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

描述（由申请人提供）：尽管来自临床试验的数据显示激素治疗（HT）增加了乳腺癌的风险，并且缺乏一级预防的总体益处，但临床医生和妇女仍然大量使用激素治疗中度至重度全身性更年期症状。由于这些制剂可能增加风险，目前的临床建议提倡使用最低剂量和尽可能短的持续时间，但平均持续时间通常为2-4年。然而，常用的低剂量高温疗法对乳腺密度和乳腺癌风险的影响尚不清楚。干预试验的最新数据支持长期存在的假设，即激素对乳腺癌风险的影响是通过乳腺密度介导的。Kronos早期雌激素预防研究（KEEPS）是一项正在进行的，已经获得资助的随机临床试验，其主要目标是检查4年低剂量透皮雌激素与口服雌激素联合环微化孕酮对新近绝经妇女亚临床动脉粥样硬化进展的影响。拟议的辅助研究将有效地检查随机低剂量HT对关键乳腺癌替代终点的影响：乳房x线摄影密度和乳房x线摄影异常率。在KEEPS研究中，共有720名女性被随机分为口服结合马雌激素（0.45 mg/d）、经皮17- β雌二醇（50 mcg/d）或安慰剂、环微孕酮（200 mg， 12天）的活性激素治疗组。所有参与者在研究开始前都需要进行乳房x光检查，并在随访期间每年进行一次；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，将获得基线、1年和3年的数字乳房x光片（510名参与者），并对其进行集中处理，以计算乳房x光片密度。我们将确定这两种低剂量高温疗法是否与乳房x线摄影密度的变化有关。我们还将研究基线乳房x线摄影密度或循环生物标志物（包括雌二醇、雌酮和硫酸雌酮）是否会改变或介导激素治疗后乳腺密度的变化。此外，激素治疗方案对乳房x光检查和活检异常率的影响将被确定。通过确定低剂量联合激素治疗对乳房的影响，本研究将及时提供有关低剂量激素治疗的风险和益处评估平衡的重要信息，并将有助于指导未来的研究。

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.