A longitudinal, nationally representative study of cognition-related effects of breast cancer and its treatment

摘要 更多的乳腺癌患者接受抗雌激素药物治疗，如芳香酶抑制剂（AI），而不是 除了手术以外的任何治疗由于其有效性，最近的指南绝经后妇女 建议将人工智能治疗延长至10年。因此，在超过350万的AI中， 乳腺癌幸存者将很快增加。乳腺癌幸存者的一个主要问题是治疗引起的 认知功能障碍大约75%的女性在化疗期间遭受癌症相关的认知障碍 治疗，持续数月至数年。有理论和经验的理由相信， 雌激素缺乏也可能发生认知损害。令人惊讶的是，很少有经验主义的人类 AI对认知影响的研究;没有认知测量癌前。利用18年的数据， 健康和退休研究-一项全国代表性的纵向调查， 医学和制药索赔，我们提出了一个纵向研究，旨在：（1）表征乳房 癌症幸存者在开始辅助AI治疗后60个月内的认知功能， 验证的神经心理学措施，并比较他们的表现与（i）妇女与事件 未接受AI治疗的乳腺癌患者和（ii）非癌症对照。横断面分析 对应于AI治疗开始后大约一年、三年和五年， （2）对比认知功能的纵向轨迹， 接受AI治疗的女性与（i）未接受AI治疗的癌症幸存者之间的癌症诊断和治疗 接受AI治疗和（ii）无癌症对照，超过18年。我们预计， 在研究期间无癌症女性的认知功能。然而，AI集团预计将 在AI启动后表现出更陡的下降斜率，表明AI对上述认知产生不利影响， 超越正常认知老化;（3）量化总体和无病寿命年之间的权衡， 接受不同辅助治疗的乳腺癌女性患者的认知功能。使用 目标2的结果结合至疾病复发时间和时间分析的参数估计值 我们将通过认知功能计算各种情况下的总体和无病寿命年， 患者的社会人口学特征和癌症治疗。这些分析的结果将提供 关于人工智能暴露对认知的潜在不利影响的严格证据， 临床干预的基础。他们还将产生人口水平的生存和认知的估计 由于AI和其他癌症治疗（超出正常认知老化）而导致的衰退， 更好地告知患者不同乳腺癌治疗的“真实的世界”权衡。最后，我们的结果将 对于所有有兴趣更好地了解癌症相关认知障碍的挑战的人来说都很重要 并改善大量且不断增长的乳腺癌幸存者的功能和生活质量。

ABSTRACT More breast cancer patients are treated with anti-estrogen agents, such as aromatase inhibitors (AIs), than with any treatment other than surgery. Due to their effectiveness, recent guidelines for postmenopausal women advise extending AI therapy to 10-years duration. Therefore, exposure to AIs among the more than 3.5 million breast cancer survivors will soon increase. A major concern of breast cancer survivors is therapy-induced cognitive dysfunction. About 75% of women suffer cancer-related cognitive impairment during chemotherapy treatment, which persists for months to years. There are theoretical and empirical reasons to believe that cognitive impairment may also occur with estrogen deprivation. Surprisingly, there are few empirical human studies of AI effects on cognition; none with cognition measured pre-cancer. Leveraging 18 years of data from the Health and Retirement Studies―a nationally-representative, longitudinal survey augmented by Medicare medical and pharmaceutical claims, we propose a longitudinal study designed to: (1) Characterize breast cancer survivors’ cognitive functioning post-initiation of adjuvant AI therapy over a 60-month period using a validated neuropsychological measure and compare their performance to those of (i) women with incident breast cancer who did not receive AI therapy and (ii) non-cancer controls. Cross-sectional analyses corresponding to roughly one-, three-, and five years post-AI therapy initiation will provide estimates of early and late effects of AIs; (2) Contrast the longitudinal trajectory of cognitive functioning preceding and following cancer diagnosis and treatment among women treated with an AI to those of (i) cancer survivors who did not receive AI therapy and (ii) cancer-free controls, over an 18-year span. We anticipate a gradual decline in cognitive functioning among cancer-free women over the study period. The AI group, however, is expected to exhibit a steeper downward slope after AI initiation, indicating an adverse AI effect on cognition above and beyond normal cognitive aging; and (3) Quantify the tradeoff between overall and disease-free life years and cognitive functioning among women with incident breast cancer undergoing different adjuvant therapies. Using findings from Aim 2 combined with parameter estimates from analyses of time to disease recurrence and time to death, we will calculate overall and disease-free life years by cognitive functioning for various scenarios of patients’ sociodemographic characteristics and cancer treatment(s). Results from these analyses will provide rigorous evidence regarding the potentially adverse effects of AI exposure on cognition that may serve as the basis for clinical interventions. They will also generate population-level estimates of survival and cognitive decline attributable to AI and other cancer-treatments (beyond normal cognitive aging) that could be used to better inform patients about “real world” tradeoffs of different breast cancer treatments. Finally, our results will be important for all interested in the challenges of better understanding cancer-related cognitive impairment and improving the functioning and quality of life of the large and growing number of breast cancer survivors.