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

项目摘要 随着人口的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%的人年龄≥65岁。一个关键 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。癌症和大脑 衰老有共同的和不同的病因。例如，确定了共有的生殖系遗传力， 乳腺癌和阿尔茨海默病（AD）之间的大型跨性状遗传分析，而其他研究 显示p53和Pin 1在癌症和AD中的差异调节。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认知功能缺陷（<2 年），并一致支持化疗对认知的急性毒性（即，化学脑）。与此相反， 人群研究，通常有长期随访（>10年），显示癌症幸存者的AD发病率较低 与无癌对照组相比。虽然这些反向关联一直存在于试图 减少诊断和竞争风险偏差，生存偏差的可能性，这将随着时间的推移而增加 因为癌症诊断，不能排除。在我们确定乳腺癌及其治疗 （化疗、放疗和激素治疗）影响认知轨迹，我们将无法提高质量 乳腺癌幸存者的生活和护理。然而，大多数以前的研究是有限的，缺乏（a） 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） 5年相对存活率为90%的乳腺癌偏倚）;（B）重复的全局和域特异性 治疗前后的认知测量;（c）侧重于诊断后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）和识别共享和独特的 癌症和AD的分子病因学。本提案的总体目标是全面确定 乳腺癌诊断和治疗与认知轨迹随时间的关系，并确定 癌症标志性途径与AD的交叉点，为靶向干预提供信息。该提案利用了 来自护士健康研究的独特资源，对3，120名乳腺癌幸存者进行了超过30年的随访， 并反复收集客观认知评估;基因表达综合数据库有2,520名人类 AD患者和对照组的脑转录组学，并解决了以下假设：（1）女性 被诊断和治疗的癌症患者在短期内经历更快的认知能力下降，以及（2）癌症 基因组不稳定性、氧化应激和炎症的标志是癌症和炎症之间的共同机制。 AD，但增殖和细胞多能性的标志是差异调节的。彭博士计划 接受老龄化研究，癌症生存，高级统计建模和专业领域的培训 技能发展。总之，K 01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老龄化和癌症研究的整合。

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.