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

项目摘要 早发性乳腺癌（BC）的发病率在世界范围内急剧增加，包括在美国， 最大的增长发生在年轻的非西班牙裔黑人（NHB）妇女。确定可改变的原因 早发型BC对于减少卫生不公平至关重要，是公共卫生和BC预防的首要任务， 解决了NCI 2020年关于40岁以下成人癌症病因学的挑衅性问题之一。 成年期的体力活动是癌症的一个既定危险因素， 提示青少年时期的体力活动可能在早发性BC的发展中起重要作用。 然而，目前支持这一观点的流行病学数据有限，特别是来自种族多样性队列的数据。它 我们必须解决证据基础中的这一重大差距。本研究的总体目标是阐明 青少年体力活动在早发性BC的风险和结果中的作用，包括是否 体力活动影响青春期女孩和年轻妇女的乳腺组织生物标志物。目标1（K99）将评估 青少年体力活动与年轻女性诊断后早发性BC风险和结果相关 在BC易感性的连续体中，使用生存建模方法结合因果方法， 包括孟德尔随机化和同胞集分析。这一目标将使用来自不同种族的现有数据， 一个以家庭为基础的队列，包括31，640名妇女，该队列富含BC家族史（BCFH），包括7，703名（1，422 NHB或西班牙裔）女性在50岁之前被诊断患有BC（3，108人在40岁之前被诊断）。目标2（K99）将 确定体力活动是否与青春期女孩BC风险的中间标志物相关，包括 乳房发育的时间和通过光学光谱（OS）测量的乳房组织组成（BTC）。这 aim将使用来自两个青少年队列的现有前瞻性数据，其中包括一个由1,040名女孩组成的多种族队列 这是丰富的BCFH和216 NHB和西班牙裔女孩在纽约市的队列。目标3（R 00）将评价是否 青少年的身体活动与年轻人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 在独立的R 00阶段完成，在150名40岁以下的妇女中进行病例对照研究， 新诊断为BC的患者和300名匹配的对照（样本≥50% NHB或西班牙裔）。BTC将以 使用OS和乳腺X射线摄影的病例和对照。总之，这项研究将提供最全面的 评估青少年的身体活动和早发性BC到目前为止，这是需要移动BC领域 预防研究在为早期癌症风险增加的人群制定新的干预策略方面取得了进展 发病这项研究将辅之以分子和遗传学方面的经验和教学培训。 流行病学，先进的统计方法，身体活动研究和干预设计，以及职业生涯 发展活动。因此，K99/R 00奖项将有助于实现领导一个 一个独立的研究项目，研究癌症风险的改变因素，这些因素适合于早期生活干预。

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.