Older Breast Cancer Patients: Risk For Cognitive Decline

 描述(由申请人提供)：有令人信服的数据表明，癌症及其治疗与某些幸存者的认知能力下降(“化疗脑”)有关。认知 衰退是我们老龄化国家面临的一个重要的公共卫生问题，因为它是功能衰退、住院、死亡率和医疗费用的强烈预测因素。在美国300万乳腺癌幸存者中，有71%是60岁及以上的女性，对于她们来说，认知能力的下降尤其明显，因为即使是微小的下降也会对日常生活产生负面影响。虽然对年轻幸存者的多项研究都显示出持续性和晚期认知问题，但关于老年幸存者认知功能下降的长期轨迹和风险的数据不足，因为过去的研究只有较小的老年幸存者样本；缺乏治疗前数据；没有控制；和/或没有包括随访。为了认识到这一重要的证据差距，医学研究所最近呼吁收集影响老年幸存者癌症存活期的因素的数据，强调认知结果。在这个修订的续篇中，我们的多学科团队将使用生物行为癌症和衰老框架，通过利用思考和与癌症共存(TLC)队列来填补这一空白。TLC是唯一对老年乳腺癌幸存者在治疗前和12个月后进行评估的前瞻性队列，其中包括匹配的对照组。我们取得了很好的进展，完成了招生目标，发表了19篇论文，提交了两篇摘要。我们也有具有挑衅性的初步结果，显示了不同治疗和基因的不同轨迹，APOE4阳性化疗暴露的幸存者在几个认知领域表现出比其他幸存者和对照组显著更陡峭的12个月下降。此外，体力活动倾向于减少，多发病增加了12个月下降的几率。为了了解认知功能下降的长期轨迹和风险，我们建议对TLC队列进行新的评估(24、36、48个月)，使用库中的DNA进行COMT多态测试，并增加对体力活动的客观监测和炎症标志物的测量。其目的是：1)确定纵向认知功能的轨迹 并测试治疗暴露对照组中的差异；2)确定在登记后48个月内认知能力下降的风险因素，并确定治疗暴露(化疗和激素控制)如何减缓效果；以及3)评估炎症产物(CRP、IL6和sTNFRII)如何与认知轨迹一起变化；以及测试炎症是否中介体力活动和多种疾病对认知下降的影响。这些结果将产生很大的影响，因为它建议未来的机械性研究和干预试验，并支持患者与医生关于治疗益处和危害的讨论。了解衰退的轨迹是停滞、加速还是作为晚期效应发生，可以改善老年乳腺癌幸存者的生存护理计划。

 DESCRIPTION (provided by applicant): There are compelling data indicating that cancer and its therapies are associated with cognitive decline ("chemo-brain") in certain survivors. Cognitive decline is an important public health issue facing our aging nation since it is a strong predictor f functional decline, hospital admission, mortality, and healthcare costs. For women 60 and older ("older"), who represent 71% of the three million US breast cancer survivors, cognitive decline is especially salient, since even small declines have negative effects on daily life. While there are multiple studies in younger survivors showing both persistent and late cognitive problems, there are insufficient data on long-term trajectories of and risks for cognitive decline in older survivos since past research has had small samples of older survivors; lacked pre-treatment data; was uncontrolled; and/or did not include follow-up. In recognition of this important evidence gap, the Institute of Medicine issued a recent call for collection of data about factors that influence the course of cancer survivorship in older survivors, stressing cognitive outcomes. In this revised continuation, our multi-disciplinary team will use a bio-behavioral cancer and aging framework to fill this gap by leveraging the Thinking and Living with Cancer (TLC) cohort. TLC is the only prospective cohort of older breast cancer survivors evaluated pre-treatment and 12 months later that includes matched controls. We have made excellent progress, meeting enrollment targets, publishing 19 papers, and presenting two abstracts. We also have provocative preliminary results showing divergent trajectories by treatment and genotype, with APOE 4 positive chemotherapy-exposed survivors demonstrating dramatically steeper 12-month declines in several cognitive domains than other survivors and controls. Additionally, physical activity tended to decrease and multi-morbidity to increase the odds of 12-month decline. To understand longer-term trajectories of and risks for cognitive decline, we propose to conduct new assessments (24, 36, 48 months) of the TLC cohort, use banked DNA for COMT polymorphism testing, and add objective monitoring of physical activity and measurement of inflammatory markers. The aims are to: 1) ascertain trajectories of longitudinal cognitive function and test for differences in treatment exposure-control groups; 2) identify risk factors for cognitie decline in the 48 months post-enrollment and determine how effects are moderated by treatment exposure (chemotherapy>hormonal>control); and 3) assess how inflammatory products (CRP, IL6, and sTNFRII) co-vary with trajectories of cognition; and test if inflammation mediates effects of physical activity and multi-morbidity on cognitive decline. The results will have high impact by suggesting future mechanistic research and intervention trials, and supporting patient-physician discussions about treatment benefits and harms. Knowledge about whether trajectories of decline plateau, accelerate, or occur as late effects could improve survivorship care planning for older breast cancer survivors.