Does the timing and order of breast surgery and hormone treatment affect the quality of life and the amount of surgery required in post-menopausal women with breast cancer? The EndoNET study
| ISRCTN | ISRCTN11896599 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11896599 |
| EudraCT/CTIS number | 2022-000582-40 |
| IRAS number | 1005155 |
| Secondary identifying numbers | PID15899, IRAS 1005155, CPMS 52372 |
- Submission date
- 02/04/2022
- Registration date
- 04/05/2022
- Last edited
- 12/05/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English Summary
Background and study aims
50,000 women develop breast cancer each year in the United Kingdom, mostly women after menopause and of a type known as oestrogen-receptor positive (ER+), HER-2 (human epidermal receptor-2) negative. The current usual standard treatment is surgery within a month of diagnosis, followed by radiotherapy for some where required, and anti-hormone therapy (known as endocrine therapy; ET) for 5-10 years. Most post-menopausal women with early breast cancer will not require chemotherapy. Almost one half will be treated by surgical removal of the breast (mastectomy). For others, lumpectomy (breast conservation surgery), enables a more limited amount of breast tissue to be removed and breast preservation. ET 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 ET before surgery, known as neoadjuvant endocrine therapy (NET). This study is to determine whether giving some of the ET before surgery will shrink the tumour before 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). After mastectomy, many women do not want or are unsuitable for breast reconstruction. Even if received, this may not always fully compensate for breast removal. If it is shown that NET reduces the amount of breast tissue that has to be removed and increases the rates of breast preservation, this would be anticipated to improve cosmetic outcomes, leading to a better quality of life. This study therefore compares the traditional order of surgery within a month, to a period of pre-surgical ET followed by surgery.
Who can participate?
Post-menopausal women with breast cancer who do not require chemotherapy
What does the study involve?
Participants start their endocrine treatment on trial entry. Surgery is required in both arms of the trial, but it is the timing that differs. The surgery will be within the standard NHS treatment target of 2-4 weeks in the comparator arm (standard of care; up to 8 weeks permitted for trial purposes), or at 6 +/- 1 months in the NET arm. The surgical operation performed will be decided by the patient and treating clinical team in the usual way. Patients in both arms will complete quality-of-life questionnaires at intervals during their 15-month participation and rates of lumpectomy (breast conservation surgery) will be documented.
What are the possible benefits and risks of participating?
This treatment is normally given and its risks and side effects are well documented and should be no different for participants taking these treatments within the trial compared to those outside of the trial. Both arms of the trial therefore constitute treatment strategies consistent with current NICE guidance. The risks relating to the surgery itself will be discussed with the participant in detail as part of the standard, routine consent for an operation. The researchers do not think that being part of this study will change any of the risks of the operation but this is one of the things they will be studying. The trial endpoints include measures to determine if the intervention approach (NET) reduces the burden of surgery and so improves quality of life. Patients in the NET group will be monitored closely with an early clinic visit at 6 weeks, and then further clinical reviews with ultrasound monitoring at 3 and 5 months. In the unlikely event that the clinical team feel the tumour is not responding to the NET as anticipated, this will enable cross-over to early surgery with minimal delay.
Where is the study run from?
University of Oxford (UK)
When is the study starting and how long is it expected to run for?
June 2021 to February 2027
Who is funding the study?
NIHR Health Technology Assessment Programme (UK)
Who is the main contact?
