Exploring the Impact of Initiating Endocrine Therapy on Metabolic Health in Early Breast Cancer: Protocol for the Prospective Follow-Up EMETA-Study.

Background: Adjuvant endocrine therapy is a cornerstone in managing estrogen receptor-positive early breast cancer but may adversely affect metabolic health, including weight gain, insulin resistance, and dyslipidemia. These changes increase the risk of cardiovascular disease and may influence breast cancer outcomes. However, the timing and magnitude of early metabolic changes following endocrine therapy initiation remain poorly characterized. Conventional definitions such as metabolic syndrome rely on dichotomous thresholds and may lack sensitivity to detect early treatment-related metabolic changes, highlighting the need for refined assessment approaches. Objective: This prospective follow-up study aims to investigate early metabolic effects of initiating adjuvant endocrine therapy in women with estrogen receptor-positive early breast cancer and to compare conventional and expanded approaches to metabolic health classification. Methods: This single-center, prospective observational study was conducted at Aarhus University Hospital, Denmark. Women aged≥18 years with early-stage estrogen receptor-positive breast cancer initiating adjuvant endocrine therapy and without pre-existing diabetes were eligible. Metabolic health was assessed at baseline and after 3 months using biometric measurements (weight, waist and hip circumference, waist-to-hip ratio, and blood pressure) and non-fasting blood samples (plasma glucose; hemoglobin A1c, (HbA1c); lipid profile; and estradiol). The 3-month follow-up was selected to capture early metabolic changes while aligning with routine clinical care to minimize additional visits and reduce selection bias. Metabolic health will be evaluated using two conventional measures and two extended, exploratory measures. Conventional measures are metabolic syndrome (MetS), defined as meeting ≥3 of 5 established criteria (blood pressure ≥130/85 mmHg, triglycerides >2 mmol/l, high-density lipoprotein cholesterol <1.295 mmol/l, waist circumference >88 cm, and plasma glucose >7.8 mmol/l), and the Metabolic Syndrome z score (MetS-Z), a continuous standardized composite of the MetS components. Additional extended measures are exploratory: the extended MetS, which expands the standard MetS definition by incorporating low-density lipoprotein cholesterol (>3 mmol/l), body mass index (≥30 kg/m²), waist-to-hip ratio (>0.85), and HbA1c (≥42 mmol/mol), and the EMETA score, a standardized composite of the extended MetS components calculated using the same approach as the MetS-z score. Results: The study was funded in July 2024. Recruitment occurred between November 2024 and April 2025, and follow-up was completed in September 2025. Statistical analyses are planned for February 2026, with results expected to be published in summer 2026. Conclusions: This study is expected to provide insights into early metabolic changes following initiation of adjuvant endocrine therapy and evaluate different approaches to classifying metabolic health. The aim to inform future research by helping to identify patients at increased risk of cardiometabolic complications and adverse breast cancer outcomes, warranting confirmation and validation of expanded metabolic measures in longer-term, larger cohorts.