Associate Professor Simon Lord, Director of the Early Phase Clinical Trials Unit within the Department of Oncology and Consultant Medical Oncologist at Oxford University Hospitals NHS Foundation Trust, has been awarded funding from the NIHR to launch a clinical study investigating the impact of insulin resistance on response to endocrine therapy in patients with oestrogen receptor (ER)-positive breast cancer.
The project, Trans-EndoNET, aims to determine whether insulin resistance could serve as an important clinical marker of resistance to aromatase inhibitors– a standard of care treatment for ER-positive breast cancer used widely across the NHS. The study is being funded through the NIHR Efficacy and Mechanism Evaluation (EME) programme, which supports research designed to give new insights into the mechanisms of action of health interventions.
Aromatase inhibition in breast cancer
Oestrogen plays an important role in the development and progression of breast cancer, acting as fuel for cancer cell growth. One of the key distinctions between different types of breast cancer lies in the expression of hormone receptors on tumour cells. The most common type is oestrogen receptor-positive, HER2-negative (ER+HER2-) breast cancer. In these tumours, oestrogen acts as a major driver of cancer growth by binding to its receptor and promoting cell proliferation.
To tackle this, aromatise inhibitors have become a cornerstone of treatment for post-menopausal women with ER+HER2- breast cancer. Aromatase inhibitors are a type of endocrine therapy that work by lowering oestrogen levels. This treatment is typically given for 5-10 years following surgery for early-stage breast cancer in order to prevent recurrence.
Insulin Resistance and Treatment Response
The Trans-EndoNET study is a translational substudy of the Phase III EndoNET trial which is sponsored by the Nuffield Department of Surgical Sciences at the University of Oxford. The main EndoNET trial is investigating the clinical benefit of using aromatase inhibitors prior to surgery in post-menopausal women with early-stage ER+HER2- breast cancer. Specifically, it aims to determine whether administering aromatase inhibitors for 6 months prior to surgery can reduce mastectomy rates by shrinking tumours enough to allow breast-conserving surgery.
Led by Dr Simon Lord and Professor Ramsey Cutress, Professor of Breast Surgery at the University of Southampton and an EndoNET lead investigator, the Trans-EndoNET substudy will make use of patient samples collected as part of the main trial to explore an additional question: is there a link between insulin resistance and response to aromatase inhibitors?
This research builds on growing evidence that insulin metabolism may influence how patients respond to endocrine therapy. Increased insulin levels are associated with higher incidence of breast cancer, as well as greater rates of breast-cancer related mortality. At the molecular level, the PI3K-AKT-mTOR signalling pathway has been identified as a major driver of hormonal therapy resistance. Importantly, this pathway lies downstream of the insulin receptor, suggesting that elevated insulin levels could drive activation of PI3K-AKT-mTOR signalling and potentially undermine the effectiveness of aromatase inhibitors.
Laboratory studies have shown that lowering insulin levels through fasting results in inhibition of AKT-mTOR signalling and notably, improved response to endocrine therapy.
It is known that the degree of reduction in cancer cell growth (or proliferation) after a short course of treatment with an aromatase inhibitor is an excellent guide as to long term outcome for patients. To explore this relationship with insulin levels in the Trans-EndoNET study, the research team will compare the change in tumour proliferation with the patient’s insulin levels. To do this, the researchers will use Ki67: a proliferation marker that can be measured by staining tumour samples. The team will also collect fasted blood samples to measure glucose and insulin, from which insulin resistance will be calculated, using a measure called HOMA-IR.
"This study will provide evidence to help inform whether future clinical trials looking into dietary or drug interventions targeted towards lowering insulin levels might be used in conjunction with aromatase inhibitors to improve outcomes for breast cancer patients." - Simon Lord, Trans-EndoNET study lead
Exploratory analyses will also examine whether genetic alterations in the PI3K-AKT-mTOR pathway are associated with insulin resistance and if this pathway is activated in the context of high insulin levels.
With rates of obesity and insulin resistance rising globally, and breast cancer cases also projected to increase, it is important to understand how metabolic health impacts 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 inform the development of future clinical trials testing interventions that reduce insulin levels to improve endocrine therapy response.