Living beyond cancer: the short- and long-term cognitive effects of breast cancer and its treatment for cancer survivors

超越癌症的生活：乳腺癌的短期和长期认知影响及其对癌症幸存者的治疗

• 批准号: 10570360
• 负责人: Cheng Peng
• 金额: $ 13.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570360
• 关键词: ABCB1 gene; Acceleration; Address; Adherence; Affect; Aftercare; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Antineoplastic Agents; Area; Attenuated; Brain; Breast Cancer Treatment; Breast Cancer survivor; Cancer Etiology; Cancer Survivor; Cancer Survivorship; Caring; Clinical Research; Cognition; Cognitive; Diagnosis; Diagnostic; Disease; Drug Transport; Elderly; Epidemiology; Etiology; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genomic Instability; Genomics; Goals; Healthy Eating; Heritability; Human; Impaired cognition; Incidence; Inflammation; Interdisciplinary Study; Intervention; Investigation; Joints; Life Style; Long-Term Effects; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediterranean Diet; Mitochondria; Molecular; Mutation; Nurses' Health Study; Observational Study; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Physical activity; Population; Population Study; Positioning Attribute; Proliferating; Quality of life; Radiation; Radiation therapy; Recording of previous events; Regulation; Reporting; Research; Research Personnel; Resources; Risk; Role; Statistical Models; Strategic vision; Subgroup; Survival Rate; Survivors; TP53 gene; Tamoxifen; Time; Toxicity due to chemotherapy; Training; Woman; acute toxicity; aging brain; aging population; anticancer research; blood-brain barrier crossing; brain tissue; breast cancer diagnosis; cancer care; cancer diagnosis; cancer therapy; chemobrain; chemotherapy; cognitive function; cognitive testing; experience; follow-up; genetic analysis; good diet; high risk; hormone receptor-negative; hormone therapy; human old age (65+); improved; indexing; malignant breast neoplasm; molecular subtypes; neural repair; oxidation; pluripotency; prevent; prospective; risk prediction; skill acquisition; trait; transcriptomics

PROJECT SUMMARY With the rapidly aging population and improved survival rate, the number of breast cancer survivors in the U.S. is projected to reach 4.4 million by 2030, among which more than 60% of them will be aged ≥65 years. A key issue facing older cancer survivors is the impact of cancer and its treatment on their cognition. Cancer and brain aging have both common and distinct etiologies. For example, shared germline genetic heritability was identified between breast cancer and Alzheimer’s disease (AD) in large cross-trait genetic analyses, while other studies showed differential regulation of p53 and Pin1 in cancer and AD. Compelling clinical and observational studies report deficits in cognitive functioning in women diagnosed and treated for breast cancer over the short-term (<2 years), and consistently support acute toxicity of chemotherapies on cognition (i.e., chemo-brain). In contrast, population studies, often with long follow-up (>10 years), show lower incidence of AD in cancer survivors compared with cancer-free controls. While these inverse associations have persisted in studies with attempts to reduce diagnostic and competing risk biases, the possibility of survival bias, which would increase with time since cancer diagnosis, cannot be ruled out. Until we can determine how breast cancer and its treatment (chemotherapy, radiation, and hormone therapy) affect cognitive trajectory, we will not be able to improve quality of life and care for breast cancer survivors. However, most previous research is limited by a lack of (a) consideration of both the short- and long-term effect of breast cancer on cognition (which may reduce survival bias for breast cancer with a 5-year relative survival rate of 90%); (b) repeated global and domain specific cognition measures before and after treatment; (c) focus on the role of post-diagnostic lifestyles in the treatment- cognition relation; (d) investigation of gene-treatment interactions; (e) and identification of shared and distinct molecular etiologies of cancer and AD. The overarching goal of this proposal is to comprehensively determine the association of breast cancer diagnosis and treatment with cognitive trajectory over time, and identify the intersection of cancer hallmark pathways with AD to inform targeted intervention. This proposal leverages the unique resources from the Nurses’ Health Study with follow-up of 3,120 breast cancer survivors for >30 years, and repeatedly collected objective cognitive assessments; and the Gene Expression Omnibus with 2,520 human brain transcriptomics on AD patients and controls, and addresses the following hypothesis: (1) Women diagnosed and treated with cancer experience more rapid cognitive decline over the short-term, and (2) Cancer hallmarks of genomic instability, oxidative stress and inflammation are shared mechanisms between cancer and AD, but the hallmarks of proliferation and cellular pluripotency are differentially regulated. Dr. Peng plans to receive training in areas of aging research, cancer survivorship, advanced statistical modeling, and professional skill development. Together, the scientific and training components of this K01 will position Dr. Peng to become an independent interdisciplinary investigator specialized in the integration of aging and cancer research.

项目摘要 随着人口迅速衰老和存活率的提高，美国的乳腺癌存活率数量 预计到2030年将达到440万，其中60％以上的年龄≥65岁。钥匙 癌症生存的问题面临的问题是癌症及其治疗对认知的影响。癌症和大脑 衰老具有常见和不同的病因。例如，确定了共享的种系遗传遗传力 在乳腺癌和阿尔茨海默氏病（AD）中，在大型跨特征遗传分析中 在癌症和AD中显示了p53和PIN1的差异调节。引人入胜的临床和观察性研究 报告定义了在短期内被诊断和治疗乳腺癌的妇女的认知功能（<2） 年），并始终支持化学疗法对认知的急性毒性（即化学脑）。相比之下， 人口研究通常进行长期随访（> 10年），显示AD在癌症幸存者中的较低事件 与无癌症对照相比。尽管这些逆关联一直在研究中，但 减少诊断和竞争风险偏见，生存偏见的可能性，这会随着时间而增加 由于癌症的诊断，不能排除。直到我们可以确定乳腺癌及其治疗方式 （化学疗法，放射线和骑马疗法）影响认知轨迹，我们将无法提高质量 乳腺癌生存的生活和护理。但是，大多数以前的研究受到缺乏（a）的限制 考虑乳腺癌对认知的短期和长期影响（这可能会降低生存率） 乳腺癌的偏见为5年，相对存活率为90％）； （b）重复全局和域特异性 治疗前后的认知措施； （c）关注诊断后生活方式在治疗中的作用 - 认知关系； （d）研究基因处理相互作用； （e）并识别共享和独特的 癌症和AD的分子病因。该提案的总体目标是全面确定 随着时间的流逝，乳腺癌诊断和治疗与认知轨迹的关联，并确定 癌症标志途径与AD的交集，以告知有针对性的干预措施。该提议利用了 护士健康研究的独特资源，随访了3,120个乳腺癌生存超过30年， 并反复收集客观的认知评估；和2,520人类的基因表达综合 广告患者和对照组的脑转录组学，并解决以下假设：（1）女性 在短期内被诊断和治疗的癌症经验更快地认知下降，（2）癌症 基因组不稳定性，氧化应激和炎症的标志是癌症和 AD，但是增殖和细胞多能的标志受到不同的调节。彭博士计划 接受衰老研究，癌症生存，高级统计建模和专业领域的培训 技能发展。该K01的科学和培训组成部分一起将彭博士定位为 独立的跨学科研究人员，专门研究衰老和癌症研究的整合。