Short-term Impacts of Endocrine Therapy on Cardiovascular and Brain Health Outcomes in Breast Cancer

Not yet recruiting

• Conditions: Breast Cancer Females

• Registration Number: NCT06781762
• Lead Sponsor: University of Toronto

Brief Summary

Aromatase inhibitors are the most used endocrine therapy for hormone-positive breast cancer. While there is a clear linear relationship between the duration of aromatase inhibitor use and the cumulative incidence of cardiovascular events and mortality, the underlying mechanisms contributing to this risk remain unknown. This study will characterize the short-term effects of aromatase inhibitor therapy on established and novel health indices for cardiovascular diseases in breast cancer patients.

Using a longitudinal case-control design this study will assess the effects of short-term (first 6 months) aromatase inhibitor use in breast cancer patients compared to age- and BMI-matched controls, aiming to determine the cardiovascular, metabolic, and behavioural health impacts of endocrine treatment during this early period. Specifically, our objectives are as follows:

1. To examine the effects of aromatase inhibitor therapy on early risk indicators for cardiovascular disease in the peripheral vasculature and heart, including blood biomarkers (lipids), blood pressure, aortic and peripheral stiffness, carotid artery stiffness and intima media thickness, endothelial function, and left ventricular ejection fraction, longitudinal strain, volumes, and mass, including the responsiveness of the cardiovascular system to an oral glucose tolerance test, in breast cancer survivors compared to controls.

2. To examine the effects of aromatase inhibitor therapy on factors related to cerebrovascular health, autonomic regulation, and cognitive function, including BDNF, heart rate variability, cerebrovascular function in response to a supine-sit-stand maneuver and squatting challenge, and a core battery of cognitive function tests, in breast cancer survivors compared to controls.

3. To examine the effects of aromatase inhibitor therapy on body composition and bone mineral density, along with assessments of glycemic regulation in response to an oral glucose tolerance test and in 24h periods of free-living (continuous glucose monitoring), in breast cancer survivors compared to controls.

4. To examine the effects of aromatase inhibitor therapy on lifestyle factors (behavioural), including diet, physical activity (including cardiorespiratory fitness), sleep, stress, and quality of life, in breast cancer survivors compared to controls.

The investigators hypothesize that cardiovascular and metabolic health outcomes will be similar between breast cancer survivors and controls at baseline but will deteriorate relative to controls within the first 6 months of aromatase inhibitor therapy.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-12-30
• Status Verified: 2025-01
• Study First Submitted QC: 2025-01-13
• Last Update Submitted: 2025-01-13
• Study First Posted: 2025-01-17
• Last Update Posted: 2025-01-17
• Study Start: 2025-03-01
• Primary Completion: 2026-09-30
• Study Completion: 2026-09-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 40

Inclusion Criteria

Case group:

• Biologically female
• Post-menopausal with natural (no bilateral oophorectomy) amenorrhea for at least 1 year
• If using hormone replacement therapy, limit of a maximum of 3 years of treatment but not within the last 6 months.
• Diagnosis of stage I, II, or III breast cancer
• Hormone receptor positive breast cancer
• HER negative (ER+/PR+/HER-) breast cancer
• Confirmed to start aromatase inhibitor therapy for the first time in next 2-3 months
• Received surgery/radiation therapies

Control group:

• Biologically female
• Post-menopausal with natural (no bilateral oophorectomy) amenorrhea for at least 1 year
• If using hormone replacement therapy, limit of a maximum of 3 years of treatment but not within the last 6 months.

