Effects of Exercise on Changes in Cardiovascular Biomarkers in Patients with Breast Cancer During Anthracycline-based Chemotherapy

Anthracyclines and human epidermal growth factor receptor 2 (HER2)-targeted agents have improved overall breast cancer control and survival; however, the benefits of these cancer therapies are offset by cardiovascular (CV) toxicity that can occur acutely during therapy or years after completion. Our group has shown that chemotherapy for primary breast cancer causes both direct injury to the cardiac-lung-skeletal muscle axis (e.g. cytotoxic/targeted/radiation therapy-associated injury) and secondary adverse effects (e.g. deconditioning, sarcopenia) which lead to significant declines in cardiorespiratory fitness (CRF), an integrative measure of global cardiopulmonary function. We recently completed the Optimal Timing Trial, a randomized, open-label trial evaluating the tolerability and effects of three different AT sequencing strategies versus physical activity (PA) advice control on CRF in 158 women with early stage (I–III) breast cancer undergoing primary adjuvant or neoadjuvant chemotherapy (NCI R01CA164751, NCT01943695). The results demonstrated that AT during and after chemotherapy was safe and attenuated CRF decline compared to PA advice. However, a fundamental question related to AT is whether it is an effective strategy to mitigate the direct cardiac injury from anthracyclines and HER2-targeted therapy. To address this knowledge gap, we propose an ancillary biomarker study to the Optimal Timing Trial and will include CV biomarkers that are used for early detection of subclinical cardiotoxicity during cancer treatment and predictive of subsequent cardiac dysfunction. The overall objective of the proposed study is to determine the effects of AT during cardiotoxic breast cancer treatment on correlative measures of CV injury, stress, and inflammation. We will study a subset of 69 patients treated with anthracycline chemotherapy (with or without HER2-targeted therapy) who had blood samples collected preand post-chemotherapy (n = 138 total samples). The aims of our study are to: (1) determine the effect of AT on changes in CV biomarkers of myocardial injury (high-sensitivity troponin-I, cardiac cell-free DNA), stress (Nterminal pro B-type natriuretic peptide), and inflammation (CXCL10, IL-6); and (2) explore factors that modify the effect of AT on changes in CV biomarkers. The results of the study will provide insights on the impact of AT to prevent adverse CV effects of breast cancer therapy, improve understanding of the underlying mechanisms of AT-induced physiologic adaptation, and inform the design of future studies to mitigate the CV toxicity of cancer treatment.