OLDER BREAST CANCER PATIENTS: RISK FOR COGNITIVE DECLINE

描述（由申请人提供）：65岁及以上的妇女（“老年妇女”）占所有新发乳腺癌病例的近一半。随着“美国的老龄化”，到2030年，被诊断并接受乳腺癌治疗的老年妇女的绝对数量将几乎翻一番。这些老年患者的治疗指南包括全身治疗，老年妇女对化疗感兴趣，即使是在延长生存期的小回报。但全身治疗并非没有副作用，大量研究表明，接受这些药物后认知能力下降。影像和动物研究证实，癌症化疗会影响大脑结构和功能。然而，实际上我们对老年患者的认知能力下降知之甚少，因为几乎所有现有的研究都是在年轻患者身上进行的。由于衰老本身与认知能力下降有关，老年患者可能特别容易受到全身治疗的不利认知影响。我们的初步工作表明情况确实如此，但这从未经过实证检验。这项研究将是第一个评估老年癌症患者认知变化的大规模、前瞻性、对照研究。我们使用癌症生存的易感性模型来描述12个月期间的全身治疗对认知的影响，测试认知和生活质量之间的关系，并评估APOE多态性是否会调节认知结果。我们召集了一个由肿瘤学家、老年病学家、神经学家、神经、认知和行为心理学家以及来自隆巴迪综合癌症中心、纪念斯隆-凯特琳癌症中心、波士顿大学和Y- Me（一个全国消费者权益组织）的消费者组成的团队。我们将招募325名新诊断的老年乳腺癌患者和同等数量的非癌症朋友作为对照。参与者将接受基线（全身治疗前）神经心理测试和电话访谈；临床资料将从记录中提取。参与者将在基线后12个月重复认知测试和生活质量测量。主要结果是在注意力、工作记忆和精神运动速度领域的测试中总结得分的变化。另外四个领域被纳入次要结果，以评估更广泛的认知功能并检查差异影响：语言；执行能力;学习与记忆；视觉空间的。本研究结果将有助于设计适合老年妇女的治疗方案，制定预防干预措施，为临床治疗决策提供信息，并指导第二代研究。总的来说，考虑到预计老年人口的增长、发病率随着年龄的增长而上升、老年患者越来越多地使用全身治疗的趋势、使用更积极的给药方案、高生存率和预期寿命的增加，这个主题具有很高的研究、临床和公共卫生重要性。公共卫生相关性：在美国，癌症是导致死亡的主要原因，而乳腺癌是我国女性中第二常见的癌症。老年妇女（65岁及以上妇女）目前占所有新发乳腺癌病例的近一半。随着“美国的老龄化”和乳腺癌治疗的进步，到2030年，接受乳腺癌治疗并存活下来的老年妇女的绝对人数将几乎翻一番。全身激素和非激素化疗被认为可以提高生存率，并且在过去的二十年中，这些方式的使用率大幅增加。在我们的初步工作中，我们发现老年妇女对化疗很感兴趣，即使是为了延长生存期的小回报。然而，认知障碍已经在大多数乳腺癌系统治疗的研究中得到证实，但实际上所有这些研究都是在年轻人群中进行的。由于衰老本身与认知能力下降有关，老年妇女似乎特别容易受到全身治疗的不利认知影响；我们的初步工作有力地表明，情况确实如此，但这从未经过实证检验。这项研究将是第一个评估老年癌症患者认知变化的大规模、前瞻性、对照研究，并将为下一代机制、治疗和干预研究提供基础。这很重要，因为年轻患者的数据不能直接转化为老年人群。我们将使用癌症生存的脆弱性模型来前瞻性地描述老年乳腺癌患者在12个月期间的全身治疗对认知的影响，测试认知和生活质量（QOL）之间的关联，并评估APOE基因多态性是否会调节认知结果。为了实现我们的目标，我们组建了一个由肿瘤学家、老年病学家、神经学家、神经和认知心理学家、行为科学家和消费者组成的多学科团队，他们来自隆巴迪综合癌症中心（LCCC）、纪念斯隆-凯特琳癌症中心（MSKCC）、波士顿大学（BU）和Y-Me（一个全国消费者权益组织）。该团队将共同努力，从LCCC和MSKCC这两个高容量三级转诊中心招募325例新诊断的老年乳腺癌病例。BU将协调认知测试方案。我们将招募同等数量的非癌症朋友对照。我们选择了朋友对照，因为他们在大多数方面与患者相似，除了暴露于癌症及其治疗之外，他们应该被激励参与。如果没有朋友，我们将招募与年龄、教育、种族和地区（DC/NY）相匹配的对照。我们将在任何系统治疗前（或在对照组入组时）进行基线神经心理测试，调查女性的主观认知功能、社会心理因素、生活质量和日常生活活动（IADLS）。我们将从医疗记录中提取临床数据。我们将在入组时采集血液检测APOE多态性；这些结果将不会提供给参与者，因为这被认为是一个研究测试)。我们进行随访访谈，并在基线评估后12个月重复神经心理测试；这个时间点对应于接受化疗的妇女治疗后3-6个月。我们的主要认知结果将是在注意力、工作记忆和精神运动速度领域的测试中总结得分的变化。在二次分析中，我们检查了4个额外领域的分数变化，以评估更广泛的认知功能，并检查不同影响的问题：语言；执行能力;学习与记忆；视觉空间。本研究的数据将指导未来的干预措施，以更好地选择全身治疗利大于弊的老年妇女，并制定方法来减轻全身治疗的负面影响，提高对日益增长的老年乳腺癌患者的护理质量。

DESCRIPTION (provided by applicant): Women 65 and older ("older women") account for nearly half of all new cases of breast cancer. With the "graying of America" the absolute number of older women diagnosed and undergoing breast cancer treatment will almost double by the year 2030. Treatment guidelines for these older patients include systemic therapy and older women are interested in chemotherapy for even small returns in survival extension. But systemic therapy is not without side effects, and numerous studies have documented cognitive decline after receipt of these agents. Imaging and animal studies confirm that cancer chemotherapy affects brain structure and function. However, very little is actually known about cognitive decline in older patients, because virtually all of the existing research has been conducted in younger patients. Since aging itself is associated with cognitive decline, older patients are likely to be particularly vulnerable to the adverse cognitive effects of systemic therapy. Our preliminary work suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients. We use the vulnerability model of cancer survivorship to describe systemic therapy effects on cognition over a 12 month period, test associations between cognition and quality of life and to evaluate whether APOE polymorphisms moderate cognitive outcomes. We have assembled a team of oncologists, geriatricians, neurologists, neuro-, cognitive and behavioral psychologists and consumers from Lombardi Comprehensive Cancer Center, Memorial Sloan-Kettering Cancer Center, Boston University and Y- Me (a national consumer advocacy organization). We will enroll 325 newly diagnosed older breast cancer patients and an equal number of non-cancer friend controls. Participants will undergo baseline (pre-systemic therapy) neuropsychological testing and telephone interviews; clinical data will be abstracted from records. Participants will repeat cognitive testing and QOL measures 12 months after baseline. The primary outcome is change in the summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. Four additional domains are included as secondary outcomes to assess broader cognitive function and examine differential impact: Language; Executive Functioning; Learning and Memory; Visuospatial. The results of this study will contribute to designing appropriate regimens for older women, developing