Cohort Study on Sequential ADC Therapy in HR-positive/HER2-negative Advanced Breast Cancer

Real-world Cohort Study on Sequential Therapy With ADC Drugs Following Progression of Endocrine Therapy Guided by Molecular Biomarkers in HR-positive/HER2-negative Advanced Breast Cancer

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.