Integrating Mammograms in Analyses of Genes and Environment in Sisters (IMAGES)

摘要 准确的乳腺癌风险评估有可能区分出哪些女性需要 加强筛查，预防或降低风险的治疗和手术，从妇女在较低的风险，谁可以 不采取干预措施，好处不大，可能造成伤害。乳腺癌风险评估目前 由于现有风险预测模型的精确度和准确度有限而受到阻碍。有以下家族史的女性 乳腺癌（FHBC）最需要更好的风险评估，因为他们经常接受相同的临床 尽管FHBC的程度在潜在风险中存在很大的异质性，一体化 乳房X线摄影乳腺密度（MBD）是乳腺癌的一个强而易评估的风险因素， 结合详细的FHBC数据，为加强现有的风险评估提供了一个绝佳的机会 方法. MBD通常随年龄增长而下降，但女性之间的变化率差异很大， 可能对乳腺癌风险特别重要;我们已经证明， 随着时间的推移，MBD比MBD下降的女性更有可能被诊断出患有乳腺癌。 通过引入MBD来改进风险预测模型的尝试取得了有限的成功，因为研究 使用MBD的一次性测量，主要包括绝经后妇女， 可能已经发生了。我们建议调查在10- 20岁之间MBD的个体内变化， FHBC（目标1）的程度与乳腺癌发病率的关系，并评估 MBD可能会改善几个临床风险预测模型（目标2）和临床风险分层形成的基础 进行基于风险的监测和预防护理（目标3）。我们将在美国的基础上实现这些目标。 姐妹研究，一项前瞻性队列研究，包括50，884名女性，其中一名或多名姐妹篇被诊断患有乳腺癌 在2003-2009年入组时个人无乳腺癌;每年进行积极的随访， 每个女人都至少十年使用嵌套病例对照设计，我们将检索现有的乳房X线照片 对于年龄≤ 60岁时诊断的所有乳腺癌病例（迄今为止n= 1，242例病例）和对照组 年龄和入组年份匹配（在病例识别时，每例病例选择2例对照）。我们将 使用临床可用的定性指标对MBD进行全面评估， 临床实践，并评估定量措施，允许测量较小的变化， MBD的不同组分（例如，致密、非致密组织），这些组织独立地与乳腺癌相关 癌症风险。我们团队在领导MBD研究方面的经验和姐妹研究中的前瞻性可用数据 研究将提供一个无与伦比的调查，前瞻性MBD的变化与乳腺癌的风险， 改变和遗传因素，以及如何利用这些信息来加强妇女的风险评估， FHBC。这些结果对于为个性化的基于风险的监测和预防计划提供信息是必要的。

ABSTRACT Accurate breast cancer risk assessment has the potential to distinguish women at higher risk who need enhanced screening, preventive or risk-reducing therapies and surgeries from women at lower risk who can be spared interventions that yield little benefit and may cause harm. Breast cancer risk assessment is currently hampered by limited precision and accuracy of existing risk prediction models. Women with a family history of breast (FHBC) have the greatest need for better risk assessment as they often receive the same clinical recommendations despite substantial heterogeneity in the underlying risk by the extent of FHBC. Integration of mammographic breast density (MBD), a strong and readily assessable risk factor for breast cancer, in combination with detailed FHBC data, offers an exceptional opportunity for enhancing existing risk assessment methods. MBD generally declines with age, but the rate of change varies considerably between women, and may be particularly important to breast cancer risk; we have demonstrated that women who remain at high MBD over time are more likely to be diagnosed with breast cancer than women whose MBD decreases. Attempts to improve risk prediction models by incorporating MBD has had limited success as studies have used one-time measures of MBD and included mostly postmenopausal women for whom the largest changes in MBD may have already occurred. We propose to investigate within-individual changes in MBD over a 10- year period in relation to incident breast cancer by the extent of FHBC (Aim 1), and evaluate how changes in MBD may improve several clinical risk prediction models (Aim 2) and clinical risk stratification forming the basis for risk-based surveillance and preventive care (Aim 3). We will address these aims by building upon the U.S. Sister Study, a prospective cohort of 50,884 women with one or more sisters diagnosed with breast cancer who were personally breast cancer-free at enrollment in 2003-2009; active annual follow-up is conducted for at least 10 years with each woman. Using a nested case-control design, we will retrieve existing mammograms for all incident breast cancer cases diagnosed at ages ≤ 60 years (n=1,242 cases to date) and controls matched on age and enrollment year (2 controls selected per case at the time of case identification). We will undertake a comprehensive assessment of MBD, using both clinically available qualitative measures used in clinical practice, and assessing quantitative measures that allow for measurement of smaller changes and different components of MBD (e.g., dense, nondense tissue) that are independently associated with breast cancer risk. Our team’s experience in leading studies of MBD and prospective available data in the Sister Study will afford an unparalleled investigation of prospective MBD changes in relation to breast cancer risk, modifiable and genetic factors, and how to use this information to enhance risk assessment in women with FHBC. These results are necessary to inform personalized risk-based surveillance and prevention programs.