This study plans to initiate a prospective, randomized controlled trial to investigate the optimal timing of antibody drug conjugate (ADC) therapy in the management of advanced Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer.

Primary Objective:

To compare the difference in PFS2 (Time from randomization to disease progression after second therapy) between antibody-drug conjugate (ADC) followed by chemotherapy versus chemotherapy followed by ADC in the treatment of advanced HER2-negative breast cancer.

Secondary Objectives:

To compare overall survival (OS), adverse events, patient-reported outcomes, and cost-effectiveness between the two treatment sequences. Additionally, to identify potential biomarkers predictive of benefit from frontline ADC therapy.

Inclusion Criteria:

1. Female patients aged 18-75 years;

2. Histologically confirmed advanced HER2-negative breast cancer, including IHC 2+/ISH-, IHC 1+/ISH-, and IHC 0/ISH- subtypes;

3. Completed first-line combination chemotherapy for advanced/metastatic disease (specific regimen not restricted), with disease progression (PD) evaluated per RECIST criteria (HR-positive patients must have received at least one line of endocrine therapy);

4. Electrocorticography (ECOG) performance status < 2;

5. Estimated life expectancy ≥ 12 weeks;

6. Adequate bone marrow function, defined as:

   • ANC ≥ 1.5 × 10⁹/L
   • Platelets ≥ 90 × 10⁹/L
   • Hemoglobin ≥ 90 g/L

7. Adequate hepatic and renal function, defined as:

   • Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
   • AST or ALT ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases)
   • Creatinine clearance ≥ 60 mL/min

8. Signed informed consent obtained prior to any study-related procedures or treatments, confirming the patient's willingness to participate and comply with study requirements.

Exclusion Criteria:

1. Prior treatment with an ADC after disease recurrence or metastasis;
2. Pregnant or breastfeeding women;
3. No evaluable recurrent or metastatic lesions as defined by RECIST 1.1 criteria;
4. Symptomatic brain parenchymal and/or leptomeningeal metastases with symptoms not adequately controlled by treatment;
5. History of other malignancies within the past 5 years, except for adequately treated carcinoma in situ of the cervix, cutaneous squamous cell carcinoma, or well-controlled localized basal cell carcinoma of the skin;
6. Psychiatric disorders or other conditions that may interfere with patient compliance;
7. Recent history of serious and uncontrolled systemic diseases, such as clinically significant cardiovascular disease, pulmonary disease, metabolic disorders, or arterial/venous thromboembolic events;
8. Concurrent use of other investigational drugs, or participation in another clinical trial within 30 days prior to enrollment;
9. Known or suspected allergy to any study drug or its excipients;
10. Any other condition that, in the opinion of the investigator, renders the patient unsuitable for participation in this trial.