Background:

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with limited treatment options. Research suggests that using High-Intensity Focused Ultrasound (HIFU) to destroy the tumor and/or PD-1 inhibitor drugs to activate the immune system before starting chemotherapy may improve treatment effectiveness. This study aims to investigate this new approach.

Objective:

To evaluate the effectiveness and safety of using HIFU, with or without a PD-1 inhibitor (Sintilimab), before and during combination chemotherapy in patients with early-stage TNBC. The primary goal is to determine if this strategy can increase the rate of pathological complete response (pCR).

Study Design:

This is a single-center, Phase II clinical study. Approximately 40 participants with Stage II-III TNBC will be enrolled and assigned to one of two groups (cohorts) without randomization:

Cohort A: Receives HIFU treatment. Two weeks later, begins standard chemotherapy (Abraxane and carboplatin) combined with the PD-1 inhibitor Sintilimab for 6 cycles.

Cohort B: Receives HIFU treatment combined with a single dose of the PD-1 inhibitor Sintilimab. Two weeks later, begins the same 6 cycles of chemotherapy (Abraxane and carboplatin) combined with Sintilimab.

Main Measures:

The primary measure is the rate of pathological complete response (pCR), defined as the absence of invasive cancer in the breast and lymph nodes after surgery following the completion of neoadjuvant therapy.

Other important measures include:

The ability of the treatment to activate the immune system (measured by changes in CD8+ T cells or IFN-γ).

The percentage of patients whose tumors shrink significantly (Objective Response Rate).

How long patients live without their cancer getting worse (Event-Free Survival).

The rate of patients who can undergo breast-conserving surgery. The frequency and severity of side effects.

Inclusion Criteria:

1. Female patients aged ≥18 and ≤70 years.

2. Histologically confirmed invasive breast cancer, classified as Stage II-III triple-negative breast cancer (TNBC) according to the 8th edition AJCC TNM staging.

3. At least one measurable lesion as per RECIST v1.1 criteria.

4. No prior chemotherapy, immunotherapy, endocrine therapy, radical surgery, or radiotherapy for breast cancer.

5. ECOG performance status of 0 or 1.

6. Adequate organ function, defined as:

   • Hemoglobin ≥90 g/L
   • White blood cell count ≥3.5×10^9/L
   • Platelet count ≥100×10^9/L
   • Absolute neutrophil count ≥1.5×10^9/L
   • AST and ALT ≤3× upper limit of normal (ULN)
   • Total bilirubin ≤1.5× ULN
   • Serum creatinine ≤1.5× ULN
   • No evidence of pneumonia on chest CT

7. Adequate cardiac function, defined as:

   • No myocardial ischemia on ECG
   • NYHA class I
   • LVEF ≥55% on echocardiogram
   • Normal cardiac markers (cTnI and BNP)

8. Normal thyroid function (T3, T4, FT3, FT4, TSH).

9. Willing and able to provide written informed consent.

Exclusion Criteria:

1. Male or inflammatory breast cancer.

2. Metastatic (Stage IV) breast cancer.

3. History of active autoimmune or inflammatory diseases requiring systemic treatment within the past 2 years (e.g., systemic lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Hashimoto's thyroiditis). Exceptions: type I diabetes, hypothyroidism controlled with hormone replacement therapy, or skin disorders not requiring systemic treatment (e.g., vitiligo, psoriasis).

4. Concurrent other malignancies or history of other malignancies within the past 5 years (except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix).

5. Any other serious non-malignant disease that may compromise compliance or place the patient at risk.

6. Major surgery within 4 weeks prior to study initiation or anticipated need for major surgery during the study.

7. Prior radiotherapy, chemotherapy, targeted therapy, endocrine therapy, or major surgery for breast cancer.

8. Known hypersensitivity to any component of the study drugs.

9. Poorly controlled cardiac disease (e.g., NYHA class II+ heart failure, unstable angina, myocardial infarction within the past year, or clinically significant arrhythmias requiring intervention).

10. History of interstitial lung disease (ILD), current ILD, or suspected ILD on imaging during screening.

11. Active infections, including:

    • HIV positive
    • Active tuberculosis
    • Active hepatitis B (HBV-DNA > 10^3 IU/mL)
    • Active hepatitis C (HCV antibody positive with detectable HCV-RNA)

12. Active autoimmune disease requiring systemic treatment.

13. Dementia, significant intellectual impairment, or any psychiatric condition that impairs understanding of the informed consent.

14. Unhealed wounds, ulcers, or fractures within 4 weeks prior to signing consent; or any history of clinically significant bleeding or bleeding tendency.

15. Any other condition deemed by the investigator to be unsuitable for trial participation.