Randomised controlled trial evaluating effectiveness of neoadjuvant endocrine treatment in post-menopausal women (EndoNET)

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).

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?

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.

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).

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.

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.

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