Mammographic density, genes and estradiol/norethisterone based EPT regimens

描述(由申请人提供)： 妇女健康倡议(WHI)的临床试验和观察流行病学研究的结果有力地表明，雌激素和孕激素联合治疗(EPT)与乳腺癌风险有关。在WHI研究发表后，美国使用的EPT类型发生了变化。其中一些新的替代品是基于雌二醇(E2)和睾酮衍生物作为孕激素成分。这些制剂在欧洲已经使用了一段时间，没有证据表明这些制剂对乳房组织的保护会比美国使用的经典EPT疗法更好。然而，仍然存在一些不确定因素，这些化合物对乳房的作用还没有完全了解。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的妇女乳房X光摄影密度的变化，这是乳腺癌风险的一个标志。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方案的妇女的乳房X光照相密度。改变EPT对乳房影响的因素也可能很重要。在PEPI研究中，我们发现随机接受相同EPT的妇女的乳房X光摄影密度变化有很大差异。此外，血清雌酮水平的变化可以预测随机接受EPT的妇女的乳房X光照相密度变化。荷尔蒙吸收或新陈代谢的变化可能会预测谁会出现这种乳房X光检查密度增加。拟议的项目利用了挪威乳腺癌筛查计划中已经收集到的关于妇女的数据。直到最近，基于高剂量和低剂量E2的EPT药物在挪威都得到了相对普遍的使用。我们建议评估1648名妇女的乳房X光照相密度，这些妇女提供了问卷数据、口腔细胞，她们1996-2004年的乳房X光检查正在挪威奥斯陆进行扫描。该项目的具体目标是确定1)目前正在接受基于E2的EPT的妇女与非激素使用者相比的乳腺摄影密度；2)停止服用基于E2的EPT的妇女在一次又一次筛查中的乳腺摄影密度变化；3)编码激素代谢的基因的选定变异在预测EPT使用者的乳腺摄影密度中的作用。

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.