Prof. Michael Douek
michael.douek@nds.ox.ac.uk
Contact information
Scientific
Faculty of Medicine
University of Southampton
Southampton General Hospital
Tremona Rd
Southampton
SO16 6YD
United Kingdom
 ORCID ID |
0000-0002-1719-7255 |
|---|---|
| Phone | +44 (0)23 8120 6676 |
| R.I.Cutress@soton.ac.uk |
Public
Botnar Research Centre
Nuffield Orthopaedic Centre
Old Road
Headington
Oxford
OX3 7LD
United Kingdom
| Phone | +44 (0)1865 223464 |
|---|---|
| endonet@nds.ox.ac.uk |
Principal Investigator
Surgical Intervention Trials Unit
Nuffield Department of Surgical Sciences
Botnar Research Centre
Old Road
Headington
Oxford
OX3 7LD
United Kingdom
| ORCID ID |
0000-0003-2872-8514 |
|---|---|
| Phone | +44 (0)1865 223492 |
| michael.douek@nds.ox.ac.uk |
Study information
| Study design | Randomized controlled open parallel-group trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN11896599_PIS_V5.0_21Aug2024.pdf |
| Scientific title | Randomised controlled trial evaluating effectiveness of neoadjuvant endocrine treatment in post-menopausal women |
| Study acronym | EndoNET |
| Study hypothesis | Current study hypothesis as of 04/10/2024: Neoadjuvant endocrine therapy (NET) reduces breast cancer size prior to surgery, reducing surgical burden, and resulting in a higher proportion of breast conservation surgery (BCS). Current study hypothesis as of 12/10/2022 to 04/10/2024: Neoadjuvant endocrine therapy (NET) reduces breast cancer size prior to surgery, reducing surgical burden leading to better HRQoL and higher rates of breast conservation surgery (BCS). Previous study hypothesis: The overall aim is to evaluate whether 6 (+/-1) months of neoadjuvant endocrine therapy (NET) reduces surgical burden resulting in better health-related quality of life (HRQoL) over 15 months and higher rates of breast conservation surgery (BCS) for post-menopausal women with >T1, strongly ER+, HER2- invasive breast cancer who do not require chemotherapy. 1. Evaluate tumour response rates following NET 2. Compare invasive tumour size, histological grade and lymph node status (including the number of involved nodes) 3. Compare the HRQoL related to body image and surgery (FACT-B with ES and +4, Breast Q, EQ-5D-5L, Hopwood Body Image Scale) 4. Provide an estimate of the risk of relapse and measure of endocrine sensitivity in NET arm 5. Compare post-surgical complications and AI side effects 6. Assess treatment compliance (MARS-5) 7. Evaluate the prognostic significance of Ki67 8. Assess surgical management of the breast 9. Assess surgical management of the axilla 10. Compare rates of local and distant recurrence 11. Compare breast cancer specific survival and overall survival 12. Assess the cost-effectiveness of implementing NET followed by surgery and adjuvant ET compared with current practice of surgery followed by adjuvant ET for a reduction in mastectomy 13. Compare the accuracy of USS and MRI 14. Compare requirements for adjuvant chemotherapy |
| Ethics approval(s) | Approved 03/05/2022, East Midlands - Nottingham 2 Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, UK; +44 (0)207 104 8169; nottingham2.rec@hra.nhs.uk), ref: 22/EM/0086 |
| Condition | Newly diagnosed strongly ER-positive negative breast cancer |
| Intervention | Patients will be randomised 1:1 upon joining the trial through an online platform to either the comparator arm or the intervention arm. The intervention in this trial is endocrine treatment tablets of a type known as aromatase inhibitors (AIs). All participants will start their endocrine treatment tablets for oral use: letrozole (2.5 mg/day), anastrozole (1 mg/day) or exemestane (25 mg/day) at randomisation. The endocrine treatment offered in both arms of the trial is the same but the timing of the surgery differs: 1. Comparator arm – surgery after 2-4 weeks of endocrine treatment; up to 8 weeks permitted for trial purposes 2. Intervention arm – surgery after 6 +/- 1 months of endocrine treatment Participants will complete quality-of-life questionnaires periodically during their 15-month participation and rates of breast conservation surgery (lumpectomy) will be recorded. Participants will continue their adjuvant treatment including their endocrine treatment for 5-10 years as per their usual standard treatment. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Letrozole, anastrozole, exemestane |
| Primary outcome measure | Current primary outcome measure as of 04/10/2024: Rates of breast conservation surgery measured using surgical burden data stored in patient records at 6 months (+/- 1 month) of NET Previous primary outcome measure: The EndoNET Trial has co-primary outcome measures: 1. Global HRQoL is measured by FACT-B at baseline, 6 weeks or post-operative, 5, 7, 12, and 15 months 2. Rates of breast conservation surgery measured using surgical data stored in patient records at 15 months |
