The effects of randomized, low-dose hormone therapy on mammographic density in KE

说明(申请人提供)：尽管来自临床试验的数据显示乳腺癌风险增加，激素疗法(HT)一级预防缺乏整体益处，但临床医生和妇女仍大量使用HT治疗中到重度的全身性更年期症状。由于这些制剂可能增加风险，目前的临床建议主张在尽可能短的时间内使用最低剂量，但平均持续时间通常为2-4年。然而，常用的低剂量HT方案对乳房密度和乳腺癌风险的影响尚不清楚。来自干预试验的最新数据支持长期存在的假设，即荷尔蒙对乳腺癌风险的影响是通过乳房密度来调节的。Kronos早期雌激素预防研究(Keep)是一项正在进行的、已经得到资助的随机临床试验，主要目的是检验4年的低剂量透皮与口服雌激素结合周期微粒化孕酮对最近更年期妇女亚临床动脉粥样硬化进展的影响。这项拟议的辅助研究将有效地检验随机低剂量羟色胺对乳腺癌关键替代终点的影响：乳房X线摄影密度和异常乳房X线摄影的比率。在Keep试验中，共有720名妇女被随机分配到主动激素治疗组，分别服用马匹结合雌激素(0.45 mg/d)、经皮17-β雌二醇(50微克/d)或安慰剂(加周期微粒化黄体酮(200 mg/d，共12天)。所有参与者都被要求在进入研究之前以及在随访期间每年进行乳房X光检查；在这些时间点也采集了血液样本。随机化于2008年完成。在这项辅助研究中，将获得并集中处理基线、第一年和第三年的数字乳房X光照片(可在510名参与者中获得)，以计算乳房X光照片密度。我们将确定这两个低剂量的HT方案是否与乳房X光摄影密度的变化有关。我们还将检查基线乳腺摄影密度或循环生物标记物，包括雌二醇、雌酮和雌酮硫酸盐，是否改变或调节HT患者乳房密度的变化。此外，还将确定激素方案对乳房X光检查和活检异常率的影响。通过确定低剂量联合羟色胺对乳房的影响，拟议的研究将增加有关与低剂量羟色胺相关的风险和益处估计平衡的及时和重要的信息，并将有助于指导未来的研究。 公共卫生相关性：在随机试验中，雌激素和孕激素联合治疗已被证明增加乳房X光摄影密度和乳腺癌发病率。我们建议在正在进行的、已经得到资助的Kronos早期雌激素预防研究(Keep)中，检查目前常用的低剂量联合激素治疗(HT)方案对乳房密度、异常乳房X光检查和循环雌激素的影响。Keep是一项随机临床试验，主要目的是检查低剂量透皮与口服雌激素与环状微粒化黄体酮联合使用对最近绝经妇女亚临床动脉粥样硬化进展的影响。以前对低剂量羟色胺的研究持续时间短，规模小。通过确定低剂量激素治疗对乳房的影响，拟议的辅助研究将增加与低剂量羟色胺相关的风险和益处估计平衡的重要信息，并将有助于指导未来的研究试验。

DESCRIPTION (provided by applicant): Despite data from clinical trials showing an increased risk of breast cancer and lack of overall benefit for primary prevention with hormone therapy (HT), there is still significant usage of HT by clinicians and women for treatment of moderate-to-severe systemic menopausal symptoms. Due to the possible increased risks with these preparations, current clinical recommendations advocate utilizing the lowest dose for the shortest possible duration, but average duration is often for 2-4 years. However, the effects of commonly used low-dose HT regimens on breast density and breast cancer risk are unknown. Recent data from intervention trials support the long standing hypothesis that hormonal effects on breast cancer risk are mediated through breast density. The Kronos Early Estrogen Prevention Study (KEEPS) is an ongoing, already- funded randomized clinical trial with a primary goal of examining the effects of 4 years of low- dose transdermal versus oral estrogen combined with cyclic micronized progesterone on progression of subclinical atherosclerosis in recently menopausal women. The proposed ancillary study will efficiently examine the effects of randomized low-dose HT on key breast cancer surrogate endpoints: mammographic density and rates of abnormal mammograms. In KEEPS, a total of 720 women were randomized to oral conjugated equine estrogens (0.45 mg/d), transdermal 17-beta estradiol (50 mcg/d), or placebo, with cyclic micronized progesterone (200 mg for 12 days) for active hormonal therapy groups. All participants were required to have mammography prior to study entry as well as yearly during follow-up; blood samples also were collected at these time points. Randomization was completed in 2008. In this ancillary study, digital mammograms (available on 510 participants) from baseline, year 1 and year 3 will be obtained and processed centrally to calculate mammographic density. We will determine if these two low-dose HT regimens are associated with change in mammographic density. We will also examine if baseline mammographic density or circulating biomarkers including estradiol, estrone, and estrone sulfate, modify or mediate changes in breast density with HT. In addition, the effects of hormonal regimens on the rates of abnormal mammogram and biopsy will be determined. By determining the effects of low-dose combined HT on the breast, the proposed study will add timely and important information about the estimated balance of risks and benefits associated with low-dose HT and will help guide future research. PUBLIC HEALTH RELEVANCE: Combined estrogen and progestin therapy has been shown to increase mammographic density and incidence of breast cancer in randomized trials. We propose to examine the effects of now commonly used low-dose combined hormone therapy (HT) regimens on breast density, rates of abnormal mammogram, and circulating estrogens in the ongoing, already-funded Kronos Early Estrogen Prevention Study (KEEPS). KEEPS is a randomized clinical trial with a primary goal of examining the effects of low-dose transdermal versus oral estrogen combined with cyclic micronized progesterone on progression of subclinical atherosclerosis in recently menopausal women. Prior studies of low-dose HT have been of short duration and small size. By determining the effects of low-dose hormone therapy on the breast, the proposed ancillary study will add important information about the estimated balance of risks and benefits associated with low-dose HT and will help guide future research trials.