The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy is the standard first-line treatment for advanced HR+ (hormone receptor-positive)/HER2- (human epidermal growth factor receptor 2-negative) breast cancer. However, the optimal treatment strategy after CDK4/6i progression remains unclear. In recent years, antibody-drug conjugates (ADCs) such as sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) have demonstrated significant activity in HR+/HER2- breast cancer, providing new options post-CDK4/6i progression. Yet, the optimal sequencing of different ADCs (e.g., SG followed by T-DXd vs. T-DXd followed by SG) after CDK4/6i failure remains uncertain. Determining how to further optimize treatment selection to prolong survival and improve quality of life has become a key research focus in clinical practice. This study aims to explore the efficacy, safety, and potential resistance mechanisms of biomarker-guided sequential ADC therapy (e.g., SG→T-DXd vs. T-DXd→SG) following CDK4/6i progression. The findings may guide clinical decision-making and provide evidence for precision medicine.

Inclusion Criteria:

1. Adult patients ≥18 years old;
2. Histologically or cytologically confirmed HR+/HER2- (HER2 IHC 0/IHC 1+ or IHC 2+ with FISH-negative) locally advanced unresectable or metastatic breast cancer, as defined by ASCO/CAP guidelines;
3. Prior treatment with CDK4/6i combined with endocrine therapy, with radiologically confirmed disease progression;
4. Presence of evaluable lesions;
5. Received ≤2 lines of chemotherapy for advanced disease;
6. Adequate organ function and performance status (ECOG score ≤2);
7. Signed informed consent.

Exclusion Criteria:

1. Previous treatment with topoisomerase 1 (TOP-1) inhibitor-based therapy;
2. Severe cardiac, hepatic, or renal dysfunction or other serious comorbidities;
3. History of moderate to severe interstitial lung disease (ILD) with concurrent pulmonary insufficiency;
4. Symptomatic brain metastases;
5. History of allergy to key components of the investigational ADC drugs (e.g., payload, antibody, or linker);
6. Patients with active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or a history of intestinal obstruction or gastrointestinal (GI) perforation;
7. Uncontrolled cardiovascular diseases (e.g., NYHA Class III/IV heart failure, myocardial infarction within 6 months);
8. Active infections (e.g., HIV, active HBV/HCV infection);
9. Pregnant or lactating women.

Since the research data involves patient privacy and intellectual property protection from collaborating institutions, the original data will not be publicly shared at this time. Summarized results will be published in academic papers.