Omission of axillary lymph node dissection in ultrasound-detectable axillary metastases in primary breast cancer treated by upfront surgery: prospective randomized SENOMAC-ULTRA non-inferiority trial

BACKGROUND: Axillary lymph node dissection (ALND) in breast cancer causes substantial arm morbidity and long-term functional impairment. Less extensive axillary surgery, such as targeted axillary dissection (TAD), significantly reduces this risk. Although omission of ALND is standard in clinically node-negative disease with limited sentinel node involvement, this is not the case for patients with clinically node-positive disease undergoing upfront surgery. The aim of the SENOMAC-ULTRA trial is to evaluate whether TAD can safely replace ALND in patients with clinically node-positive breast cancer receiving upfront surgery. METHODS: SENOMAC-ULTRA is a prospective, international, multicentre, randomized non-inferiority trial. Adults with stage II-III invasive breast cancer and axillary metastases detectable by ultrasound and confirmed by fine needle aspiration or core biopsy are eligible for inclusion. Participants are randomized 1 : 1 to TAD (removal of marked metastatic nodes plus sentinel lymph node biopsy) or standard ALND. The primary endpoint is recurrence-free survival, assessed for non-inferiority using a Cox proportional hazards model. Secondary endpoints include overall survival, locoregional recurrence, regional nodal recurrence, distant relapse-free survival, invasive breast cancer-free survival, patient-reported arm morbidity, and health-related quality of life, as well as performance measures of axillary ultrasound and marking techniques. A sample size of 1380 patients has been calculated to provide 81% power to exclude a hazard ratio > 1.47 for recurrence-free survival at 5 years, adopting a non-inferiority margin of 4.5%. Follow-up is planned for 10 years. The trial protocol has been approved by the Swedish Ethical Review Authority (Dnr 2025-07730-01); each participating country will obtain local ethics approval. CONCLUSION: It is anticipated that the SENOMAC-ULTRA trial will fill an important knowledge gap guiding the surgical management of patients with clinically node-negative breast cancer. Registration number: NCT06869629 (https://clinicaltrials.gov).