Predicting risk of cardiotoxicity among young and emerging adult breast cancer patients from treatment to survivorship

乳腺癌是女性最常见的癌症，心血管疾病(CVD)在 乳腺癌幸存者。这是由于心血管疾病和癌症之间的共同风险因素，但也是由于乳房 癌症治疗通常是心脏毒性的，稍后可能会导致心力衰竭(HF)。乳房的心脏毒性 癌症化疗影响了10%-20%的风险增加的患者，这些患者存在传统的 心血管疾病危险因素。然而，在我们对心脏毒性的认识上，在快速的 年轻和新兴成年(YA)乳腺癌幸存者人数不断增长，占所有幸存者的5%-12% 乳腺癌的诊断。随着乳腺癌存活率的增加，暴露在心脏毒性化疗药物中 年龄越小，乳腺癌存活者发生心衰的风险越高。此外，是的，乳腺癌 患者更有可能有基因突变，这种突变也可能损害心脏组织功能，并合并 独特的健康行为模式和心血管危险因素。然而，我们目前无法预测是哪一个 患者的心脏毒性风险最高。研究表明，基因表达可能会改进对 心脏毒性风险增加的妇女。到目前为止，还没有研究检查结合基因表达 具有心血管危险因素的基因突变可以识别出心脏毒性效应风险增加的YA患者 化疗。为了解决这个问题，我将完成以下具体目标：1)开发预测模型 结合心理社会和传统心血管危险因素识别高发乳腺癌患者 心脏毒性的风险，其定义为整体纵向应变(GLS)或左心室射血分数下降 分数(LVEF)；2)研究诊断时的危险因素概况是否与GLS和 乳腺癌治疗期间和治疗后的LVEF；以及3)研究分子生物标记物对风险的影响 预测模型。我们将招募n=300岁接受治疗的乳腺癌患者的纵向队列。 西北医学。在这些参与者中，我们将在嵌套病例对照设计中选择病例 被诊断为化疗期间GLS下降的患者(n=50)与年龄匹配且无心脏毒性的对照组 (n=50)。对于所有参与者，我们将把电子健康记录(EHR)数据与心理社会和 传统的心血管疾病危险因素在三个时间点。对于嵌套式病例对照研究，我们将额外测量 两个时间点的基因表达。这直接告诉我短期的职业发展目标是1)收获 在心力衰竭和心血管疾病病因学、流行病学和风险因素方面有经验；2)发展机器学习和 用于预测的生物信息学方法；以及3)改进卫生信息学方法，将EHR与 流行病学和分子数据。通过此K01生成的技能和试点数据将使我能够 解决NHLBI令人信服的问题(5.CQ.10)以降低癌症的心脏发病率和死亡率 幸存者。因此，我将实现我的长期职业目标，即识别和干预心血管疾病对 癌症幸存者的健康和长寿。

Breast cancer is the most common cancer among women and cardiovascular disease (CVD) is prevalent among breast cancer survivors. This is due to shared risk factors between CVD and cancer, but also that breast cancer therapies are often cardiotoxic, which may later cause heart failure (HF). Cardiotoxicity from breast cancer chemotherapy affects between 10-20% of patients with enhanced risk in the presence of traditional CVD risk factors. However, there is a significant gap in our knowledge of cardiotoxicity among the rapidly growing population of young and emerging adult (YEA) breast cancer survivors, which comprise 5-12% of all breast cancer diagnoses. As survival from breast cancer increases, exposure to cardiotoxic chemotherapies at a younger age may enhance HF risk among YEA breast cancer survivors. Moreover, YEA breast cancer patients are more likely to have gene mutations that may also impair cardiac tissue function combined with a unique pattern of health behaviors and CVD risk factors. However, we are currently unable to predict which patients are at highest risk of cardiotoxicity. Studies suggest that gene expression may refine identification of women at increased risk of cardiotoxicity. To date, no studies examined whether combining gene expression and genetic mutations with CVD risk factors can identify YEA patients at increased risk of cardiotoxic effects of chemotherapy. To address this issue, I will complete the following specific aims: 1) Develop a predictive model combining psychosocial and traditional CVD risk factors to identify YEA breast cancer patients at increased risk of cardiotoxicity as defined by a decline in global longitudinal strain (GLS) or left ventricular ejection fraction (LVEF); 2) Investigate if the risk factor profile at diagnosis is associated with trajectory of GLS and LVEF during and after breast cancer treatment; and 3) investigate the impact of molecular biomarkers to risk prediction models. We will recruit a longitudinal cohort of n=300 YEA breast cancer patients treated at Northwestern Medicine. Among these participants, in a nested case-control design, we will select cases diagnosed with decline in GLS during chemotherapy (n=50) with age-matched controls without cardiotoxicity (n=50). For all participants, we will combine electronic health record (EHR) data with psychosocial and traditional CVD risk factors at three timepoints. For the nested case-control study, we will additionally measure gene expression at two timepoints. This directly informs my short-term career development goals to 1) Gain experience in HF and CVD etiology, epidemiology, and risk factors; 2) Develop skills in machine learning and bioinformatics approaches for prediction; and 3) Refine health informatics methods to integrate EHR with epidemiologic and molecular data. The skills and pilot data generated through this K01 will enable me to address the NHLBI compelling question (5.CQ.10) to reduce cardiac morbidity and mortality in cancer survivors. I will thus achieve my long-term career goal to identify and intervene on the CVD threats to the health and longevity of YEA cancer survivors.