Biomarkers and Breast Cancer Risk Prediction in Younger Women

描述(由申请人提供)：背景：这项建议的目标是通过增加生物标记物(睾酮或游离睾酮和/或苗勒氏抑制物质(MIS))来改善35-49岁女性的Gail乳腺癌风险预测模型2的性能。在迄今为止的唯一一项前瞻性研究中，仅在绝经前女性中检测到的MI与绝经前和绝经后乳腺癌风险的大幅增加有关(OR=9.8，最高四分位数与最低四分位数的95%CI=3.3至28.9)。绝经前的睾酮水平和游离睾酮水平也一直被证明与绝经前和绝经后乳腺癌风险的增加呈正相关。所有这三种生物标志物在月经周期中变化很小，测量成本相对较低，并且具有良好的时间可靠性，即一次测量合理地代表了女性的长期平均水平，使它们成为纳入风险预测模型的良好候选者。目的：1)评估绝经前女性血清睾丸素水平与乳腺癌风险的关系；2)评估在Gail模型2中加入生物标志物(睾酮或游离睾酮，和/或女性女性信息系统)是否能改善该模型对35-49岁女性的预测效果。方法：这项研究将使用8个前瞻性队列的资源，这些队列收集了健康年轻女性的血清或血浆，并对她们进行了乳腺癌发病率的跟踪调查(Breakthrough Generes Study；CLUE II；哥伦比亚大学MO血清库；格恩西队列；护士健康研究II；纽约大学妇女健康研究；瑞典北部乳房筛查研究；Ordet)。对于目标1，将进行1：2嵌套病例：对照研究(2500例)。对于目标2，除了包括在Gail模型2中的因素(年龄、初潮年龄、首次活产年龄、以前的乳腺活检次数和有乳腺癌病史的一级亲属的数量)之外，包括一个或两个生物标志物的风险预测模型的性能将在校准和判别准确性方面与Gail模型2进行比较。影响：改进的风险预测模型将帮助女性在乳腺癌筛查和化学预防方面做出更明智的决定。这与筛查指导方针不一致的年轻妇女尤其相关。此外，他莫昔芬在美国被批准用于预防35岁及以上乳腺癌风险增加的女性的乳腺癌，最有可能使年轻女性受益，因为她们比老年女性受到他莫昔芬不良影响的风险更低。

DESCRIPTION (provided by applicant): Background: The goal of this proposal is to improve the performance of the Gail breast cancer risk prediction model 2 for women 35-49 years of age, by the addition of biomarkers (testosterone or free testosterone, and/or Mullerian Inhibiting Substance (MIS)). MIS, which is detectable only in premenopausal women, was associated with a large increase in risk of both pre- and post-menopausal breast cancer in the only prospective study to date (OR = 9.8, 95% CI = 3.3 to 28.9 for the highest vs. lowest quartile). Premenopausal levels of testosterone and free testosterone have also been consistently shown to be positively associated with increased risk of both pre- and post-menopausal breast cancer. All three biomarkers vary little during the menstrual cycle, can be measured relatively inexpensively, and have good temporal reliability, i.e. a single measurement is reasonably representative of a woman's long-term average level, making them good candidates for inclusion in a risk prediction model. Aims: 1) To evaluate the association of premenopausal levels of MIS with breast cancer risk; 2) To assess whether adding biomarkers (testosterone or free testosterone, and/or MIS) to the factors included in the Gail model 2 improves the prediction performance of the model for women 35-49 years of age. Methods: The study will use the resources of eight prospective cohorts which collected serum or plasma from healthy young women and followed them up for incidence of breast cancer (Breakthrough Generations Study; CLUE II; Columbia, MO Serum Bank; Guernsey Cohort; Nurses' Health Study II; New York University Women's Health Study; Northern Sweden Mammary Screening Study; ORDET). For aim 1, a 1:2 nested case:control study (2500 cases) will be conducted. For aim 2, the performance of risk prediction models including one or two biomarkers, in addition to factors included in the Gail model 2 (age, age at menarche, age at first live birth, number of previous breast biopsies and number of first degree relatives with a history of breast cancer), will be compared to the Gail model 2 with respect to calibration and discriminatory accuracy. Impact: An improved risk prediction model will help women make more informed decisions regarding breast cancer screening and chemoprevention. This is particularly relevant to younger women for whom guidelines on screening are inconsistent. Further, tamoxifen, which is approved in the US for prevention of breast cancer in women age 35 and older who are at increased risk of breast cancer, is most likely to benefit younger women because they are at lower risk than older women of the adverse effects of tamoxifen.