| Secondary outcome measures | 1. Tumour response rates are measured by the RECIST scale (CR, PR, PD or SD) at 2-4 weeks, 3 and 5 months (intervention arm) 2. Tumour size, histological grade and lymph node status according to histology reports pre- and post-surgery 3. Health-related QoL is measured by FACT-B +4/ES, Breast-Q, EQ-5D-5L and Hopwood Body Image Scale at baseline, 6 weeks or post-operative, 5, 7, 12 and 15 months 4. Risk of relapse and ability to measure endocrine sensitivity according to PEPI score at baseline, 2-4 weeks and post-operative sample (intervention arm) 5. Post-surgical complications and endocrine treatment side effects reported at 2-4 weeks, 6 weeks (intervention arm), surgery, post-operative, 3, 5, 6, 12 and 15 months 6. Participant compliance to ET/NET is measured by the MARS-5 questionnaire at 2-4 weeks, 5 months and 15 months 7. Significance of Ki67 in the prognosis of breast cancer measured using Ki67 score in tumour sample(s) at baseline, after 2-4 weeks of endocrine treatment and at surgery (in comparator arm) 8. Surgical management of the breast using rates of re-excision and further surgery after lumpectomy, requirement for advanced lumpectomy and rates of reconstruction post-mastectomy, and radiotherapy post-operative and at 15 months 9. Surgical management of the axilla using rates of sentinel node biopsy, axillary clearance and radiotherapy post-operative and at 15 months 10. Rates of local and distance recurrence measured using data stored in patient records post-surgery, at 15 months and periodically for long-term follow up 11. Breast cancer specific and overall survival measured using data stored in patient records post-surgery, at 15 months and periodically for long-term follow up 12. Resource use, cost and cost-effectiveness of implementing intervention compared with current practice measured by the Health Care Use questionnaire at baseline, 7, 12 and 15 months 13. Accuracy of ultrasound (and MRI if available) for assessing initial disease extent and detection of tumour response at 2-4 weeks, 3 and 5 months 14. Requirement of adjuvant chemotherapy measured using chemotherapy data stored in patient records by 15 months Added 12/10/2022: *subject to additional funding and/or resource |
| Overall study start date | 01/06/2021 |
| Overall study end date | 28/02/2027 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Adult |
| Sex | Female |
| Target number of participants | 1060 |
| Participant inclusion criteria | Current participant inclusion criteria as of 04/10/2024: Main study: 1. Female 2. Clinically post-menopausal, according to established local criteria, and suitable for an aromatase inhibitor 3. Strongly ER+; defined as Allred scores of 7 or 8 or equivalent* 4. Tumour size ≥15mm 5. Suitable for surgery and radiotherapy 6. Unifocal, newly diagnosed breast cancer visible on USS Note: Satellite lesions ≤5 mm and ≤10 mm in distance from the edge of the primary lesion are permitted as long as they can be removed en bloc; 7. Participant is able and willing to give informed consent for participation in the trial 8. In the Investigator's opinion, is able to comply with all trial requirements * or equivalent may include a histochemical score (H-score) ≥ 200. QRI (information study) Patients: 1. Patients approached for participation in the EndoNET study 2. Patient inclusions are the same as for the EndoNET study Healthcare professionals (HCPs) and research personnel (RPs): 1. HCPs or RPs involved in management, operation or recruitment for the EndoNET study 2. Trial management group (TMG) members with a role in planning/coordinating recruitment Current inclusion criteria as of 02/06/2023 to 04/10/2024: Main study: 1. Female 2. Clinically post-menopausal; including one of: 2.1. Amenorrhoea >12 months and an intact uterus 2.2. Bilateral oophorectomy 2.3. For those with a history of hysterectomy, or hormone replacement therapy (HRT) within 12 months, venous FSH levels classified as post-menopausal by the testing laboratory if any doubt 3. Unifocal, newly diagnosed breast cancer visible on USS 4. Strongly ER+; defined as Allred scores of 7 or 8 or equivalent* 5. HER2- by immunohistochemistry, or 2+ and not amplified by in situ hybridisation 6. T-stage 1, 2 or 3 (≥15 mm) 7. Axillary N0-1 on diagnostic USS +/- negative fine-needle aspiration (FNA) or core biopsy 8. Suitable for surgery and radiotherapy 9. Chemotherapy unlikely to be indicated 10. Participant is able and willing to give informed consent for participation in the trial 11. In the Investigator's opinion, is able to comply with all trial requirements * or equivalent may include a histochemical