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).