Background: Neoadjuvant chemotherapy (NACT) results in eradication of cancer in the axillary nodes in 40-70% of patients. This raises questions about the benefit of further axillary treatment in patients with no evidence of residual nodal disease (ypN0) post NACT. Methods: Design: ATNEC is a phase 3, randomized (1:1), multi-center UK trial, with embedded economic evaluation. Patients with proven axillary node metastases on needle biopsy receive NACT followed by sentinel node biopsy (SNB). If the sentinel nodes have converted to benign (ypN0), ATNEC randomly assigns patients to axillary treatment (nodal radiotherapy [ART] or axillary nodal clearance [ALND]) vs no further axillary treatment. Stratification: Institution, type of surgery (breast conserving surgery vs mastectomy), receptor status (triple negative vs HER2 positive vs ER positive and/or PR positive and HER2 negative).Inclusion criteria: Age ≥ 18; Male or female; T1-3N1M0 breast cancer at diagnosis (pre-NACT); FNA or core biopsy confirmed axillary nodal metastases at presentation; ER and HER2 status evaluated on primary tumor; Received standard NACT as per local guidelines; Imaging of the axilla to assess response to NACT;Dual tracer SNB post-NACT and at least 3 nodes removed (sentinel nodes and marked node): If a single tracer is used, the patient is eligible if the involved node is marked pre-NACT and at least 3 nodes removed (including the marked node), If axillary node sampling is performed following failed localization of sentinel nodes, patient is eligible if at least 3 nodes removed (including the marked node), If node is not marked, or marked node is not removed, patient is eligible if the histology report shows evidence of down-staging with complete pathological response in at least one node and at least 3 nodes removed; No evidence of nodal metastases post NACT (ypN0). Exclusion criteria: Bilateral invasive breast cancer; SNB prior to NACT; Previous ipsilateral axillary nodal surgery; Previous cancer within last 5 years or concomitant malignancy. Aims: To assess whether omitting further axillary treatment (ALND & ART) for patients with early-stage breast cancer and axillary nodal metastases on needle biopsy - who after NACT have no residual nodal disease on SNB (ypN0) - is non-inferior to axillary treatment in terms of disease-free survival, and reduces lymphoedema at 5 years. Statistical methods: All analyses will be carried out on an intention-to-treat basis to preserve randomization, avoid bias from exclusions and preserve statistical power. Radiotherapy Quality Assurance: Study has in-built radiotherapy QA program that will be coordinated by National Radiotherapy Trials QA (RTTQA) group. Target accrual: 1,900 Status: Recruiting. As of 11-Feb-2022, 39 sites open, 87 patients enrolled, 31 randomized. Clinical trial information: NCT04109079.