The Trans-EndoNET study will examine the relationship between insulin levels and response to aromatise inhibitors in women with oestrogen receptor-positive, HER2-negative (ER+HER2-) breast cancer. Torbay Hospital and Southampton General Hospital have now opened the study, with a further 30 hospitals, including Oxford University Hospitals NHS Foundation Trust, expected to begin recruiting patients in the coming months. The study has been funded by a partnership between the UKRI Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR).
ER+HER2- breast cancer accounts for the majority of breast cancer diagnoses, particularly among post-menopausal women. In these tumours, oestrogen is a key driver of cancer growth, binding to cancer cells and promoting their proliferation. Aromatase inhibitors, such as letrozole, tackle this by lowering oestrogen levels and are given as a standard of care treatment for 5-10 years following surgery for early-stage breast cancer to reduce the risk of recurrence.
However, growing evidence suggests that metabolic factors, including insulin levels, may influence how well patients respond to hormone therapies such as aromatase inhibitors. Type 2 diabetes and elevated insulin levels have been associated with a higher incidence of breast cancer and increased breast cancer-related mortality. Laboratory studies have also shown that high insulin levels can activate a key biological pathway known to drive resistance to hormone treatments, while lowering insulin levels appears to inhibit this pathway and improve treatment response.
'Insulin resistance and metabolic syndrome are increasingly common, particularly in older adults,' said Dr Simon Lord, Director of Oxford Cancer Trials within the Department of Oncology, and Consultant Medical Oncologist at Oxford University Hospitals NHS Foundation Trust. 'The Trans-EndoNET study will help us understand whether insulin levels play a role in determining how well patients respond to aromatase inhibitors, which are among the most widely used treatments in breast cancer.'
It is estimated that around one in three adults over the age of 50 may be affected by insulin resistance or metabolic syndrome, raising important questions about how metabolic health interacts with cancer treatments.
Trans-EndoNET is a sub-study embedded within the Phase III EndoNET trial of women with early-stage ER+HER2- breast cancer that have been through the menopause. The EndoNET trial, conduced by the Surgical Intervention Trials Unit (SITU) at the Nuffield Department of Surgical Sciences, is investigating the clinical benefit of giving part of the five-year course of aromatase inhibitors prior to surgery, with a view to shrink the breast cancer, to see if this will reduce the extent of surgery then needed. 250 people are participating in EndoNET in the UK and patients joining EndoNET will now have the opportunity to participate in both studies.
Led by Associate Professor Simon Lord and Professor Ramsey Cutress, Professor of Breast Surgery at the University of Southampton and an EndoNET lead investigator, Trans-EndoNET will use patient samples collected during the main trial to investigate the link between insulin resistance and aromatase inhibitors.
'By analysing tumour samples taken before and after aromatase inhibitor treatment, alongside blood samples measuring insulin levels, this study allows us to directly explore whether insulin resistance could serve as an important clinical marker of resistance to aromatase inhibitors”, said Professor Ramsey Cutress. “Integrating this work within the EndoNET trial gives us a unique opportunity to link biological changes in the tumour with real-world treatment outcomes.'
This study will provide the evidence needed to inform whether future clinical trials exploring dietary or drug-based interventions to lower insulin levels could be used alongside aromatase inhibitors to improve outcomes for people with breast cancer.
Patricia Fairbrother, EndoNET PPI member and trustee of Independent Cancer Patients' Voice (ICPV), said: 'Trans-ENDONET is an important study, it’s important to patients and a research priority for post-menopausal women with early breast cancer. Throughout the study, patient representatives will be acting on behalf of participants, advising on patient facing documents, giving the research more impact, making it more meaningful, and ensuring that along with the trial team, participant’s needs are met.'
Torbay Hospital was the first site to open recruitment for the study, marking an important milestone in its delivery. Louise Merker, Consultant Oncoplastic and Reconstructive Surgeon and Local PI for EndoNET and TransEndoNET at Torbay Hospital, said: 'We are excited to be able to offer our patients the opportunity to take part in this unique and meaningful research. Aromatase inhibitors are the mainstay medication for reducing recurrence risk in ER-positive breast cancer. If insulin resistance reduces their efficacy this is an important clinical question to answer to help reduce breast cancer recurrence rates and improve disease free survival.'
With rates of obesity and insulin resistance rising globally, and breast cancer cases also projected to increase, it is important to understand what impact this may have on response to widely used cancer treatments. It is hoped that the findings from the Trans-EndoNET study will shed light on the value of healthy lifestyle habits for patients, as well as informing the development of future clinical trials testing interventions that reduce insulin levels to improve hormone therapy response.
Professor John Simpson, Director of the MRC-NIHR Efficacy and Mechanism Evaluation (EME) Programme, said: 'One of NIHR’s key aims is to fund cutting-edge research which can make a positive difference to people's health and wellbeing. The TransEndoNET study has the potential to add significantly to our understanding of how breast cancer behaves, and to suggest better future treatments, which in turn could make a real difference to people’s lives.'