Neoadjuvant Toripalimab and Radiotherapy Treatment in N+ HR+ Breast Cancer

Neoadjuvant Toripalimab and Radiotherapy Treatment in Lymph Nodes Positive HR Positve Breast Cancer（NEOTRIO-HR）

The goal of this clinical trial is to compare the efficacy and safety in patients with lymph node-positive HR+/HER2- breast cancer. The main questions it aims to answer are:

• Can the incorporation of intensified radiation to the tumor (tumor boost) enhance the pCR rate on the basis of neoadjuvant immuno-chemotherapy？
• Can it improve the level of residual cancer burden (RCB) and change the tumor immune microenvironment? and How safe will be the combined therapy?

Participants will be randomly assigned to one of three treatment regimens:

1. Preoperative toripalimab combined with SBRT targeting both the primary tumor and axillary lymph nodes, followed by chemotherapy;
2. Preoperative toripalimab combined with SBRT focused solely on the primary tumor, followed by chemotherapy;
3. Preoperative toripalimab combined with chemotherapy alone.

Following the completion of their respective treatment regimens, participants will proceed to undergo surgery. The effectiveness of the treatments will be assessed through pathological evaluations, as well as by measuring levels of residual cancer burden (RCB) and examining changes in the tumor immune microenvironment.

The study aims to evaluate the safety of these combined treatment approaches and to determine if they offer superior efficacy compared to outcomes reported in previous studies.

Breast cancer is a leading malignancy among women globally, with early diagnosis and treatment being crucial for better outcomes. Over 90% of breast cancer patients are diagnosed at an early stage, and approximately two-thirds have the hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) subtype. Despite this, these patients often exhibit resistance to neoadjuvant chemotherapy, with a pathologic complete response (pCR) rate of only 5-15%, which is significantly lower compared to other subtypes and is associated with poor prognosis. This indicates the necessity for optimizing current treatment strategies.

In recent years, significant advancements have been made in the application of immunotherapy for breast cancer. The studies demonstrated that the addition of immune checkpoint inhibitors to neoadjuvant chemotherapy for patients with high-risk early-stage HR+/HER2- breast cancer significantly improved pCR rates.

Building on these findings, this study proposes a novel strategy of dose-intensified radiation to the tumor (tumor boost) during the neoadjuvant immuno-chemotherapy phase. The advantage of this approach is that it can activate the immune system while the tumor tissue is still intact, providing a rich source of tumor antigens, which aids in enhancing the immune system's recognition and destruction of cancer cells.

Toripalimab is an optimal immunotherapy agent to study, as this agent has recently been approved by the FDA for use in multiple tumor types. It is therefore ready to be tested for efficacy in other disease sites and in combination with other treatments. This study will provide valuable insights into the potential of immunotherapy in combination with radiotherapy to improve outcomes for patients with lymph nodes-positive, high-risk HR+/HER2- breast cancer.

Inclusion Criteria:

• High-risk HR+/HER2-negative breast cancer is defined as ER≥1%, HER2-negative (<2+ Her2 IHC or <2.2 HER2/CEP17 ratio by FISH) and either histologic grade II-III or a high-risk genomic assay score (Oncotype RS>25, high risk Mammaprint, PAM-50, EndoPredict or ProSigna score). primary tumor size ≥1.0 cm in maximum diameter and axillary node-positive breast cancer;
• Stage T1-4N+M0 (i.e., Stage II, III), with confirmed N+ by biopsy, and no signs of distant metastasis;
• The initial PD-L1 expression level conducted on the tumor tissue sample with Combined Positive Score (CPS) or Tumor Proportion Score (TPS)< 10%;
• ECOG score of 0-1;
• Screening laboratory values must meet the following criteria: i. White blood cells (WBCs) ≥ 2000/μL ii. Absolute neutrophil count (ANC) ≥ 1500/μL iii. Platelets ≥ 100 x 103/μL iv. Hemoglobin ≥ 11.0 g/dL v. Serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 40 ml/min) vi. AST ≤ 2.5 x upper limit of normal (ULN) vii. ALT ≤ 2.5 x ULN viii. Total bilirubin within normal limits (except subjects with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL) ix. INR ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulant(s) x. Negative HIV screening test xi. Negative screening tests for Hepatitis B and Hepatitis C. Patients with positive results that do not indicate true active or chronic infection may enroll after discussion and consensus agreement by the treating physician and principal investigator.

Exclusion Criteria:

• Inflammatory breast cancer
• Life-threatening organ dysfunction or complications, active infectious diseases, active hepatitis B, hepatitis C virus infection, autoimmune diseases within two years, undergoing immunosuppressive drug treatment or chronic systemic corticosteroid therapy (dose exceeding 10mg per day of prednisone or equivalent);
• Clinically symptomatic heart disease;
• Previous systemic treatment or radiotherapy for breast cancer;
• Patients with cosmetic breast implants, i.e., having implants under the skin at the time of diagnosis;
• Radiotherapy contraindications: history of radiotherapy;
• Women shall not be breastfeeding.