Brain Health in Breast Cancer Survivors: Interaction of Menopause and Endocrine Therapy

项目摘要 拟议的职业奖旨在支持PI在癌症生存研究方面的高级培训， 神经影像学，同时检查雌激素功能的变化与内分泌治疗（ET）如何影响大脑 乳腺癌幸存者的健康状况。这两个广泛的目标与NCI支持研究的使命是一致的 与癌症患者的持续护理和生存有关。 ET广泛用于治疗激素受体阳性乳腺癌，并通过下调 雌激素功能然而，雌激素很容易穿过血脑屏障，干扰雌激素的作用， 大脑雌激素支持认知，绝经状态与女性的认知健康密切相关。 这引起了人们的担忧，即抗雌激素药物可能会影响认知和大脑健康。然而，证据表明， 现有的研究是不一致的，这些影响仍然知之甚少。不完全理解 ET的影响可能是由于早期研究的局限性-即， 绝经状态和标准认知测量的不敏感性。 为了解决这些局限性，这项拟议中的研究将从一名妇女的大脑健康中探索ET对大脑健康的影响。 健康的角度，通过检查ET和绝经状态之间的相互作用，使用敏感的功能 磁共振成像（fMRI）测量与任务相关的大脑活动。我们的目标是进行一次跨部门的 比较绝经状态（前后）和患者组（乳腺癌）的2x2析因设计研究 ET的幸存者和健康对照在年龄、种族、教育程度和自末次月经以来的时间方面相匹配 (post仅限））。我们将在工作记忆任务中使用敏感的fMRI测量大脑活动-测量 成功地用于揭示健康女性更年期和雌激素变化的影响，但还没有 广泛用于研究ET的影响。我们假设，前额叶区域的任务相关性过度活跃 将在接受ET治疗的乳腺癌幸存者中观察到与对照组相比。此外，ET可能更显着 破坏绝经前妇女的雌激素功能。因此，我们假设ET效应的大小 在绝经前的女性中会更高。我们亦会研究及比较环境教育对标准 认知测量和新的细胞老化测量。此外，终生激素暴露史将被 探讨可能的调节因素-第一次这样的审讯这些重要因素。开展 在这项研究中，PI，一位该领域的临床神经心理学家，将接受功能磁共振成像和细胞衰老方法的培训， 提高乳腺癌生存率临床研究的执行技能。这些获得的技能是高度相关的 PI的职业目标是发起一个关于癌症生存中大脑健康的有力研究计划， 健康和老龄化-美国医疗保健需求的关键交叉点。

PROJECT SUMMARY The proposed career award is designed support the PI’s advanced training in cancer survivorship research and neuroimaging, while examining how changes in estrogen function with endocrine therapy (ET) influence brain health in breast cancer survivors. Both broad goals are consistent with the NCI’s mission to support research related to the continuing care of cancer patients and survivorship. ET is widely used to treat hormone receptor positive breast cancer and prevent recurrence by downregulating estrogen function. However, ETs readily cross the blood brain barrier and interfere with the action of estrogen in the brain. Estrogen supports cognition and menopausal status is closely linked to cognitive health in women. This has raised concern that anti-estrogen ETs may affect cognition and brain health. However, evidence across existing studies is inconsistent and these effects remain poorly understood. The incomplete understanding of the effects of ET are likely due to limitations of earlier studies – namely, the under-appreciation of the role of menopausal status and insensitivity of standard cognitive measures. To address these limitations, the proposed study will probe the effects of ET on brain health from a women’s health perspective by examining the interaction between ET and menopausal status using sensitive functional magnetic resonance imaging (fMRI) measures of task-related brain activity. We aim to conduct a cross-sectional study in a 2x2 factorial design comparing menopausal status (pre and post) and patient group (breast cancer survivors on ET and healthy controls matched on age, race, education, and time since final menstrual period (post only)). We will use sensitive fMRI measures of brain activity during a working memory task – measures successfully used to reveal the effects of menopause and estrogen changes in healthy women, but yet to be extensively used to study the effects of ET. We hypothesize that task-related hyperactivity in pre-frontal regions will be observed in breast cancer survivors on ET compared to controls. Further, ET may more dramatically disrupt estrogen function in pre-menopausal women. We therefore hypothesize that the magnitude of ET effects will be greater in pre-menopausal women. We will also examine and compare the effects of ET on standard cognitive measures and novel cellular aging measures. In addition, lifetime hormone exposure histories will be explored as possible moderating factors – the first such interrogation of these important factors. In carrying out this study, the PI, a clinical neuropsychologist in this field, will train in fMRI and cellular aging methods, while refining executive skills in clinical research in breast cancer survivorship. These acquired skills are highly relevant to the PI’s career goal of launching a vigorous research program on brain health in cancer survivorship, women’s health, and aging – a critical intersection for healthcare needs in the U.S.