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.

项目总结 随着人口迅速老龄化和生存率的提高，美国乳腺癌幸存者的数量。 预计到2030年将达到440万人，其中超过60%的人将年龄在≥65岁。一把钥匙 老年癌症幸存者面临的问题是癌症及其治疗对他们认知的影响。癌症与脑 衰老既有共同的也有不同的病因。例如，确定了共享的生殖系遗传遗传力 在大型跨性状遗传分析中乳腺癌和阿尔茨海默病(AD)之间的关系，而其他研究 P53和Pin1在肿瘤和AD中的表达存在差异。引人注目的临床和观察性研究 报告短期内诊断和治疗乳腺癌的女性的认知功能缺陷(&lt；2 多年)，并一贯支持化疗对认知的急性毒性(即，化学脑)。相比之下， 人群研究，通常有长期的随访(&gt；10年)，表明癌症幸存者中AD的发病率较低 与非癌症对照组相比。虽然这些反向关联在研究中持续存在，试图 减少诊断和竞争风险偏差、生存偏差的可能性，这种偏差将随着时间的推移而增加 既然确诊为癌症，就不能排除。直到我们能够确定乳腺癌及其治疗 (化疗、放射和激素治疗)影响认知轨迹，我们将无法提高质量 生命和对乳腺癌幸存者的关怀。然而，以前的大多数研究都受到缺乏(A)的限制 同时考虑乳腺癌对认知的短期和长期影响(这可能会降低存活率 对5年相对生存率为90%的乳腺癌的偏见)；(B)重复的全球和特定领域 治疗前后的认知措施；(C)侧重于诊断后的生活方式在治疗中的作用-- 认知关系；(D)基因治疗相互作用的调查；(E)共享和不同的识别 癌症和阿尔茨海默病的分子病因。这项提案的总目标是全面确定 乳腺癌的诊断和治疗与随时间推移的认知轨迹的关联，并确定 癌症标志性通路与阿尔茨海默病的交叉，以提供有针对性的干预。这项提议充分利用了 来自护士健康研究的独特资源，对3120名乳腺癌幸存者进行了30年的跟踪调查， 并反复收集客观的认知评估；以及2520名人类的基因表达总览 AD患者和对照组的脑转录转录，并解决了以下假设：(1)女性 诊断和治疗癌症的人在短期内认知能力下降更快，以及(2)癌症 基因组不稳定、氧化应激和炎症的特征是癌症和 AD，但增殖和细胞多能性的特征是不同的调节。彭博士计划 接受老龄化研究、癌症存活率、高级统计建模和专业领域的培训 技能发展。总而言之，K01的科学和培训部分将使彭博士成为 一个独立的跨学科研究人员，专门从事衰老和癌症研究的整合。