score (H-score) ≥ 200. QRI (information study) Patients: 1. Patients approached for participation in the EndoNET study 2. Patient inclusions are the same as for the EndoNET study Healthcare professionals (HCPs) and research personnel (RPs): 1. HCPs or RPs involved in management, operation or recruitment for the EndoNET study 2. Trial management group (TMG) members with a role in planning/coordinating recruitment Previous inclusion criteria: Main study: 1. Female 2. Clinically post-menopausal; including one of: 2.1. Amenorrhoea >12 months and an intact uterus 2.2. Bilateral oophorectomy 2.3. For those with a history of hysterectomy, or hormone replacement therapy (HRT) within 12 months, venous FSH levels classified as post-menopausal by the testing laboratory if any doubt 3. Unifocal, newly diagnosed breast cancer visible on USS 4. Strongly ER+; defined as Allred scores of 7 or 8 or equivalent 5. HER2- by immunohistochemistry, or 2+ and not amplified by in situ hybridisation 6. T-stage 2 or 3 (>2 cm) 7. Axillary N0-1 on diagnostic USS +/- negative fine-needle aspiration (FNA) or core biopsy 8. Suitable for surgery and radiotherapy 9. Chemotherapy unlikely to be indicated 10. Participant is able and willing to give informed consent for participation in the trial 11. In the Investigator's opinion, is able to comply with all trial requirements QRI (information study) Patients: 1. Patients approached for participation in the EndoNET study 2. Patient inclusions are the same as for the EndoNET study Healthcare professionals (HCPs) and research personnel (RPs): 1. HCPs or RPs involved in management, operation or recruitment for the EndoNET study 2. Trial management group (TMG) members with a role in planning/coordinating recruitment |
| Participant exclusion criteria | Current participant exclusion criteria as of 04/10/2024: Main study: The participant may not enter the trial if ANY of the following apply: 1. Bilateral breast cancer 2. cN3 disease 3. cT4 disease Note: T4 is defined as (i) chest wall (rib/intercostal) involvement (adherence/invasion to pectoralis is NOT an extension to the chest wall and is not defined as T4 here) or (ii) skin ulceration, skin nodules or oedema such as in inflammatory breast cancer. Dimpling of the skin, nipple retraction or other skin other changes without ulceration, nodules or oedema, do not make a tumour T4; 4. Metastatic breast cancer (Stage IV disease) 5. Chemotherapy or anti-HER-2 therapy for current breast cancer started or planned at the time of randomisation 6. Previous invasive malignancy within 5 years which is likely to affect the safety or efficacy assessment or compliance with the protocol or interpretation of results 7. Concurrent use (at the time of randomisation) of HRT or any other oestrogen-containing medication (including vaginal oestrogens) Note: Presence of Mirena coil at the time of randomisation is not an exclusion; 8. If clinically pre-menopausal, ovarian suppression/ablation for the purposes of trial entry is not permitted 9. Aromatase inhibitor endocrine treatment following current breast cancer diagnosis taken for longer than 14 days at time of randomization. QRI (information study): Patients: 1. Patient exclusions are the same as for the EndoNET study 2. Patient does not wish to have consultations recorded and/or participate in interview HCPs and RPs: 1. HCPs or RPs who do not wish to have consultations recorded and/or participate in interview Previous participant exclusion criteria: Main study: The participant may not enter the trial if ANY of the following apply: 1. Bilateral breast cancer 2. ER- or HER2+ 3. Stage IV disease (distant metastasis) 4. Previous neoadjuvant treatment for breast cancer 5. Previous invasive malignancy within 5 years other than basal cell carcinoma 6. Concurrent use (at the time of randomisation) of HRT or any other oestrogen-containing medication (including vaginal oestrogens) 7. Ovarian suppression/ablation for the purposes of trial entry not permitted QRI (information study): Patients: 1. Patient exclusions are the same as for the EndoNET study 2. Patient does not wish to have consultations recorded and/or participate in interview HCPs and RPs: 1. HCPs or RPs who do not wish to have consultations recorded and/or participate in interview |
| Recruitment start date | 23/08/2022 |
| Recruitment end date | 31/01/2026 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Aberdeen
AB25 2ZN
United Kingdom
Exeter
EX2 5DW
United Kingdom
Belfast
BT9 7AB
United Kingdom
Southampton
SO16 6YD
United Kingdom
Llandough
Penarth
CF64 2XX
United Kingdom
Headington
Oxford
OX3 7LE
United Kingdom
Wigan
WN1 2NN
United Kingdom
Basildon
SS16 5NL
United Kingdom
Westcliff-on-Sea
SS0 0RY
United Kingdom
Bristol
BS10 5NB
