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

Beyond Cardiotoxicity: Characterizing the Short-term Cardiovascular Side Effects of Breast Cancer Endocrine Treatment

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer Females
• Intervention / Treatment: Other: N/A (Usual Care)

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Amy A. Kirkham, PhD; Phone Number: 416-946-4069; Email: amy.kirkham@utoronto.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5S2C9
      • Recruiting
      • University of Toronto
      • Contact: Amy A. Kirkham, PhD; Phone Number: 416-946-4069; Email: amy.kirkham@utoronto.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Breast Cancer Patients Receiving Aromatase Inhibitor; Breast Cancer patients using aromatase inhibitors for 6 months	Other: N/A (Usual Care); BC survivors will be using aromatase inhibitors as prescribed in their usual care treatment.
Matched Non-Cancer Controls; Arm Description: A woman without a history of cancer will be recruited to match each patient with breast cancer on age and BMI (within 3 years and 3 kg/m2, whenever possible)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 months
Carotid Artery Stiffness	Functional assessment of the carotid artery stiffness will be assessed using B-mode ultrasound and artery edge-tracking software	Baseline, 6 months
Carotid Intima Media Thickness	Structural assessment of the carotid artery thickness will be assessed using B-mode ultrasound and artery edge-tracking software	Baseline, 6 months
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%.	Baseline, 6 months
Global Longitudinal Strain	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.	Baseline, 6 months
Left Ventricular Diastolic Function	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).	Baseline, 6 months
Arterial Stiffness	Measured by Pulse Wave Velocity (PWV) of the arm and leg	Baseline, 6 months
Cerebrovascular Response	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).	Baseline, 6 months
Brain Derived Neurotrophic Factor	Brain derived neurotrophic factor will be assessed via fasted venipuncture using in-house assays.	Baseline, 6 months
Lipid profile	HDL, LDL, total Cholesterol, Triglycerides analyzed from blood serum using a clinical assay at a core lab.	Baseline, 6 months
Hemoglobin A1c	Analyzed from blood plasma using a clinical assay at a core lab.	Baseline, 6 months
Insulin resistance	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.	Baseline, 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiorespiratory fitness	Measured as peak volume of oxygen consumption via indirect calorimetry during a cardiopulmonary exercise test on a cycle ergometer.	Baseline, 6 months
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.	Baseline, 6 months
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.	Baseline, 6 months
Heart Rate Variability	Measured as the variability in beat-to-beat heart rate during supine rest.	Baseline, 6 months
avO2 difference	Measured by a non-invasive optical technique used to assess tissue oxygenation and hemodynamics (Near-Infrared Spectroscopy - NIRS) at rest, and during cycling exercise at ventilatory threshold, respiratory compensation point, and peak oxygen uptake.	Baseline, 6 months
Cardiac Output	Measured continuously by a finger cuff (Finger Arterial Pressure - Finapres) at rest, and during cycling exercise at ventilatory threshold, respiratory compensation point, and peak oxygen uptake.	Baseline, 6 months
Stroke Volume	Measured continuously by a finger cuff (Finger Arterial Pressure - Finapres) at rest, and during cycling exercise at ventilatory threshold, respiratory compensation point, and peak oxygen uptake.	Baseline, 6 months
Resting Blood Pressure	Measured as the average of the last 5 of 6 blood pressure measurements taken 60 seconds apart using an automatic blood pressure device.	Baseline, 6 months
Beat-by-beat Blood Pressure	Measured continuously by a finger cuff (Finger Arterial Pressure - Finapres) at rest, and during cycling exercise at ventilatory threshold, respiratory compensation point, and peak oxygen uptake.	Baseline, 6 months
Glucose Levels	Measured during a 10-day period by a Dexcom G7 Continuous Glucose Monitor (CGM)	Baseline, 6 months
Hemoglobin	Analyzed from blood plasma using a clinical assay at a core lab.	6 months
