Response-Adapted Omission of Nodal Boost In N3 Breast Cancer After Neoadjuvant Systemic Therapy

Background Clinical N3 (cN3) breast cancer represents a high-risk subgroup of locally advanced disease. After neoadjuvant systemic therapy (NST), patients who achieve a clinical complete response (cCR) in initially involved but undissected nodal stations currently receive a boost to these regions as part of standard postoperative radiotherapy. However, whether this boost is necessary in this setting remains unknown, and prospective evidence on the safety of boost omission is lacking.

Objective The REACT-N3 trial aims to evaluate whether omitting the boost to undissected nodal stations that achieve cCR after NST is non-inferior to standard boost in terms of 3-year invasive breast cancer recurrence-free interval (IBCRFI), while reducing toxicity to adjacent organs.

Methods This is an open-label, multicenter, randomized phase 3 trial. Eligible patients are women with cN3 breast cancer who have completed NST, undergone breast/axillary surgery with the internal mammary, supraclavicular, and infraclavicular nodes left undissected, and have no macroscopic residual disease in these stations on post-NST \[¹⁸F\]FDG PET-CT or other imaging. Participants will be randomized 1:1 to receive either a standard boost (10 Gy in 5 fractions) or no boost to the initially involved but cCR-converted undissected nodal stations. Randomization is stratified by postoperative axillary nodal status (ypN- vs. ypN+), location of the involved nodal station (SCV vs. non-SCV), and molecular subtype (TNBC vs. non-TNBC). The primary endpoint is 3-year IBCRFI. Secondary endpoints include locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival, overall survival, toxicity, and patient-reported outcomes. With a non-inferiority margin of 8%, a one-sided α of 0.05, 80% power, and 10% drop-out rate, a total of 534 patients will be enrolled.

Discussion The REACT-N3 trial will provide high-level evidence on the safety of boost omission in cN3 breast cancer patients with cCR after NST. If non-inferiority is confirmed, this strategy could establish a new, toxicity-sparing standard for regional nodal irradiation in this high-risk population.