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

描述（由申请人提供）：尽管临床试验数据显示乳腺癌风险增加，激素治疗（HT）的一级预防缺乏总体获益，但临床医生和女性仍大量使用HT治疗中度至重度全身性绝经症状。由于这些制剂可能增加的风险，目前的临床建议提倡使用最低剂量，持续时间尽可能短，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、已经资助的随机临床试验，主要目的是检查4年低剂量经皮与口服雌激素联合环微粒化孕酮对近期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：乳腺摄影密度和异常乳腺摄影率。在KEEPS中，共有720名妇女被随机分配到口服结合马雌激素（0.45 mg/d），经皮17-β雌二醇（50 mcg/d）或安慰剂，与环状微粒化孕酮（200 mg，12天）的活性激素治疗组。所有参与者在进入研究之前以及随访期间每年都需要进行乳房X光检查;在这些时间点也收集了血液样本。2008年完成了随机化。在这项辅助研究中，将获得基线、第1年和第3年的数字乳腺X线摄影（510名受试者可用），并集中处理，以计算乳腺X线摄影密度。我们将确定这两种低剂量HT方案是否与乳腺摄影密度的变化相关。我们还将检查基线乳腺摄影密度或循环生物标志物（包括雌二醇、雌酮和硫酸雌酮）是否改变或介导HT乳腺密度的变化。此外，将确定激素治疗方案对乳腺X线检查和活检异常率的影响。通过确定低剂量联合HT对乳腺的影响，拟议的研究将增加有关低剂量HT相关风险和益处估计平衡的及时和重要信息，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可增加乳腺摄影密度和乳腺癌的发病率。我们建议在正在进行的、已经资助的Kronos早期雌激素预防研究（KEEPS）中，检查现在常用的低剂量联合激素治疗（HT）方案对乳腺密度、乳腺X线异常率和循环雌激素的影响。KEEPS是一项随机临床试验，主要目的是检查低剂量经皮与口服雌激素联合环微粒化孕酮对近期绝经妇女亚临床动脉粥样硬化进展的影响。先前的低剂量HT研究持续时间短，规模小。通过确定低剂量激素治疗对乳腺的影响，拟议的辅助研究将增加有关低剂量HT相关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.