ATNEC - Axillary management in T1-3N1M0 breast cancer patients with needle biopsy proven nodal metastases at presentation after neoadjuvant chemotherapy

Background The presence of cancer in the axillary lymph nodes on needle biopsy in patients with early stage breast cancer before neoadjuvant chemotherapy (NACT) has been the determinant of the need for axillary treatment (in the form of axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) after completion of NACT. Treatment in the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, chronic pain, numbness, and other sensory problems. As more effective chemotherapy is now available that results in complete eradication of cancer in the axilla in around 40 to 70% of patients, extensive axillary treatment might no longer be necessary in patients with no residual nodal disease. Aims and objectives To assess whether, omitting further axillary treatment (either ALND or ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy (SNB), is non-inferior to axillary treatment in terms of axillary recurrence free interval (ARFI) and results in reduced risk of lymphoedema at 5 years. Methods Study design: A pragmatic, open, phase 3, randomised, multicentre, trial. Study population: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer SNB and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: Participants randomised to the intervention group will not receive further axillary treatment, whereas those receiving standard care will receive axillary treatment (ALND or ART) as per local guidelines. Follow-up is annually for at least 5 years. Outcomes: The co-primary outcomes are ARFI and patient reported lymphoedema defined as answering 'yes' to the two questions('arm heaviness during the past year' and 'arm swelling now') on the Lymphoedema and Breast Cancer questionnaire at 5 years. Secondary outcomes: arm function assessed by the QuickDASH questionnaire; health related quality of life assessed using the EQ-5D-5L; local recurrence; regional (nodal) recurrence; distant metastasis; invasive disease-free survival; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years and cost-effectiveness. Sample size: 1900 patients would have the ability to demonstrate a 2% non-inferiority margin with a 5% 1-sided significance level and 80% power, allowing for 3% dropouts assuming a 98% 5-year ARFI rate on the control arm. It would also be able to detect at least a 5% difference in lymphoedema rates with 90% power, a 5% 2-sided significance level and allowing for 25% dropout. Timelines for delivery Total project duration is 120 months based on 6 months for set up; 60 months recruitment period (including an 18 months internal pilot phase); and 54 months for follow up, analysis, writing up and dissemination. Anticipated impact and dissemination The UK multidisciplinary guidelines recommend participation in this study. This research offers the potential of reducing unnecessary axillary treatment, its associated side effects and improving patients’ health related quality of life in the future. As the study is evaluating removing axillary treatment, the results will potentially lead to significant cost-savings for the NHS.