Whole-body fat mass	Measured using a body composition device (BodPod) to estimate whole body fat (in kg and %).	Baseline, 6 months
Whole-body fat-free mass	Measured using a body composition device (BodPod) to estimate whole body fat free mass (in kg and %).	Baseline, 6 months
Waist Circumference	Circumference of the waist measured using an inelastic tape	Baseline, 6 months
Hip Circumference	Circumference of the hip measured using an inelastic tape	Baseline, 6 months
Neck Circumference	Circumference of the neck measured using an inelastic tape	Baseline, 6 months
Body weight	Assessed fasted in lab using a calibrated scale	Baseline, 6 months
Body mass index (BMI)	Calculated from a measurement of height using a stadiometer and body weight (detailed above).	Baseline, 6 months
Dietary intake	Various components of dietary intake including macronutrients and micronutrients will be assessed through 3-day food records over 2 weekdays and 1 weekend collected using ASA-24 online system.	Baseline, 6 months
Diet quality	An overall measure of alignment with Canada's dietary guidelines measured via the Healthy Eating Food Index-2019 calculated from 3-day diet records	Baseline, 6 months
Depression & Anxiety	Measured by the Hospital Anxiety and Depression Scale (HADS); score ranges from 0-21 for each of depression and anxiety with a higher score indicating more severe depression or anxiety	Baseline, 6 months
Autonomic symptoms	Assessed by the COMPASS 31 (Composite Autonomic Symptom Score) questionnaire. This questionnaire provides clinically relevant scores of autonomic symptom severity. Scores range from 0 to 31 with questions in six domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor, with a higher scoring indicating worse autonomic dysfunction.	Baseline, 6 months
Cognitive Function: Verbal Fluency	Assessed using the Controlled Oral Word Association of the Multilingual Aphasia Exam (verbal fluency), with higher number of words produced indicative of better cognitive health.	Baseline, 6 months
Cognitive Function: Verbal Learning & Memory	Assessed the Hopkins Verbal Learning Test (learning, memory) with an immediate recall, delayed recall, and recognition accuracy from a list of 12 words. Higher number of words are indicative of better cognitive health.	Baseline, 6 months
Cognitive Function: Processing Speed	Assessed by the Trail Making Test (attention, speed, executive function). Shorter test time on 2 forms of the test is indicative of better cognitive health.	Baseline, 6 months
Cognitive Impairment (Composite Measure)	Assessed by Global Deficit Score (GDS). GDS is calculated as an average score from 3 tests previously described in outcomes 36, 37, and 38: 1) Hopkins Verbal Learning Test (learning, memory), 2) Trail Making Test (attention, speed, executive function), 3) Controlled Oral Word Association of the Multilingual Aphasia Exam (verbal fluency). Each subtest of the GDS has a complex scoring system, detailed above, with higher values indicating greater cognitive deficits.	Baseline, 6 months
Cancer-specific Quality of life (only assessed in cancer group): General	Assessed using the Functional Assessment of Cancer Therapy - General (FACT-G). This is a patient-reported outcome measurement used to assess health-related quality of life in patients with a history of cancer. The FACT-G is calculated from the sum of four subscales on general health related quality of life with a range of 0-108 points. Higher scores on each scale is indicative of better quality of life.	Baseline, 6 months
Cancer-specific Quality of life (only assessed in cancer group): Endocrine	Assessed using the Functional Assessment of Cancer Therapy - Endocrine (FACT-ES). This is a patient-reported outcome measurement used to assess health-related quality of life in patients with a history of cancer. The FACT-ES is a score of 19 questions with scores ranging from 0-76. Higher scores on each scale is indicative of better quality of life.	Baseline, 6 months
Cancer-specific Quality of life (only assessed in cancer group): Cognitive	Assessed using the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog). This is a patient-reported outcome measurement used to assess health-related quality of life in patients with a history of cancer. The FACT-Cog contains 37 questions with a score of 0 to 132. Higher scores on each scale is indicative of better quality of life.	Baseline, 6 months
