Neoadjuvant SBRT Followed by Nab-Paclitaxel Combined With Toripalimab in HR+/HER2- Breast Cancer

Inclusion criteria

• Female patients aged ≥18 and ≤75 years at the time of signing informed consent.
• ECOG PS status of 0-1.
• Histologically confirmed non-metastatic (M0) breast cancer, meeting all of the following:
• a) Clinical stage (per AJCC 8th edition) meeting one of the following: i. cT3N0, cT2-4N1-3, or cT1N2-3 (Stage IIB, IIIA, IIIB, or IIIC); ii. cT2N0 or cT1N1 (Stage IIA) with at least two of the following high-risk features: Histologic grade 3; Ki-67 ≥50%; Age \<50 years and premenopausal status.
• b) Imaging assessments within 28 days prior to enrollment including: abdominal CT or ultrasound, bone scan (ECT), chest CT, and brain MRI.
• Histologically or pathologically confirmed invasive carcinoma, with all of the following:
• Grade 2 or 3 (confirmed by central laboratory);
• ER-positive (\>1% staining) and/or PR-positive (\>1% staining) by IHC;
• HER2-negative (IHC 0/1+ or HER2/neu FISH ratio ≤1.8);
• Ki-67 ≥15%.
• Patient deemed eligible for radiotherapy after MDT evaluation.
• No prior antitumor therapy within 1 month before enrollment.
• Organ Function Requirements (within 7 days prior to enrollment):
• Complete blood count (no transfusion or hematopoietic growth factors within 7 days): ANC ≥1.5×10⁹/L; ALC ≥0.5×10⁹/L; Platelets ≥100×10⁹/L; Hemoglobin ≥90 g/L; WBC ≥3.0×10⁹/L and ≤15×10⁹/L;
• Blood biochemistry (no transfusion/albumin within 7 days): ALT/AST ≤2.5×ULN; ALP ≤2.5×ULN；BUN/Cr ≤1.5×ULN; Cr≥60 mL/min (Cockcroft-Gault formula);
• Coagulation: PT/APTT ≤1.5×ULN; INR ≤1.5×ULN (if no anticoagulant therapy);
• Urinalysis: Urine protein \<2+; if ≥2+, 24-hour urine protein must be ≤1g;
• Thyroid function:TSH ≤1×ULN; if abnormal, normal T3/T4 levels required for eligibility.
• Women of childbearing potential must:
• Have a negative serum pregnancy test within 7 days before treatment;
• Use highly effective contraception during the study and for 180 days after the last dose.
• Voluntarily sign informed consent, demonstrate good compliance, and commit to follow-up.

Exclusion criteria

• Inflammatory Breast Cancer.
• Comorbidities/Medical History:
• Autoimmune disease: patients with any known or suspected autoimmune disease, except: hypothyroidism due to autoimmune thyroiditis managed with hormone replacement therapy only, stable type-1 diabetes with well-controlled blood glucose.
• Cardiovascular Diseases: poorly controlled hypertension despite medication (SBP \>140 mmHg or DBP\>90 mmHg). And with the history (within 6 months prior to enrollment) of myocardial infarction, severe/unstable angina, NYHA Class ≥2 heart failure, clinically significant arrhythmias as well as symptomatic congestive heart failure.
• Interstitial lung disease, non-infectious pneumonitis, or other uncontrolled systemic diseases (e.g., diabetes, pulmonary fibrosis, acute pneumonia);
• Vaccination: receipt of live attenuated vaccines within 28 days prior to enrollment or planned during the study;
• Infections: HIV/AIDS, active hepatitis(HBV-DNA ≥500 IU/mL; HCV-RNA above detection limit), or co-infection with HBV and HCV, severe infections within 4 weeks prior to enrollment (e.g., bacteremia, severe pneumonia requiring hospitalization), active infection requiring systemic antibiotics (CTCAE≥Grade 2) within 2 weeks prior to treatment, active tuberculosis within 1 year prior to enrollment;
• Unexplained fever \>38.5°C during screening (unless deemed tumor-related by the investigator);
• Malignancy History: other malignancies diagnosed within 5 years prior to enrollment (except adequately treated basal cell carcinoma, squamous cell skin cancer, or cervical carcinoma in situ);
• Surgery:Major surgery within 28 days prior to enrollment (diagnostic biopsies or PICC line placement are allowed);
• Transplant: Prior or planned allogeneic bone marrow or solid organ transplant;
• Neurological: peripheral neuropathy ≥Grade 2;
• Gastrointestinal: clinically significant bowel obstruction;
• Thrombotic Events: arterial/venous thrombosis within 6 months prior to enrollment (e.g., stroke, transient ischemic attack, DVT, pulmonary embolism);
• Bleeding Risk: hemoptysis (≥2.5 mL/day) within 2 months prior to enrollment, clinically significant bleeding within 3 months prior to enrollment (e.g. gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood≥++), and the known bleeding/thrombotic disorders (e.g., hemophilia, coagulopathy, thrombocytopenia, hypersplenism);
• Coagulation abnormalities (INR \>1.5×ULN or APTT \>1.5×ULN), or requiring long-term anticoagulation (warfarin/heparin) or antiplatelet therapy (aspirin≥300 mg/day or clopidogrel ≥75 mg/day).
• Treatment-Related Exclusions:
• Prior systemic targeted therapy or immunostimulants (e.g., interferon, IL-2) within 4 weeks before treatment;
• Known allergy to the investigational drug (recombinant humanized anti-PD-1 mAb) or its excipients.
• Clinical Trial Participation: participation in another drug trial within 4 weeks prior to enrollment, or within 5 half-lives of the last investigational drug dose.
• Substance Abuse: history of drug/alcohol abuse or dependency.
• Pregnancy/Lactation: pregnant, breastfeeding, or planning pregnancy during the study.
• Investigator' s Discretion: other conditions that may compromise subject safety or study integrity (e.g., severe lab abnormalities, social factors).