Women with breast cancer treated using anthracyclines and/or trastuzumab are at an increased risk of cardiovascular disease (CVD) following treatment completion. Exercise is known to reduce CVD risk in healthy and several clinical populations, but, whether existing cardiac rehabilitation programs can be leveraged to reduce CVD risk in breast cancer survivors is unknown. This study aims to: i) understand the feasibility of virtual versus in-person cardiac rehabilitation in breast cancer survivors; and ii) compare the effect of virtual versus in-person cardiac rehabilitation on cardiovascular function and injury biomarkers, physical fitness, and psychosocial health. 50 breast cancer survivors with increased CVD risk will be recruited and randomized to either the in-person or virtual arm of the cardiac rehabilitation program at Women's College Hospital (WCH). Data will be collected at baseline, following program completion, and 6-months after program completion. The primary outcomes are measures of study feasibility. Other clinically relevant outcomes to be collected include: i) imaging and blood-based biomarkers of cardiovascular function; ii) physical fitness; iii) objective and self-reported physical activity levels; and iv) self-reported measures of psychosocial wellbeing. These findings will be used to inform the design of a larger-scale cardio-oncology trial and will facilitate development of more comprehensive CVD risk management strategies for breast cancer survivors at WCH.

Rationale Our overarching goal is to support the development of innovative and scalable approaches to CVD prevention in early breast cancer (EBC) survivors. Cardiac rehabilitation (CR) is a cornerstone of both primary and secondary CVD risk management and may be similarly beneficial for survivors at risk of cancer-related CVD. However, it remains unknown if CR-based interventions can reduce CVD risk in those who have received cardiotoxic therapies. Further, the impact of exercise setting (i.e., in-person versus virtual) on intervention safety, adherence, and efficacy has also not been evaluated in this context. Lastly, whether psychosocial wellbeing affects program participation is also not well understood. Ultimately, our study will provide important pilot and feasibility data to inform future randomized trials in this area. It will also lay the foundation for a prospective cohort study that can evaluate the importance of biomarkers and clinical risk factors in predicting future CVD and will provide data that will help identify individuals who are most likely to benefit from aggressive CVD risk factor management.

Design The proposed study is a pragmatic randomized trial of in-person supervised versus virtually delivered CR in EBC survivors treated with anthracyclines and/or trastuzumab. The investigators will also study the evolution of cardiovascular risk markers in women with breast cancer after completion of potentially cardiotoxic chemotherapy.

Objectives and hypotheses

Our specific objectives and related hypotheses are:

1. Primary objective: Assess the feasibility of conducting an adequately powered randomized trial of supervised versus virtual CR in older women (>50 years) with breast cancer who have been treated with anthracyclines and/or trastuzumab Hypothesis: The trial will demonstrate feasibility via the achievement of pre-determined thresholds for participant recruitment, retention, and intervention adherence to CR protocols.

2. Secondary objectives:

   i. Derive estimates of intervention efficacy on markers of cardiac function and injury, aerobic fitness, non-trial physical activity behaviours (i.e., exercise behaviours beyond what is prescribed as part of CR), and psychosocial wellbeing (anxiety, depression, stress) Hypothesis: Improvements in imaging and serum biomarkers, aerobic fitness, and psychosocial measures will be comparable between the two intervention groups.

   ii. Describe the prevalence of abnormal biomarkers from blood, cardiac imaging and stress testing with cardiovascular risk after breast cancer treatment Hypothesis: A substantial proportion of participants will have abnormal global longitudinal strain and serum biomarkers despite having normal LVEF. Estimated aerobic capacity will also be compromised when compared with age- and sex-norms.

3. Tertiary objectives:

   i. Inform the development a novel pathway for cardiometabolic risk reduction for women with breast cancer at WCH, with these data being used to guide out-of-institution scalability Hypothesis: The investigators will identify potential barriers to referral and participation to inform the future development of this program pathway and will be able to determine any cancer-specific needs that may need to be addressed via the program.

   ii. Quantify the differences in intervention delivery costs between the two study arms.

   Hypothesis: Both in-person and virtual CR will be comparable in terms of utilization of consumable resources. Virtual rehabilitation will incur a greater healthcare professional (HCP) time cost for delivery when compared with in-person CR.

   Intervention Briefly, in-person CR consists of once-weekly (or twice weekly if the participant is classified is being high risk, i.e., elevated blood pressure with exercise, or <85% age-predicted aerobic fitness) group-based supervised exercise training at WCH, supplemented with home-based exercise training, with the goal of reaching Canadian Physical Activity Guidelines of 150 minutes a week of moderate-intensity exercise per week. Exercise prescriptions are individualized at baseline by the CR team based on a symptom-limited stress test. Virtual CR consists of once-weekly telephone or video conferencing-based follow-ups (according to participant preference and access to internet/smart device) by one of the HCPs. Similar to the in-person program, the virtual program also encourages participants to set goals to achieve 150 minutes a week of moderate-intensity exercise. The exercise prescription is individualized to each participant's ability and can vary in number of sessions per week and duration of each exercise session, as per the HCP's discretion. Unlike the in-person program, all these sessions are completed at home in an unsupervised manner. Additionally, both study arms get have the opportunity to attend weekly synchronous virtual group video education sessions for the duration of the 12-week CR program with the focus on self-management education and support. The program's Registered Dietitian, Social Worker, and Pharmacist (who teach some of the education sessions) may offer 1:1 visits with the participants if necessary.

   Statistical Analysis Participant demographics, clinical characteristics (including prevalence of abnormal biomarkers), and feasibility metrics (including reasons for non-participation) will be analyzed using descriptive statistics (mean ± standard deviation, and frequency (%), as applicable). Exercise and education session attendance will be reported as the proportion attended and compared between groups using the chi-square test (or Fisher's exact test, as appropriate). Exercise prescription adherence will be reported as the average percentage of exercise completed relative to exercise dose prescribed and will be compared between groups using independent-samples t-tests (or Wilcoxon Rank Sum test, as appropriate).

Inclusion Criteria:

• age > 50 years
• previous receipt of anthracyclines and/or trastuzumab for breast cancer
• ability to participate in in-person cardiac rehabilitation

Exclusion Criteria:

• medical contraindications that preclude safe exercise participation17
• unwillingness to comply with study protocols.