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.
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
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
Case participants will be recruited from Princess Margaret Cancer Centre in Toronto. Control participants will be local participants in the greater Toronto area, recruited through posters, newsletters, social media advertisements, and word of mouth.
Case-control
Prospective
N/A (Usual Care)
Other interventionBC survivors will be using aromatase inhibitors as prescribed in their usual care treatment.
Aortic Stiffness
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.
Brachial Artery Endothelial Function
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
Functional assessment of the carotid artery stiffness will be assessed using B-mode ultrasound and artery edge-tracking software
Carotid Intima Media Thickness
Structural assessment of the carotid artery thickness will be assessed using B-mode ultrasound and artery edge-tracking software
Left Ventricular Ejection Fraction (LVEF)
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%.
Cardiorespiratory fitness
Measured as peak volume of oxygen consumption via indirect calorimetry during a cardiopulmonary exercise test on a cycle ergometer.
Framingham 10-year cardiovascular risk (%)
Calculated using the standardized scoring system where sex-specific points are assigned to age, systolic blood pressure (dependent on treatment status), HDL, total cholesterol, smoking and diabetes status. The range for females is 0-30% where a higher score indicates a greater risk of cardiovascular disease in the next 10 years.
Heart Rate Recovery
Measured as the difference between peak heart rate during the cardiorespiratory fitness test and heart rate 2-minutes into active recovery after stopping the exercise test.
Heart Rate Variability
Measured as the variability in beat-to-beat heart rate during supine rest.
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University of Toronto
Lead sponsor
Cancer Research Society
Collaborator
Canadian Institutes of Health Research (CIHR)
Collaborator
Princess Margaret Hospital, Canada
Collaborator
