Characterizing the role of adolescent physical activity in early onset breast cancer risk for women across the familial risk continuum

项目总结 早发性乳腺癌(BC)的发病率在全球范围内急剧上升，包括在美国 增幅最大的是年轻的非西班牙裔黑人(NHB)女性。确定以下可修改的原因 早发性结肠炎对于减少健康不平等至关重要，这是公共卫生和预防结肠炎的首要任务，以及 解决了NCI 2020年关于40岁以下成年人癌症病因的挑衅性问题之一。 成年后的体力活动是癌症和肿瘤形成的长期潜伏期的既定风险因素 提示青春期的体力活动可能在早发性BC的发生发展中起重要作用。 然而，目前支持这一点的流行病学数据有限，特别是来自不同种族队列的数据。它 至关重要的是，我们必须解决证据基础中的这一重大差距。这项研究的首要目标是阐明 青少年体力活动在早发性BC风险和转归中的作用，包括 体育活动影响青春期女孩和年轻女性的乳房组织生物标记物。目标1(K99)将评估 年轻女性青少年体力活动与早发性BC风险和确诊后预后的关系 在BC易感性的连续统一体中，使用结合因果方法的生存建模方法， 包括孟德尔随机化和兄弟姐妹集分析。这一目标将使用来自不同种族的现有数据 以家庭为基础的31,640名妇女，其中包括7,703人(1,422人)，其中包括BC家族史(BCFH) NHB或西班牙裔)50岁前诊断为BC的妇女(40岁前诊断为3,108人)。目标2(K99)将 确定体力活动是否与青春期女孩患高血压的中间标志有关，包括 通过光学光谱(OS)测量乳房发育的时间和乳房组织成分(BTC)。这 AIM将使用来自两个青少年队列的现有预期数据，其中包括1040名女孩的多民族队列 这对BCFH和纽约市216名NHB和西班牙裔女孩来说是丰富的。AIM 3(R00)将评估是否 青少年体力活动与青少年乳房组织的结构和代谢差异有关 40岁以下的女性，并确定这些变化是否与早发性BC风险有关。这一目标将是 通过对150名40岁以下女性进行病例对照研究，在独立的R00阶段完成， 新诊断的BC和300名匹配的对照组(样本≥50%NHB或西班牙裔)。BTC将以 使用OS和乳房X光摄影的病例和对照。总而言之，这项研究将提供最全面的 到目前为止对青少年体力活动和早发性BC的评估，这是推动BC领域所需的 为早期高危人群制定新的干预策略的预防研究进展 发病的疾病。这项研究将得到分子和遗传学方面的经验和传授培训的补充。 流行病学、高级统计方法、体力活动研究、干预设计以及职业生涯 发展活动。因此，K99/R00奖项将有助于实现领导和 研究癌症风险修饰物的独立研究计划，这些修饰物可以接受早期生活干预。

PROJECT SUMMARY Early onset breast cancer (BC) incidence has increased dramatically worldwide, including in the U.S. where the greatest increase has occurred in young non-Hispanic Black (NHB) women. Identifying the modifiable causes of early onset BC is critical for reducing health inequities, a top priority for public health and BC prevention, and addresses one of the NCI’s 2020 provocative questions on the etiology of cancers in adults under age 40. Physical activity in adulthood is an established risk factor for cancer, and the long latency of tumorigenesis suggests that physical activity in adolescence may play an important role in the development of early onset BC. However, there is currently limited epidemiologic data, especially from racially diverse cohorts, to support this. It is essential that we address this major gap in the evidence-base. The overarching goal of this study is to elucidate the role of adolescent physical activity in the risk of and outcomes from early onset BC, including whether physical activity impacts breast tissue biomarkers in adolescent girls and young women. Aim 1 (K99) will evaluate adolescent physical activity in association with early onset BC risk and outcomes after diagnosis in young women across the continuum of BC susceptibility using survival modeling approaches coupled with causal methods, including Mendelian randomization and sibling set analyses. This aim will use existing data from a racially diverse family-based cohort of 31,640 women that is enriched for BC family history (BCFH) and includes 7,703 (1,422 NHB or Hispanic) women diagnosed with BC before age 50 (3,108 diagnosed before age 40). Aim 2 (K99) will determine if physical activity is associated with intermediate markers of BC risk in adolescent girls, including timing of breast development and breast tissue composition (BTC) measured by optical spectroscopy (OS). This aim will use existing prospective data from two adolescent cohorts, including a multiethnic cohort of 1,040 girls that is enriched for BCFH and a cohort of 216 NHB and Hispanic girls in NYC. Aim 3 (R00) will evaluate if adolescent physical activity is associated with structural and metabolic differences in the breast tissue of young women under age 40 and determine if these alterations are associated with early onset BC risk. This aim will be completed during the independent R00 phase by conducting a case-control study in 150 women under age 40, newly diagnosed with BC, and 300 matched controls (sample ≥50% NHB or Hispanic). BTC will be measured in cases and controls using OS and mammography. Taken together, this study will provide the most comprehensive evaluation of adolescent physical activity and early onset BC to date, which is needed to move the field of BC prevention research forward in developing novel intervention strategies for populations at increased risk of early onset disease. This research will be complemented by experiential and didactic training in molecular and genetic epidemiology, advanced statistical methods, physical activity research, and intervention design, as well as career development activities. This K99/R00 award will thus facilitate the long-term career objective of leading an independent research program studying modifiers of cancer risk that are amenable to early life intervention.