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Winchester
SO22 5DG
United Kingdom
Rainhill
Prescot
L35 5DR
United Kingdom
East Kilbride
Glasgow
G75 8RG
United Kingdom
St Albans
AL3 5PN
United Kingdom
Cottingham
HU16 5JQ
United Kingdom
Leicester
LE3 9QP
United Kingdom
Macclesfield
SK10 3BL
United Kingdom
Steeton
Keighley
BD20 6TD
United Kingdom
Gillingham
ME7 5NY
United Kingdom
Carlisle
CA2 7HY
United Kingdom
Basingstoke
RG24 9NA
United Kingdom
London
NW3 2QG
United Kingdom
Barnsley
S75 2PS
United Kingdom
London Road
Reading
RG1 5AN
United Kingdom
Rotherham
S60 2UD
United Kingdom
Wythenshawe
Manchester
M23 9LT
United Kingdom
Dundee
DD1 9SY
United Kingdom
Crumpsall
Manchester
M8 5RB
United Kingdom
Newton Road
Torquay
TQ2 7AA
United Kingdom
Birmingham
B15 2GW
United Kingdom
Londonderry
BT47 6SB
United Kingdom
Broomfield
Chelmsford
CM1 7ET
United Kingdom
Higher Kingston
Yeovil
BA21 4AT
United Kingdom
Luton
LU4 0DZ
United Kingdom
Swansea
SA2 8QA
United Kingdom
The Bays
South Wharf Road
London
W2 1BL
United Kingdom
Greetwell Road
Lincoln
LN2 5QY
United Kingdom
Sponsor information
University/education
Research Governance, Ethics and Assurance
University of Oxford
Boundary Brook House
Churchill Drive
Headington
Oxford
OX3 7GB
England
United Kingdom
| Phone | +44 (0) 1865 289884 |
|---|---|
| ctrg@admin.ox.ac.uk | |
| Website | http://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 28/02/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website 5. Submission to regulatory authorities 6. Other |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date. Upon completion of the trial, fully de-identified research data may be shared with other organisations subject to review and approval of a suitable application. Patients will be informed about this possibility within the patient information the reasons why this is important for future research and that this will be done anonymously. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Participant information sheet | version 5.0 | 21/08/2024 | 04/10/2024 | No | Yes |
| Participant information sheet | version 3.0 | 21/08/2024 | 04/10/2024 | No | Yes |
| Protocol file | version 4.0 | 21/08/2024 | 04/10/2024 | No | No |
Additional files
Editorial Notes
12/05/2025: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/05/2025 to 31/01/2026.
2. The study participating centres St Mary’s Hospital, Lincoln Hospitals NHS Trust were added.
04/10/2024: The following changes were made:
1. A protocol (not peer-reviewed), PIS and ICF were uploaded.
2. Study website link was updated.
3. The primary outcome measure was updated.
4. Condition was changed from "Newly diagnosed strongly ER-positive HER-2 negative breast cancer".
5. The inclusion and exclusion criteria were changed.
6. The target number of participants was changed from 1440 to 1060.
7. The following study participating centres were added: Barnsley Hospital, Royal Berkshire Hospital, Rotherham General Hospital, Wythenshawe Hospital, Ninewells Hospital, North Manchester General Hospital, Torbay Hospital, Queen Elizabeth Hospital, Altnagelvin Area Hospital, Broomfield Hospital, Yeovil District Hospital, Luton and Dunstable Hospital, and Singleton Hospital.
02/06/2023: The inclusion criteria were updated. Aberdeen Royal Infirmary, Royal Devon & Exeter Hospital, Belfast City Hospital, Southampton General Hospital, University Hospital Llandough, Churchill Hospital, Royal Albert Edward Infirmary, Basildon University Hospital, Southend University Hospital, Southmead Hospital, Nottingham City Hospital, Royal Hampshire County Hospital, Whiston Hospital, University Hospital Hairmyres, St Albans City Hospital, Castle Hill Hospital, Glenfield Hospital, Macclesfield District General Hospital, Airedale General Hospital, Medway Maritime Hospital, Cumberland Infirmary, Basingstoke and North Hampshire Hospital and Royal Free Hospital were added to the study participating centres.
12/10/2022: The following changes were made to the trial record:
1. The public title was changed from 'Randomised trial looking at the effectiveness of hormone therapy (neoadjuvant endocrine treatment) in post-menopausal women with early breast cancer' to 'Does the timing and order of breast surgery and hormone treatment affect the quality of life and the amount of surgery required in post-menopausal women with breast cancer? The EndoNET study'.
2. The study hypothesis, ethics approval, secondary outcome measures, trial website and contact details were updated.
3. The overall trial start date was changed from 31/03/2022 to 01/06/2021.
4. The recruitment start date was changed from 31/05/2022 to 23/08/2022.
07/06/2022: Internal review.
04/05/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 04/05/2022.
04/04/2022: Trial's existence confirmed by the HRA.
