Trans-EndoNET: The influence of patient metabolism on the response to neoadjuvant endocrine therapy in post-menopausal women with oestrogen receptor positive breast cancer

Research question and background: The study aim is to characterise the relationship between patient insulin metabolism and tumour response to endocrine therapy (ET) in early breast cancer. In the UK breast cancer is the most common cancer in females and most cases are oestrogen receptor positive, HER2 negative (ER+HER2-). The majority arise in post-menopausal women and aromatase inhibitors are the principal systemic standard of care treatment in this group. PI3K-AKT-mTOR signalling is a key resistance mechanism to ET in breast cancer and lies downstream of the insulin receptor. Increased insulin levels are associated with higher breast cancer incidence and mortality and preclinical study in mouse xenograft ER+ HER2- breast cancer models show that a periodic fasting diet lowers circulating insulin levels, inhibits AKT–mTOR signalling and enhances the effect of ET. Objectives and methods: The primary objective of this study is to determine whether there is an association between insulin resistance and antiproliferative response to aromatase inhibitors in early breast cancer. The T-EndoNET study is an integrated translational substudy to the NIHR HTA funded EndoNET trial that is designed to investigate the clinical benefit of neoadjuvant aromatase inhibitor treatment for ER+HER2- breast cancer and will recruit 1440 post-menopausal women. As part of the EndoNET trial all patients will have tumour Ki67 measured at baseline and after 2 weeks of ET, and so this data will be available. Ki67 is a well validated immunohistochemical marker of proliferation and early change in Ki67 in response to ET has been shown to be predictive of long-term outcome. The T-EndoNET study will correlate Ki67 response to the measure of insulin resistance, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), in order to determine whether insulin resistance is a marker of ET resistance in ER+HER- breast cancer. Hence, serum fasting insulin and glucose will be collected from all patients consenting to T-EndoNET. Genetic alterations in the PI3K-AKT-mTOR signalling cascade are common in breast cancer and can lead to hyperactivation of this pathway which may mask any effect from upstream insulin signalling. We shall carry out tumour genomic sequencing to allow for a secondary analysis for tumours lacking AKT1, PIK3CA mutations and PTEN loss. Further work will evaluate whether abundance of PI3K-AKT-mTOR pathway genetic alterations links to degree of insulin resistance. We shall also assess the relationship between insulin resistance and transcriptomic and immunohistochemical markers of PI3K-AKT-mTOR pathway activation, and response to ET on imaging. Timelines: T-EndoNET recruitment would commence from January 2023 (shortly after EndoNET opens). After completion of recruitment (expected May 2026) the RNASeq and immunohistochemistry analysis of the T-EndoNET samples will be completed by end of December 2026. Bioinformatic analysis of the data will take a further 12 months, up until end of December 2027. Impact: Rates of obesity, insulin resistance and breast cancer are rising and this study has the potential to show the most compelling evidence of a link between insulin metabolism and response to ET in a patient population. This would catalyse the development of clinical trials that investigate interventions to reduce insulin levels and consequently improve response to neoadjuvant ET.