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Patients in this arm will not receive axillary treatment (axillary lymph node dissection or axillary radiotherapy). Supraclavicular fossa radiotherapy is not allowed when randomised to this arm.

Patients in this arm will receive axillary treatment. Axillary treatment can be axillary lymph node dissection or axillary radiotherapy.

Participants will undergo removal of at least level I and II axillary lymph nodes.

Axillary lymph node dissection

Axillary radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.

Axillary radiotherapy

Breast or chest wall radiotherapy will be delivered as per the Radiotherapy Trials Quality Assurance (RTTQA) guidelines.

Breast or chest wall radiotherapy

Amit Goyal, MS, MD, FRCS

Claire Murphy

Ludger Barthelmes

Kaiyumars Contractor

Hisham Osman

Eileen Anderson

Sue Down

Brendan Smith

Jalal Kokan

Laura Pettit

Beatrix Elsberger

Anneliese Lawn

Pardeep Arora

Graeme Lumsden

Gareth Irwin

Daniel Henderson

Fiona Hoar

Ricardo Pardo-Garcia

Richard Linforth

Rathinasabapathy Rathinaezhil

Sasirekha Govindarajulu

Inder Kumar

John Benson

Anita Hargreaves

Susan Hignett

Sanjana Masinghe

Emanuele Garreffa

Lynda Wyld

Velin Voynov

Aisling Hennessy

Marjory Maclennan

Tareq Abdullah

Carolyn Bedi

Douglas Ferguson

Sunil Amonkar

Biswajit Ray

Kaustuv Das

Nicholas Holford

Werbena Hamilton-Burke

Kartikae Grover

Hussein Tuffaha

Musa Barkeji

Rishi Parmeshwar

Subodh Seth

Emma MacInnes

Monika Kaushik

Saira Khawaja

Lai Cheng Yew

Debashis Ghosh

Neeraj Garg

Katherine Krupa

Daniel Leff

Ruth James

Anjana Satpathy

Brinda Sethugavalar

Amanda Taylor

Henry Cain

Pankaj Roy

Abdulla Alhasso

Saed Ramzi

Tamara Kiernan

Tahir Masudi

Lee Min Lai

Muhammed Baki

Matei Dordea

Sekhar Marla

Zoe Goldthorpe

Lubna Noor

Duncan Wheatley

Daniel Glassman

Abdul Syed

Konstantinos Zacharioudakis

Shaveta Mehta

Raman Vinayagam

Raghavan Vidya

Caroline Osborne

Bhavani Rengabashyam

The aim of this study is to assess whether, omitting further axillary treatment (ALND and 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, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years.

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 to the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, 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 evidence of residual nodal disease.

Aim: To assess whether, omitting further axillary treatment (ALND and 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, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years.

Methods:

Study design: A pragmatic, phase 3, open, randomised, multicentre trial and embedded economic evaluation in which participants will be randomised in a 1:1 ratio.

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 sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node).

Intervention: All participants will receive human epidermal growth factor receptor 2 (HER2)-targeted treatment, endocrine therapy and radiotherapy to breast or chest wall, if indicated according to local guidelines. Patients in the intervention group will not receive further axillary treatment (ALND or ART), 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 disease free survival(DFS) and self-reported lymphoedema defined as 'yes' to the two questions participants will be asked - 'arm heaviness during the past year' and 'arm swelling now' from the Lymphoedema and Breast Cancer Questionnaire at 5 years.

Secondary outcomes: arm function assessed by the QuickDASH (disabilities of the arm, shoulder and hand) questionnaire; health related quality of life assessed using euroqol EQ-5D-5L; axillary recurrence free interval (ARFI); local recurrence; regional (nodal) recurrence; distant metastasis; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years (QALYs) and cost-effectiveness.

Sample size: A sample size of 1900 patients would have the ability to demonstrate a 3.5% non-inferiority margin with a 5% 1-sided significance level and 85% power, allowing for 7% non-collection of primary outcome data assuming a 90% 5-year disease free survival rate in the control arm. It would also be able to detect at least a 5% difference in proportion of patients with lymphoedema with 90% power, a 5% 2-sided significance level and allowing for 25% non-collection of primary outcome data over 5 years.

Analysis plan: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Time to event outcomes, including disease free survival and axillary recurrence free interval, will be assessed using Kaplan-Meier curves and compared using Cox proportional hazards models. The proportion of patients experiencing lymphoedema at 5 years will be compared across trial arms using a chi-squared test and a logistic regression model used to adjust for stratification variables. Arm morbidity and health related quality of life will be scored using the appropriate manuals and assessed using a longitudinal mixed model regression analysis if model assumptions valid or a standardised area-under-the-curve analysis. For economic evaluation, incremental cost per QALY gained at 5 years will be estimated.

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.

Axillary Management in Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases After Neoadjuvant Chemotherapy

ATNEC - Axillary Management in T1-3N1M0 Breast Cancer Patients With Needle Biopsy Proven Nodal Metastases at Presentation After Neoadjuvant Chemotherapy

DFS calculated as the time from randomisation until the date of first event of either a loco-regional invasive breast cancer relapse, distant relapse, ipsilateral or contralateral new invasive primary breast cancer or death by any cause or the censor date.

Lymphoedema is self-reported based on two items from the validated Lymphoedema and Breast Cancer Questionnaire (arm "swelling now" and arm "heaviness in the past year"). Lymphoedema is defined as 'yes' to both questions.

Arm function will be assessed using shortened version of the Disability of the Arm, Shoulder and Hand (DASH), the 11-item QuickDASH questionnaire. Physical disability is defined as a change from baseline in the QuickDASH score of at least 14 points.

Health related quality of life will be assessed with EQ-5D-5L

Axillary recurrence free interval, calculated from the date of randomisation to the date of axillary recurrence or the censor date.

Overall survival calculated as the time from randomisation until the date of death by any cause or the censor date.

Number of participants with local (breast or chest wall) recurrence

Number of participants with regional (nodal) recurrence

Number of participants with distant metastasis.

Number of participants with contralateral breast cancer.

Number of participants with non-breast cancer

University Hospitals of Derby and Burton NHS Foundation Trust

Consultant Oncoplastic Breast Surgeon & Associate Professor

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