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

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.

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.

Functional assessment of the carotid artery stiffness will be assessed using B-mode ultrasound and artery edge-tracking software

Structural assessment of the carotid artery thickness will be assessed using B-mode ultrasound and artery edge-tracking software

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%.

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.

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).

Measured by Pulse Wave Velocity (PWV) of the arm and leg

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 will be assessed via fasted venipuncture using in-house assays.

HDL, LDL, total Cholesterol, Triglycerides analyzed from blood serum using a clinical assay at a core lab.

Analyzed from blood plasma using a clinical assay at a core lab.

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.

Measured as peak volume of oxygen consumption via indirect calorimetry during a cardiopulmonary exercise test on a cycle ergometer.

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.

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.

Measured as the variability in beat-to-beat heart rate during supine rest.

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.

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.

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.

Measured as the average of the last 5 of 6 blood pressure measurements taken 60 seconds apart using an automatic blood pressure device.

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.

Measured during a 10-day period by a Dexcom G7 Continuous Glucose Monitor (CGM)

Analyzed from blood plasma using a clinical assay at a core lab.

Measured using a body composition device (BodPod) to estimate whole body fat (in kg and %).

Measured using a body composition device (BodPod) to estimate whole body fat free mass (in kg and %).

Circumference of the waist measured using an inelastic tape

Circumference of the hip measured using an inelastic tape

Circumference of the neck measured using an inelastic tape

Assessed fasted in lab using a calibrated scale

Calculated from a measurement of height using a stadiometer and body weight (detailed above).

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.

An overall measure of alignment with Canada's dietary guidelines measured via the Healthy Eating Food Index-2019 calculated from 3-day diet records

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

Assessed by the perceived stress scale (PSS-14) where individual scores can range from 0 to 56 with higher scores indicating higher perceived stress

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.

Measured via Garmin smartwatch for the total sleep duration.

Measured via Garmin smartwatch for the total sleep efficiency.

Measured via Garmin smartwatch for time in moderate-vigorous physical activity in total minutes at this intensity.

Measured via Garmin smartwatch for daily step counts.

Measured via Garmin smartwatch for time spent sitting.