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

项目总结 蒽环类药物和人表皮生长因子受体2(HER2)靶向药物总体上有所改善 乳腺癌的控制和存活率；然而，这些癌症治疗的好处被心血管疾病所抵消 (Cv)在治疗期间或完成治疗后数年内可能发生的急性毒性。我们的团队已经证明 原发性乳腺癌的化疗导致心-肺-骨骼肌轴的直接损伤(例如： 细胞毒性/靶向/放射治疗相关损伤)和继发性不良反应(例如，解除条件， 骨骼减少)，导致心肺适合度(CRF)显著下降，CRF是 全球心肺功能。我们最近完成了最佳时机试验，这是一项随机、开放的试验 三种不同AT排序策略与体力活动的耐受性及效果评价 (PA)158例早期(I-III)乳腺癌患者接受初级辅助治疗或治疗的CRF建议控制 新辅助化疗(NCI R01CA164751，NCT01943695)。结果表明，AT在运动过程中和运动后 化疗后CRF下降较PA建议安全且有所缓解。然而，一个根本的问题是 与AT相关的问题是，它是否是减轻心脏直接损伤的有效策略 蒽环类药物和HER2靶向治疗。为了解决这一知识差距，我们提出了一个辅助生物标记物。 对最佳时机试验的研究，将包括用于亚临床早期检测的心血管生物标志物 癌症治疗期间的心脏毒性和随后的心脏功能障碍的预测。总体目标 这项研究的目的是确定心脏毒性乳腺癌治疗过程中AT对 脑血管损伤、应激和炎症的相关指标。我们将研究69名患者的子集，这些患者接受 接受蒽环类药物化疗(使用或不使用HER2靶向治疗)前采集血样的患者 化疗后(n=138)。本研究的目的是：(1)确定AT对儿童心理健康的影响 心肌损伤(高敏肌钙蛋白-I、心肌细胞游离DNA)、应激(N- 末端前体B型利钠肽)和炎症(CXCL10，IL-6)；以及(2)探索改变 血管紧张素转换酶对血管生物标志物变化的影响研究结果将为AT的影响提供洞察力 预防乳腺癌治疗的不良心血管效应，提高对其潜在机制的认识 对AT诱导的生理适应的影响，并为未来研究的设计提供信息，以减轻 癌症治疗。

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.