Award Title: Randomised controlled trial evaluating effectiveness of neoadjuvant endocrine treatment in post-menopausal women (EndoNET)
Funder: Department of Health and Social Care

Abstract: There are 45,000 people who develop breast cancer each year in the UK, mostly in women after their menopause and mainly of a type known as oestrogen-receptor positive, human epidermal receptor-2 negative. The current standard of care is surgery within a month, followed by radiotherapy where required, and anti-hormone therapy (known as endocrine treatment) for 5-10 years. Most people will not require chemotherapy. Almost one half will however be treated by surgical removal of the breast (mastectomy.) For others, lumpectomy (breast conservation surgery), will ensure that a limited amount of breast tissue is removed at surgery._x000D_
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Endocrine treatment after surgery is very effective in the long-term treatment of breast cancer; it is however currently unknown whether it is also beneficial to start this same endocrine treatment before surgery. This study is to determine whether doing this – known as neo-adjuvant endocrine therapy - will shrink the tumour prior to operating.  This could increase the rates of breast preservation by reducing the number of mastectomies for some women and the extent of surgery for others (removing less tissue leaves less defect). _x000D_
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After mastectomy many patients do not want or are unsuitable for breast reconstruction.  Even if received, this may not always fully compensate for breast removal. Reducing breast surgery and increasing rates of preserving breasts by treatment with neo-adjuvant endocrine therapy is therefore anticipated to improve cosmetic outcomes, leading to better quality of life. _x000D_
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Patients with breast cancer are part of the study leadership team and others have been extensively consulted in the design. They indicated that overall quality of life and preserving the breast were the most important outcomes by which to measure study success. _x000D_
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Patients in this controlled trial are allocated by chance to one of two groups, which determines their treatment.  All patients will start hormone treatment on joining the trial: group 1 will have surgery within 31 days; group 2 will receive surgery after 6 months of neo-adjuvant endocrine therapy.  People in group 2 will be closely monitored with an ultrasound scan at 3 months and 5 months to ensure continued response to this therapy prior to surgery. _x000D_
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The trial aims to recruit 1440 post-menopausal women with oestrogen-receptor positive, human epidermal receptor-2 negative breast cancer, from at least 30 NHS hospitals across the UK. There are no age limits. We will invite participants who have chosen not to have or will not require or benefit from chemotherapy.  These patients will therefore not be using chemotherapy to reduce their tumour size.  However, this study will show if tumour size can be successfully reduced with neo-adjuvant endocrine therapy.  Where the NHS provides tests to analyse tumour cancer gene profiles, these can also help decide if chemotherapy is of benefit, in which case it will be offered. _x000D_
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Patients in both groups will be asked to fill in quality of life questionnaires at intervals during their 15-month participation in the study. We will publish the results in medical journals and present them at international conferences. People taking part will receive the study findings in writing if they wish and via dissemination on the Oxford Surgical Interventional Trials Unit website.

Lay Abstract: HYPOTHESIS: Neoadjuvant endocrine therapy (NET) reduces breast cancer (BrCa) size prior to surgery, reducing surgical burden leading to better health-related quality of life (HRQoL) and higher rates of breast conservation surgery (BCS)._x000D_
RESEARCH QUESTION: In post-menopausal women who will not require chemotherapy for >T1, ER+, HER2- invasive BrCa, does NET improve global HRQoL over 15 months and increase breast BCS rates?_x000D_
BACKGROUND: BCS leads to better HRQoL compared to mastectomy.  Neoadjuvant treatments have potential to down-size BrCa and reduce extent of surgery (reduce excised volume, reduce re-excision rate and convert mastectomy to BCS) reducing surgical burden and improving HRQoL. NICE guidance recommends NET be considered in post-menopausal women “as an option to reduce tumour size if there is no definite indication for chemotherapy”. In these patients approximately 87% of BrCa is ER+, and virtually all will receive endocrine treatment (ET) after surgery to reduce risk of BrCa recurrence. In the majority (>70%) chemotherapy is not required and so is not available as an alternative neoadjuvant option. Although widely used as an emergency measure during the COVID pandemic, NET is infrequently used in normal routine care and practice greatly varies across the NHS and worldwide. Many women could potentially benefit from having ET in the NET setting potentially increasing BCS rates and improving HRQoL. _x000D_
AIMS/OBJECTIVES: The primary aim is to determine whether global HRQoL is better over 15 months and BCS rates are higher in women who receive NET followed by surgery and adjuvant ET compared to surgery followed by adjuvant ET. Secondary outcomes include HRQoL related to body image and surgery (Breast Q, Hopwood Body Image Scale) and surgical outcomes (excision volumes following BCS, re-excision and repeat surgery rates)._x000D_
METHODS: A prospective, phase III, multicentre randomised controlled trial (RCT). We will recruit 1440 post-menopausal women with ER+, HER- invasive BrCa who are unlikely to require chemotherapy. They will be randomised 1:1 to undergo 6 (+/- 1) months of NET followed by surgery and adjuvant ET versus surgery within 31 days followed by adjuvant ET. Both arms receive the same treatments (surgery, ET, and radiotherapy where indicated), but the sequencing of surgery will differ with both arms starting ET at randomisation with 6 months of the course of ET delivered prior to surgery in the NET arm. The co-primary outcome measures are global HRQoL over 15 months measured by FACT-B and the BCS rate. _x000D_
TIMELINES FOR DELIVERY: The study duration is 69 months including 6 months set-up, 42 months recruitment, 15 months follow-up and 6 months data analysis and final reporting of results. Formal stop/go review will be at month 18 (after 12 months recruitment) to ensure 10 sites have opened and 150 patients are randomised. If met, the trial will recruit for a further 30 months. Data from the internal pilot will be included in the final analysis. Full-scale recruitment has not been factored into the trial until month 27 to allow staggered opening of centres._x000D_
ANTICIPATED IMPACT AND DISSEMINATION: Results will be disseminated at national and international conferences and to patients via the CTU and charities. Demonstration that a NET strategy is effective is likely to be incorporated into national and international guidelines enabling uptake across large numbers of patients reducing breast surgical burden and improving HR

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS