Mammographic density, genes and estradiol/norethisterone based EPT regimens

描述（由申请人提供）： 妇女健康倡议（WHI）临床试验和观察性流行病学研究的结果强烈表明，雌激素和孕酮联合治疗（EPT）与乳腺癌风险相关。在WHI研究发表后，美国使用的EPT类型发生了变化。这些新的替代品中的一些是基于雌二醇（E2）和睾酮衍生物作为孕酮成分。这些制剂已在欧洲使用了一段时间，没有证据表明这些制剂对乳腺组织的作用优于美国使用的经典EPT方案。然而，仍然存在许多不确定性，这些化合物对乳房的作用尚未完全了解。在绝经后雌激素和孕激素干预（PEPI）试验中，我们描述了随机接受EPT的女性乳腺摄影密度（乳腺癌风险的标志物）的变化。我们建议使用相同的方法和相同的读数来评估使用基于E2的EPT方案的女性的乳腺摄影密度。改变EPT对乳房影响的因素也可能很重要。在PEPI研究中，我们发现随机分配到相同EPT组的女性乳腺摄影密度变化差异很大。此外，血清雌酮水平的变化可预测随机接受EPT的女性乳腺摄影密度的变化。激素吸收或代谢的变化可能预示着谁会出现这种乳腺密度增加。拟议的项目利用了挪威乳腺癌筛查方案已经收集的妇女数据。直到最近，高剂量和低剂量的基于E2的EPT药物在挪威都相对常用。我们建议评估1648名妇女的乳房X线摄影密度，这些妇女提供了问卷调查数据、口腔细胞，并且其1996- 2004年的乳房X线摄影正在挪威奥斯陆进行扫描。该项目的具体目标是确定1）与非激素使用者相比，目前服用基于E2的EPT的妇女的乳房X线摄影密度; 2）停止服用基于E2的EPT的妇女从一次筛查到下一次筛查的乳房X线摄影密度变化; 3）编码激素代谢的基因中的选定变体的作用和预测EPT使用者乳房X线摄影密度的作用。

DESCRIPTION (provided by applicant): Results from the Women's Health Initiative (WHI) clinical trial and observational epidemiologic studies strongly show that combined estrogen and progestin therapy (EPT) is associated with breast cancer risk. After the publication of the WHI study, there has been a shift in the type of EPT used in the United States. Some of these new alternatives are based on estradiol (E2) and testosterone derivatives as the progestin component. These preparations have been used in Europe for a while, and there is no evidence that these preparations will be better for the breast tissue than the classical EPT regimens used in the US. However, a number of uncertainties remain, and the role of these compounds on the breast is not completely understood. In the Postmenopausal Estrogen and Progestin Interventions (PEPI) trial, we described changes in mammographic density, a marker for breast cancer risk, in women randomized to EPT. We propose to use the same method and same reader for assessing mammographic density in women who have used E2 based EPT regimens. Factors that modify the effects of EPT on the breast may also be important. In the PEPI study we found large variations in mammographic density changes among women randomized to the same EPT. Further, changes in serum estrone levels predicted mammographic density changes in women randomized to EPT. It is possible that variations in hormone absorption or metabolism may predict who will develop such mammographic density increase. The proposed project takes advantage of data that have already been collected on women in the Norwegian Breast Cancer Screening Program. Both a high- and a low-dose E2 based EPT medications have been relatively commonly used in Norway until recently. We are proposing to assess mammographic density on 1648 women who have provided questionnaire data, buccal cells and whose mammograms from 1996- 2004 are in the process of being scanned in Oslo, Norway. The specific aims of this project are to determine the 1) mammographic density in women currently taking E2 based EPT as compared to that of non hormone users; 2) the mammographic density change in women who stopped taking E2 based EPT from one screening exam to the next; 3) the role of selected variants in genes encoding for hormone metabolism and action in predicting mammographic density in EPT users.