our primary outcomes will help define the relationships between cancer therapy, CV injury, exercise intolerance and fatigue, while also accounting for the relative contributions of age, menopause status, race/ethnicity, radiation therapy, and psychosocial and behavioral risk factors. In addition, we will assess pre-existing cardiac risk factors (hypertension, smoking, diabetes, coronary artery disease, dynamic changes in body mass index, blood pressure, serum lipids and fasting glucose, physical activity, and chemo- and immunotherapy).

1. Understanding and Predicting Breast
Cancer Events After Treatment

2. Understanding and Predicting
Fatigue, CV Decline, and Events After
Breast Cancer Treatment (UPBEAT)
Principal Investigator: W. Gregory Hundley, MD
Co-Investigators: Nancy Avis, PhD
Peter Brubaker, PhD
Gregory Burke, MD, MSc
L. Doug Case, PhD
Ralph D’Agostino, Jr., PhD
Craig Hamilton, PhD
Jennifer Jordan, PhD
Dalane Kitzman, MD
Heidi Klepin, MD
Glenn Lesser, MD
Shannon Mihalko, PhD
Kathryn Weaver, PhD, MPH
Karen Winkfield, MD, PhD
Joseph Yeboah, MD, MS

4. Recruitment Stratification: We will recruit 840 breast cancer patients receiving adjuvant
chemotherapy – 420 receiving Anth and 420 receiving non-Anth – and 160 healthy
comparison women. Recruitment will be stratified such that in each of these groups, 50%
will be pre- and 50% post-menopausal, and 20% will be African-American (Cells 1-6).

5. Stage I-III breast cancer
Aged ≥ 18
ECOG functional status score of 0-2
Able to walk on a flat surface for >2 blocks without symptoms
Inclusion Criteria
Contra-indication to MRI
LVEF <50%
Inability to walk on a treadmill
Another severe inter-current disease
Exclusion Criteria
Study population
Study Sample: 1,000 women
Follow-up Period: 2 years
Study Duration: 5 years

6. Study measurements of potential confounders
Pre-Existing Factors:
Age
Race/Ethnicity
Hypertension
Smoking (Y/N)
Diabetes
Coronary artery disease
Menopause status
Cardiovascular medications
Physical activity
Dynamic:
BMI
Blood pressure
Serum lipids
Serum glucose
Physical activity
Psychosocial behaviors
Cancer treatment
(Chemotherapy, radiation
therapy, immunotherapy,
surgery)

7. Study Timetable T = total cohort; H = half cohort; C = total cancer group
Evaluation Baseline
1
month
3
months
12
months
24
months
Annual
Surveillance
Years 3-11
Vitals (heart rate, blood pressure) T T T T
Demographics (heart rate, blood pressure, height, weight,
BMI, waist circumference)
T T T T
Routine Labs (lipid panel, serum creatinine, CRP, glucose) T C C T
Serum and plasma C C C C
DNA C C
Questionnaires (fatigue, psychosocial/behavioral risk
factors, socio-demographics, comorbidities, health-related
quality of life,PROMIS, KCCQ-12)
T T T T
Neurocognitive Tests (Trail making A & B, COWA) T T T T
Exercise Testing: 6-minute walk T T T T
Range of Motion, Grip Strength and Expanded SPPB T T T T
MRI (15 minute scan of LVEDV, LVESV, LVSV, LVEF, LV
strain, aortic wall thickness, and PWV)
T C T
Exercise Testing: CPET (Peak VO2, Exercise time) H H
Outcomes surveillance (continues for 10 yrs. After study
initiation and 8 yrs. After enrolling each patient)
T T T

8. Questionnaires
l Fatigue (and symptoms
checklist)
l Psychosocial risk factors
related to CVD:
– Depression, perceived
stress, hostility, low social
support
l Quality of Life
l Lifestyle behaviors (physical
activity, smoking, alcohol)
l PROMISE
l KCCQ-12

9. Neurocognitive Tests
§ Trail making A and B (TMT-A, TMT-B)
§ Controlled Oral Word Association Test (COWA)

10. 6 minute walk – an exercise measure
indicative of ability to perform
activities of daily living
1) Easy to administer, and feasible to use in screening and intervention
studies
2) Cost effective and therefore can be measured at multiple time-points
3) It is a common measure utilized in many CV trials, and therefore will allow
comparisons across studies

11. Localizers (x2) 0:30
Tagging 0:30
T1 and T2 Maps 1:00
Aorta Phase Contrast 2:00
Aorta Wall Thickness 0:30
Aorta Distensibility 0:30
LV Cine Stack 3:00
Total Time 8-12 min
MRIRapidImagingProtocol

12. cMRI Validation
Training video available at
https://wakencorp.phs.wakehealth.edu
1. Oversight: Dr. Jennifer Jordan
(jenjorda@wakehealth.edu) Wake Forest University
Health Sciences, Internal Medicine -Cardiology
2. Submit 2 scans to WFUHS MRI Reading Center
(Guidelines available on WF NCORP site)
3. Scans will be reviewed and feedback is provided to
verify approval or potential violations
4. Certification notification will be sent to designated
site contact verifying that all cMRI requirements
have been met for study participation

13. Peak Exercise
VO2l The most objective measure of exercise capacity
l Physiologically and clinically meaningful
– Integrated physiological response to exercise
– Mechanisms of exercise limitation & related to QOL
– Specific, objective thresholds for levels of disability
– Responsive to interventions; predictor of mortality
– Provides wealth of additional independently valuable data: RER, VAT,
VE/VCO2 slope
l Feasible in large multicenter clinical trials
– Highly reproducible
– Standardized, semi-automated
– Non-invasive, inexpensive

14. CARDIOPULMONARY EXERCISE TEST
(CPET) Validation
*Training video available at
https://wakencorp.phs.wakehealth.edu
v Oversight: Dr. Peter Brubaker, Wake Forest University
Department of Health and Exercise Sciences
(bbrubaker@wfu.edu)
v Conduct 1 test on a healthy volunteer
v Submit data to WF CPET core laboratory c/o Dr.
Brubaker
v Data will be evaluated and feedback provided to verify
approval or potential violations
v Certification notification will be sent to designated site
contact verifying that all requirements have been met
for study participation

15. Protocol Specific Requirements
1. All sites must register through the CTSU (www.ctsu.org)
2. Approval documentation must be submitted to
CTSU prior to enrolling participants
q IRB Site Approval
q cMRI validation
q Cardiopulmonary Exercise Test
(CPET) validation
q Neurocognitive certification