preventive interventions, informing clinical decision-making about treatment, and guiding second generation studies. Overall, this topic has high research, clinical and public health importance, given the projected growth in the older population, rising incidence with advancing age, trends towards increasing use of systemic therapy in older patients, use of more aggressive dosing regimens, high survival rates, and increasing life expectancy. PUBLIC HEALTH RELEVANCE: Cancer is the leading cause of death in the US and breast cancer is the second most common cancer among women in our country. Older women (women 65 and older) presently account for nearly half of all new cases of breast cancer. With the "graying of America" and advances in treatment for breast cancer, the absolute number of older women undergoing breast cancer treatment and surviving their disease will almost double by the year 2030. Systemic hormonal and non-hormonal chemotherapy is credited with improvements in survival, and rates of use of these modalities have increased substantially over the past two decades. In our preliminary work, we have found that older women are interested in chemotherapy even for small returns in survival extension. However, cognitive impairment has been demonstrated in most studies of breast cancer systemic treatments, but virtually all of this research has been conducted in younger populations. Since aging itself is associated with cognitive declines, it seems very likely that older women are particularly vulnerable to the adverse cognitive effects of systemic therapy; our preliminary work strongly suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients and it will provide the basis for the next generation of mechanistic, treatment and intervention studies. These will be important since data from younger patients cannot be directly translated into the older population. We will use the vulnerability model of cancer survivorship to prospectively describe systemic therapy effects on cognition in older breast cancer patients over a 12 month period, test associations between cognition and quality of life (QOL) and to evaluate whether polymorphisms in the APOE gene moderate cognitive outcomes. To achieve our objectives, we have assembled a multi-disciplinary team of oncologists, geriatricians, neurologists, neuro- and cognitive psychologists, behavioral scientists and consumers from Lombardi Comprehensive Cancer Center (LCCC), Memorial Sloan-Kettering Cancer Center (MSKCC), Boston University (BU) and Y-Me (a national consumer advocacy organization). This team will work together to prospectively enroll 325 newly diagnosed older breast cancer cases from LCCC and MSKCC, tertiary referral centers with high volumes. BU will coordinate cognitive testing protocols. We will recruit an equal number of non-cancer friend controls. We have chosen friend controls since they will be similar to patients in most ways except for exposure to cancer and its treatments and they should be motivated to participate. If friends are not available, we will recruit controls matched to cases on age, education, race, and area (DC/NY). We will administer baseline neuropsychological testing prior to any systemic treatment (or at enrollment for controls), survey women about subjective cognitive function, psychosocial factors, QOL and activities of daily living (IADLS). We will abstract clinical data from medical records. We will obtain blood to test for APOE polymorphisms at enrollment; these results will not be provided to participants since this is considered a research test). We conduct follow-up interviews and repeat the neuropsychological testing 12 months after baseline assessment; this time point corresponds to 3-6 months post-treatment among women who receive chemotherapy. Our primary cognitive outcome will be change in summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. In secondary analyses we examine changes in scores on 4 additional domains to assess broader cognitive function and examine questions of differential impact: Language; Executive Functioning; Learning and Memory; Visual-spatial. Data from this study will guide future interventions to better select older women for whom the benefits of systemic therapy outweigh the harms and to develop approaches to mitigate negative consequences of systemic treatment when it is indicated, improving the quality of care for the growing population of older breast cancer patients.