PROJECT SUMMARY
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 pre-
and 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 (N-
terminal 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.
