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

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

Aromatase inhibitors are the most used endocrine therapy for hormone-positive breast cancer. Despite the evidence that aromatase inhibitor therapy is associated with increased risk of cardiovascular events, potentially related to the duration of use, no studies have been conducted to characterize the long-term effects of aromatase inhibitor therapy on the heart or vessel structure and function as underlying determinants of cardiovascular mortality. This study will characterize the long-term effects of aromatase inhibitor therapy on established and novel health indices for CVD in breast cancer patients, by examining cross-sectionally compare health indices 1-, 5- and 10-years post-diagnosis in breast cancer survivors to controls. 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 aortic stiffness (primary outcome) and secondary outcomes of peripheral and carotid artery stiffness, blood biomarkers (lipids), blood pressure, carotid intima media thickness, endothelial function, and left ventricular ejection fraction, global longitudinal strain, and left ventricular diastolic function, 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, bone mineral density, and protein metabolism, 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 biologic and behavioural cardiovascular health indices will be deteriorated relative to controls as early as 1 year post-diagnosis and that prolonged use will further accelerate aging-related impairments.

Study Overview

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

• Study Type: Observational
• Enrollment (Estimated): 112

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
      • Contact: Amy A. Kirkham, PhD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Participants will be recruited from the community in the Greater Toronto Area via 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
• Breast cancer patients ~1 post-diagnosis who have received aromatase inhibitor therapy
• Breast cancer patients ~5 and ~10 years post-diagnosis who have received aromatase inhibitor therapy for at least 2 years
• 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

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Aromatase Inhibitors (1 year); Breast cancer patients at 1-year post-diagnosis, who were treated with aromatase inhibitors	Other: N/A - Usual Care; Breast cancer survivors will have received usual care aromatase inhibitors for up to 10 years post-diagnosis.
Aromatase Inhibitors (5 year); Breast cancer patients at 5-year post-diagnosis, who were treated with aromatase inhibitors	Other: N/A - Usual Care; Breast cancer survivors will have received usual care aromatase inhibitors for up to 10 years post-diagnosis.
Aromatase Inhibitors (10 years); Breast cancer patients at 10-years post-diagnosis, who were treated with aromatase inhibitors	Other: N/A - Usual Care; Breast cancer survivors will have received usual care aromatase inhibitors for up to 10 years post-diagnosis.
Matched Controls (1 year); A woman without a history of cancer will be recruited to match each breast cancer patient will be matched on age and BMI (within 3 years and 3 kg/m2, whenever possible)
Matched Controls (5 years); A woman without a history of cancer will be recruited to match each breast cancer patient will be matched on age and BMI (within 3 years and 3 kg/m2, whenever possible)
Matched Controls (10 years); A woman without a history of cancer will be recruited to match each breast cancer patient will be matched 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.	Day 2 (In-Person Session)

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.	Day 2 (In-Person Session)
Carotid Artery Stiffness	Functional assessment of the carotid artery stiffness will be assessed using B-mode ultrasound and artery edge-tracking software	Day 2 (In-Person Session)
Carotid Intima Media Thickness	Structural assessment of the carotid artery thickness will be assessed using B-mode ultrasound and artery edge-tracking software	Day 2 (In-Person Session)
Arterial Stiffness	Measured by Pulse Wave Velocity (PWV) of the arm and leg	Day 2 (In-Person Session)
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%.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
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).	Day 2 (In-Person Session)
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).	Day 2 (In-Person Session)
Brain derived neurotrophic factor	Brain derived neurotrophic factor will be assessed via fasted venipuncture using in-house assays.	Day 2 (In-Person Session)
Lipid profile	HDL, LDL, total Cholesterol, Triglycerides analyzed from blood serum using a clinical assay at a core lab.	Day 2 (In-Person Session)
Hemoglobin A1c	Analyzed from blood plasma using a clinical assay at a core lab.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
Protein metabolism	Analyzed from breathing test and urine sample before and after the participant consume a test protein drink.	Day 1 (At-Home Session)

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.	Day 2 (In-Person Session)
Framingham 10-year 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.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
Heart Rate Variability	Measured as the variability in beat-to-beat heart rate during supine rest.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
Hemoglobin	Analyzed from blood plasma using a clinical assay at a core lab.	Day 2 (In-Person Session)
Whole-body fat and fat-free mass	Measured using a body composition device (BodPod) to estimate whole body fat (in kg and %) and fat free mass (in kg and %).	Day 2 (In-Person Session)
Body circumferences	Circumferences of the waist, hip and neck, measured using an inelastic tape	Day 2 (In-Person Session)
Bone Mineral Density	Assessed using a dual x-ray absorptiometry scan.	Day 2 (In-Person Session)
Body weight	Assessed fasted in lab using a calibrated scale	Day 2 (In-Person Session)
Body mass index (BMI)	Calculated from a measurement of height using a stadiometer and body weight (detailed above).	Day 2 (In-Person Session)
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.	Day 1 (At-Home Session)
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	Day 1 (At-Home Session)
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	Day 1 (At-Home Session)
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.	Day 1 (At-Home Session)
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.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
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.	Day 2 (In-Person Session)
Cognitive Impairment	Assessed by Global Deficit Score (GDS). GDS is calculated as an average score from 3 tests: 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.	Day 2 (In-Person Session)
Cancer-specific Quality of life (only measured in cancer group)	Assessed using the Functional Assessment of Cancer Therapy - General (FACT-G), - Endocrine (FACT-ES), Cognitive (FACT-Cog) and - Fatigue (FACT-F). These are patient-reported outcome measurements 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. The FACT-ES is a score of 19 questions with scores ranging from 0-76. The FACT-Cog contains 37 questions with a score of 0 to 132. FACT-F is calculated from the sum of 13 questions. Higher scores on each scale is indicative of better quality of life.	Day 1 (At-Home Session)
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.	Day 1 (At-Home Session)
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.	Day 1 (At-Home Session)
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.	Day 1 (At-Home Session)
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.	Day 1 (At-Home Session)
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).	Day 1 (At-Home Session)
Gender 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.	Day 1 (At-Home Session)
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.	Day 1 (At-Home Session)
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	Day 1 (At-Home Session)
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.	Day 1 (At-Home Session)
Sleep quantity and quality - device measured	Measured via Garmin smartwatch for the total sleep duration and efficiency.	Day 1 (At-Home Session)
Physical activity	Measured via Garmin smartwatch for time in moderate-vigorous physical activity, and step counts.	Day 1 (At-Home Session)
Sedentary time	Measured via Garmin smartwatch for time spent sitting.	Day 1 (At-Home Session)

Collaborators and Investigators

• Sponsor: University of Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR); Cancer Research Society

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: December 30, 2024
• First Submitted That Met QC Criteria: January 13, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 13, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Aromatase Inhibitors; Heart Disease Risk Factors; Breast Cancer Females
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: REB #46819

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