Exclusion Criteria

• Previous treatment using tamoxifen endocrine therapy in a pre-or peri-menopausal setting
• Major signs or symptoms of cardiovascular diseases, diabetes, or renal disease (taken from the American College of Sports Medicine's Guidelines for Exercise Testing and Prescription 11th edition Table 2.1: pain or discomfort in the chest, neck, jaw, arms with rest or exercise, shortness of breath at rest or with mild exertion, dizziness or syncope, loss of balance or passing out, ankle edema, palpitations or tachycardia, intermittent claudication, known heart murmur, unusual fatigue with usual activities.)
• American Heart Association's absolute or relative contraindications for symptom-limited maximal exercise testing (myocardial infarction, aortic or coronary artery stenosis, heart failure, pulmonary embolism or deep vein thrombosis, inflammation of the heart (myocarditis, pericarditis, and/or endocarditis), uncontrolled cardiac arrythmia, advanced or complete electrical heart block, stroke or transient ischemia attack, blood pressure >200mmHg/100mmHg, a cancer diagnosis other than skin cancer)
• Unable to provide informed consent or communicate in English
• Mobility limitations to exercise testing (i.e., wheelchair, walker use, limp impeding walking)
• Extreme claustrophobia

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Aortic Stiffness	Baseline, 6 months	Aortic stiffness, measured non-invasively by pulse wave velocity, will be assessed using applanation tonometry. Measurements will be taken at rest and every 30min during a 2h oral glucose tolerance test.

Secondary Outcome Measures

Name	Time	Method
Hemoglobin A1c	Baseline, 6 months	Analyzed from blood plasma using a clinical assay at a core lab.
Brachial Artery Endothelial Function	Baseline, 6 months	Endothelial function will be assessed using the gold standard method of flow mediated dilation (FMD) using non-invasive duplex ultrasound (GE Vivid IQ) and edge-tracking software. Measurements will be taken at rest and every 30min during a 2h oral glucose tolerance test.
Carotid Artery Stiffness	Baseline, 6 months	Functional assessment of the carotid artery stiffness will be assessed using B-mode ultrasound and artery edge-tracking software
Carotid Intima Media Thickness	Baseline, 6 months	Structural assessment of the carotid artery thickness will be assessed using B-mode ultrasound and artery edge-tracking software
Left Ventricular Ejection Fraction (LVEF)	Baseline, 6 months	Cardiac outcomes will be assessed via echocardiography (GE Vivid IQ) and analyzed using Echopac software, represented as a % using the following formula: stroke volume/end diastolic volume x 100%.
Global Longitudinal Strain	Baseline, 6 months	Cardiac outcomes will be assessed via echocardiography (GE Vivid IQ) and analyzed using Echopac software, expressed as a percentage of the relative change in length of the left ventricle through a cardiac cycle.
Left Ventricular Diastolic Function	Baseline, 6 months	Cardiac outcomes will be assessed via echocardiography (GE Vivid IQ) and analyzed using Echopac software, assessed by the ratio of peak early diastolic velocity to peak mitral valve velocity (E/A ratio).
Arterial Stiffness	Baseline, 6 months	Measured by Pulse Wave Velocity (PWV) of the arm and leg
Cerebrovascular Response	Baseline, 6 months	Cerebral blood flow velocity response (delta change compared to rest) of the middle cerebral artery will be assessed using transcranial Doppler ultrasound (Neurovision Transcranial Doppler System Model 500M) in accordance with recent guidelines, in response to postural changes (sit-to-stand) and exercise (squatting).
Brain Derived Neurotrophic Factor	Baseline, 6 months	Brain derived neurotrophic factor will be assessed via fasted venipuncture using in-house assays.
Lipid profile	Baseline, 6 months	HDL, LDL, total Cholesterol, Triglycerides analyzed from blood serum using a clinical assay at a core lab.
Insulin resistance	Baseline, 6 months	Calculated as Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) from fasting blood measures of glucose and insulin, analyzed using a clinical assay at a core lab. Matsuda Index will also be calculated using a standard equation requiring fasting insulin and glucose and area under the curve of the post-ingestion of 75g of glucose insulin and glucose concentrations measured at 30, 60, 90 and 120 minutes.

Trial Locations

Locations (1)

University of Toronto; 🇨🇦 Toronto, Ontario, Canada