Cancer-specific Quality of life (only assessed in cancer group): Fatigue	Assessed using the Functional Assessment of Cancer Therapy - Fatigue (FACT-F). This is a patient-reported outcome measurement used to assess health-related quality of life in patients with a history of cancer. FACT-F is calculated from the sum of 13 questions. Higher scores on each scale is indicative of better quality of life.	Baseline, 6 months
Musculoskeletal health	Assessed using the Musculoskeletal Health Questionnaire (MSK-HQ). The MSK-HQ is a series of 15 questions with a range from 0-56 with higher scores being indicative of poorer MSK health.	Baseline, 6 months
Musculoskeletal pain	Assessed using the Brief Pain Inventory (BPI). The BPI is scored as the average of seven pain-related questions with a range of 0-10 with higher scores representing greater pain.	Baseline, 6 months
Musculoskeletal osteoarthritis risk	Assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index. The WOMAC is a series of 17 questions resulting in a % (0-100) with higher scores indicative of greater osteoarthritis index.	Baseline, 6 months
Musculoskeletal disability	Assessed using the Disabilities of the Arm, Shoulder, and Hand (DASH) Questionnaire. The DASH contains 30 questions with scores of 0 to 100 with higher scores representing higher severity in disability.	Baseline, 6 months
Cardiovascular risk	Assessed using the INTERHEART Risk Score, a validated score for quantifying risk-factor burden without the use of laboratory testing (with higher scores indicating greater risk-factor burden).	Baseline, 6 months
Gender-Related Factors	Assessed by the Stanford Gender-related Variables for Health Research (GVHR) which includes questions related to seven gender-related variables: caregiver strain, work strain, independence, risk-taking, emotional intelligence, social support, and discrimination.	Baseline
Health-related quality of life	Assessed by RAND-36, where an independent score is provided for 8 scales ranging from 0 to 100 and 2 component summary scales ranging from 0-50 with a higher score indicating better quality of life.	Baseline, 6 months
Psychosocial stress	Assessed by the perceived stress scale (PSS-14) where individual scores can range from 0 to 56 with higher scores indicating higher perceived stress	Baseline, 6 months
Sleep quality - subjective	Subjectively assessed by the Pittsburgh Sleep Quality Index (PQSI), which measures components of sleep: sleep duration, disturbance, sleep latency, daytime dysfunction due to sleepiness, sleep efficiency, overall sleep quality, and sleep medication use, with higher scores reflecting poorer sleep quality. From these 7 questions, a global score of 0 to 21 is created with higher values indicative of poorer sleep quality.	Baseline, 6 months
Sleep quantity - device measured	Measured via Garmin smartwatch for the total sleep duration.	Baseline, 6 months
Sleep quality - device measured	Measured via Garmin smartwatch for the total sleep efficiency.	Baseline, 6 months
Moderate-Vigorous Physical Activity	Measured via Garmin smartwatch for time in moderate-vigorous physical activity in total minutes at this intensity.	Baseline, 6 months
Physical activity: step counts	Measured via Garmin smartwatch for daily step counts.	Baseline, 6 months
Sedentary time	Measured via Garmin smartwatch for time spent sitting.	Baseline, 6 months

Collaborators and Investigators

• Sponsor: University of Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR); Princess Margaret Hospital, Canada; Cancer Research Society

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2025
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: December 30, 2024
• First Submitted That Met QC Criteria: January 13, 2025
• First Posted (Actual): January 17, 2025

Study Record Updates

• Last Update Posted (Estimated): October 1, 2025
• Last Update Submitted That Met QC Criteria: September 26, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Obesity; Aromatase Inhibitors; Heart Disease Risk Factors; Breast Cancer Females
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity
• Other Study ID Numbers: REB #46818

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No