase II clinical trial evaluates the efficacy and safety of sequential Trastuzumab rezetecan followed by dalpiciclib plus endocrine therapy (fulvestrant or aromatase inhibitors) in 45 patients with HR+/HER2-low/ultra-low advanced breast cancer. Enrolled patients will receive Trastuzumab rezetecan monotherapy for 6-8 cycles until clinical benefit, then transition to CDK4/6 inhibitors with endocrine therapy until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), overall survival (OS), and treatment-related adverse events (TRAEs). The study will be conducted at Sun Yat-sen Memorial Hospital and collaborating centers.

Inclusion Criteria:

Participants must meet all of the following criteria:

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

1. 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).
2. Disease stage: Recurrent/metastatic disease; locally recurrent cases must be deemed unresectable by investigators.

3. Prior therapy:

1. Disease progression after endocrine therapy (ET) + CDK4/6 inhibitor in the advanced/metastatic setting.
2. Progression within 12 months of adjuvant ET + CDK4/6 inhibitor allowed.
3. ≤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).

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

1. Hematologic: ANC >1.5×10⁹/L; platelets >90×10⁹/L; Hb >90 g/L.
2. 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.
3. Renal: BUN/Cr ≤1.5×ULN.
4. Cardiac: LVEF ≥50%;
5. QTcF <470 ms. 7. Voluntary participation with signed informed consent.

Exclusion Criteria:

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

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

1) 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).

3) 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:

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

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

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

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

7. Other exclusions:

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