Breast cancer trial to investigate how insulin affects treatment response

A new study will investigate whether insulin levels influence how women with breast cancer respond to treatment.

The Trans-EndoNET study will examine the relationship between insulin levels and response to a hormone therapy in women with the most common type of breast cancer.

The study is now open for patients to take part at University Hospital Southampton (UHS). It is being led by Professor Ramsey Cutress at the University of Southampton (UoS) and Dr Simon Lord at the University of Oxford.

Professor Cutress’ research forms part of the perioperative and critical care theme of the NIHR Southampton Biomedical Research Centre.

Understanding insulin’s effect

The most common type of breast cancer is oestrogen receptor-positive, HER2-negative (ER+HER2-). This accounts for the majority of breast cancer diagnoses, particularly among post-menopausal women.

In these tumours, the hormone oestrogen is a key driver of cancer growth. Oestrogen binds to cancer cells and promotes their proliferation.

Aromatase inhibitors help to tackle this by lowering oestrogen levels. They are given as a standard of care treatment for five to 10 years following surgery for early-stage breast cancer. This aims to reduce the risk of recurrence.

Yet growing evidence suggests metabolic factors may influence how well patients respond. Type 2 diabetes and elevated insulin levels have been associated with a higher incidence of breast cancer and deaths due to it.

Laboratory studies have also shown high insulin levels can activate a biological pathway. This pathway drives resistance to hormone treatments. Lowering insulin levels appears to inhibit this pathway and improve treatment response.

It is estimated that around one in three adults over the age of 50 may be affected by insulin resistance or metabolic syndrome. This raises important questions about how metabolic health interacts with cancer treatments.

Dr Simon Lord is Director of Oxford Cancer Trials and an Associate Professor at the University of Oxford. He is also Consultant Medical Oncologist at Oxford University Hospitals NHS Foundation Trust.

“Insulin resistance and metabolic syndrome are increasingly common, particularly in older adults,” he said. “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.”

Part of a larger trial

The Trans-EndoNET study is a sub-study embedded within a larger trial. This is the Phase III EndoNET trial of women with early-stage ER+HER2- breast cancer that have been through the menopause.

EndoNET is investigating the benefits of giving part of the five year course of aromatase inhibitors before surgery. The aim is to shrink the breast cancer, reducing the extent of the surgery needed.

250 people are participating in EndoNET in the UK. Patients joining EndoNET will now have the opportunity to take part in both studies.

Trans-EndoNET will use patient samples collected during the main trial. It will investigate the link between insulin resistance and aromatase inhibitors.

Professor Cutress is Professor of Breast Surgery at UoS. He is also an EndoNET lead investigator.

“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”, he said.

“Integrating this work within the EndoNET trial gives us a unique opportunity to link biological changes in the tumour with real-world treatment outcomes.”

Informing future treatments

Rates of obesity and insulin resistance are rising globally. Breast cancer cases are also expected to increase. It's therefore important to understand what impact this may have on treatment responses.

UHS now joins Torbay Hospital as an open Trans-EndoNET study site. A further 30 hospitals are expected to start recruitment in the coming months.

The results will inform whether lowering insulin levels could improve these patients' outcomes. This could either be achieved through drug treatments or lifestyle changes.

The study is funded by the Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR).

Professor John Simpson is Director of the MRC-NIHR Efficacy and Mechanism Evaluation Programme.

"One of NIHR’s key aims is to fund cutting-edge research which can make a positive difference to people's health and wellbeing," he said.

“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."