Long-Term Trajectories of Accelerated Biological Aging and Functional Decline Associated with Breast Cancer and its Treatment

与乳腺癌及其治疗相关的加速生物衰老和功能衰退的长期轨迹

• 批准号: 10729432
• 负责人: Alexandra Margaret Lynn Binder
• 金额: $ 65.7万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729432
• 关键词: Acceleration; Address; Adjuvant Therapy; Adult; Adverse effects; Affect; Aftercare; Age; Aging; Anthracycline; Biological; Biological Aging; Biological Assay; Biology of Aging; Blood specimen; Breast Cancer Patient; Breast Cancer survivor; Cancer Survivor; Caring; Characteristics; Childhood Cancer Survivor Study; Chronology; Clinical; DNA Methylation; Data; Diagnosis; Epigenetic Process; Ethnic Origin; Follow-Up Studies; Future; Goals; Health; Impairment; Intervention; Life Style; Long-Term Survivors; Longevity; Longterm Follow-up; Malignant Neoplasms; Measures; Modality; Molecular; Morbidity - disease rate; National Cancer Institute; Nutritional; Operative Surgical Procedures; Patient Care; Patient Self-Report; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physical Function; Physical Performance; Physiological; Population; Postmenopause; Pre-Clinical Model; Race; Radiation; Recording of previous events; Rejuvenation; Research; Risk; Severities; Survival Rate; Survivors; Testing; Time; Toxic effect; United States; Variant; Woman; Women' s Health; Work; age related; anticancer research; biomarker validation; breast cancer diagnosis; cancer diagnosis; cancer therapy; chemoradiation; clinical diagnosis; cohort; comparison control; design; experience; frailty; functional decline; functional status; hazard; healthspan; human old age (65+); indexing; malignant breast neoplasm; mortality; multidisciplinary; optimal treatments; performance tests; personalized intervention; premature; survivorship; treatment duration

PROJECT SUMMARY/ABSTRACT More than 3.8 million women living in the United States have a history of invasive breast cancer, a majority of whom are over age 65. With 15-year survival rates exceeding 80%, older breast cancer survivors are a growing population with distinct health considerations relative to patterns of usual aging. Cancer survivors are at an increased risk of age-related conditions, but little is known about the trajectories of aging that underlie this elevated risk, or factors affecting the severity of decline. Evidence from preclinical models suggest cancer treatment contributes to molecular and cellular changes consistent with aging that may underlie the later emergence of functional decline. Frailty is highly prevalent in breast cancer patients and is associated with a greater hazard of long-term morbidity and mortality. Epigenetic age acceleration is an indicator of biologic aging that is influenced by cancer and its treatment, and also a strong predictor of healthspan and lifespan. We hypothesize that cancer and its treatment will contribute to accelerated trajectories of functional and epigenetic aging relative to women without a history of cancer, that these changes will be sustained long-term, and vary by treatment type and intensity. To test these hypotheses, we will combine three decades of pre- and post- diagnosis clinical, self-reported, and physiological data from post-menopausal women in the Women’s Health Initiative (WHI), including annual assessments of functional status in over 9,000 breast cancer survivors matched by age to cancer-free controls. We will estimate epigenetic age from blood samples collected at multiple pre- and post-treatment time points in a subset of breast cancer survivors and ‘usual aging’ controls. With this unique data and multidisciplinary team of relevant experts, we will conduct the first large study with long-term, longitudinal measures of epigenetic and functional aging before and after breast cancer diagnosis and treatment, addressing the following specific aims: 1) Characterize long-term trajectories of physical function in breast cancer survivors (v. usual aging in controls) and test whether they are modified by the type and intensity of cancer treatments; 2) Examine whether breast cancer and its treatment increase the rate of epigenetic aging and whether this aging continues to accelerate after treatment; and 3) Test the relationship between the rate of epigenetic aging and functional decline and how it may differ between breast cancer survivors and usual aging controls. This work is a critical first step to characterize predictors of aging trajectories among cancer survivors and identify those who could benefit from supportive interventions to maximize healthspan in this rapidly growing population.

项目摘要/摘要 超过380万生活在美国的女性有浸润性乳腺癌的病史，其中大多数是女性。 65岁以上的人。随着15年生存率超过80%，老年乳腺癌幸存者是一个 不断增长的人口，相对于通常的老龄化模式，有不同的健康考虑。癌症幸存者 与年龄有关的疾病的风险增加，但对衰老的轨迹知之甚少， 这种升高的风险，或影响因素的严重程度下降。来自临床前模型的证据表明癌症 治疗有助于与衰老一致的分子和细胞变化，这可能是后者的基础。 出现功能性衰退。虚弱在乳腺癌患者中非常普遍，并且与乳腺癌的发病有关。 长期发病率和死亡率的风险更大。表观遗传年龄加速是生物学的一个指标， 癌症及其治疗对衰老的影响，也是健康和寿命的有力预测因素。我们 假设癌症及其治疗将有助于加速功能和表观遗传的轨迹， 相对于没有癌症史的女性而言，这些变化将长期持续，并且随着年龄的增长而变化。 治疗类型和强度。为了验证这些假设，我们将结合联合收割机三十年前和后， 妇女健康杂志中绝经后妇女的临床、自我报告和生理数据 倡议（WHI），包括对9，000多名乳腺癌幸存者的功能状态进行年度评估 年龄与无癌症对照组相匹配。我们将从收集的血液样本中估计表观遗传年龄， 在乳腺癌幸存者和“正常衰老”对照组的一个子集中的多个治疗前和治疗后时间点。 有了这些独特的数据和多学科的相关专家团队，我们将进行第一次大型研究， 乳腺癌诊断前后表观遗传和功能老化的长期纵向测量 治疗，解决以下具体目标：1）表征长期的物理轨迹 功能在乳腺癌幸存者（对照组中的正常老化），并测试它们是否被类型改变 和癌症治疗的强度; 2）检查乳腺癌及其治疗是否会增加 表观遗传衰老以及这种衰老在治疗后是否继续加速;以及3）测试与衰老之间的关系。 表观遗传衰老和功能衰退的速度之间的关系，以及乳腺癌和乳腺癌之间的差异， 幸存者和正常老化对照。这项工作是描述衰老预测因素的关键的第一步 癌症幸存者的发展轨迹，并确定那些可以从支持性干预中受益的人， 在这个快速增长的人口中最大限度地延长健康寿命。