Title: ATNEC - Axillary management in T1-3N1M0 breast cancer patients with needle biopsy proven nodal metastases at presentation after neoadjuvant chemotherapy
Funder: Department of Health and Social Care

Abstract: Patients with early stage breast cancer and abnormal looking lymph gland in the armpit (axilla) on an ultrasound scan will have a sample (needle biopsy) of this lymph gland taken to see whether cancer cells are present. If the sample shows cancer cells are present, patients are often given chemotherapy prior to surgery (called neoadjuvant chemotherapy) to shrink these cancer cells before their operation. Currently after chemotherapy, all patients undergo breast surgery (lumpectomy to remove the lump or mastectomy to remove the breast) and treatment to their armpit (either removal of all lymph glands in the armpit, axillary lymph node dissection or radiotherapy to the armpit). _x000D_ _x000D_ Research already carried out shows that cancer cells in the lymph glands after chemotherapy can be found by removing three lymph glands from the armpit (including the lymph gland proven to have cancer on needle biopsy before the chemotherapy was given), using a procedure called sentinel node biopsy. These lymph glands can be found by injecting blue dye and weak radioactive liquid into the dark area that surrounds the nipple on the breast. The substances drain into the lead armpit lymph glands and surgeon can identify them by the blue colour and by using a handheld scanner to pick up the radioactivity in these lymph glands. The lymph gland shown to have cancer cells when the sample from the needle biopsy is taken can be marked by placing a clip or seed in the lymph gland or by tattooing it with black dye prior to starting chemotherapy to help the surgeon identify and remove that at the time of surgery. _x000D_ _x000D_ Neoadjuvant chemotherapy results in complete disappearance of cancer in the lymph glands in around 40 to 70 out of 100 patients treated in this way. For these patients there may be no extra benefit from more treatment to their armpit apart from the usual sentinel node biopsy. Any extra treatment to their armpit may damage lymphatic drainage from the arm, and patients could then develop arm swelling (lymphoedema), restricted shoulder movement, pain, numbness and other sensory problems. These side effects of treatment make some daily activities difficult for patients, they are distressing and affect quality of life for the patient. They are costly to the NHS in terms of treatments such as physiotherapy and attendance at lymphoedema clinics. _x000D_ _x000D_ The aim of our study is to find out whether stopping further armpit treatment for patients with no remaining cancer in the lymph glands after chemotherapy is safe, in terms of risk of cancer coming back in the armpit and results in less lymphoedema cases at 5 years. After neoadjuvant chemotherapy and at the time of breast surgery, patients will undergo removal of at least 3 lymph glands from the armpit. If there is no residual cancer in the removed lymph glands, patients will be randomly allocated to receive standard armpit treatment (armpit surgery or radiotherapy as per local standard of care) or no further treatment to the armpit._x000D_ _x000D_ Results of this study could benefit patients by avoiding unnecessary further treatment to the armpit and thus reducing future problems with the arm and shoulder, and possibly improved quality of life and reduced healthcare costs._x000D_ _x000D_ As part of this study, patients will be asked to donate tissue samples left over after routine tests for future research. Patients taking part in this study will be able to choose whether they want to do this or not.

Lay abstract: Background_x000D_ 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._x000D_ _x000D_ Aims and objectives_x000D_ 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._x000D_ _x000D_ Methods_x000D_ Study design: A pragmatic, open, phase 3, randomised, multicentre, trial._x000D_ _x000D_ 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)._x000D_ _x000D_ 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. _x000D_ _x000D_ 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. _x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ Timelines for delivery_x000D_ 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._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ 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.

Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS