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.
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;
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;
Parallel
SBRT
RadiationTarget the primary tumor region with a single dose of 8Gy, or deliver a dose of 3Gy to the axillary lymph nodes, administered once a day for three consecutive days.
Immuno-chemotherapy
DrugStandard new adjuvant treatment with toripalimab combined with chemotherapy, that is in the first phase consisting of paclitaxel and toripalimab for four cycles, followed by epirubicin, cyclophosphamide, and toripalimab for another four cycles.
pCR rate
Pathological Complete Response (pCR) is characterized by the absence of any invasive residual primary tumor in both the breast and lymph nodes. The primary objective of this study is to compare the pCR rates between two treatment approaches: neoadjuvant toripalimab combined with SBRT followed by immuno-chemotherapy, and neoadjuvant toripalimab combined with chemotherapy.
RCB level
Residual Cancer Burden (RCB) level is a classification system used to assess the amount of cancer remaining in the breast tissue and lymph nodes after neoadjuvant chemotherapy. It is determined by evaluating several factors including the primary tumor area, the percentage of the tumor area that is invasive cancer, and the extent of lymph node involvement. The RCB index categorizes patients into four groups from group 0 to III indicating none to extensive residual cancer burden.
TILs
Changes in the tumor-infiltrating lymphocyte score (TILs), as determined by the Salgado criteria, indicate an engagement of the immune system in cancer, with scores ranging from 0 to 100%. A higher score in TILs correlates with improved patient outcomes. The planned collection of biopsy samples at three critical points-before treatment, after the initial dose of Toripalimab with or without radiation therapy, and at the time of surgical resection-will enable a comprehensive serial evaluation of TILs. This approach will help to quantify the impact of radiation therapy on the immune response induced by Toripalimab.
SBRT-related Adverse Events
Treatment toxicities. radiation-related AEs, especially Acute Radiation Dermatitis.
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