WISER Sister

描述（由研究者提供）：由于特定的遗传特征（例如BRCA 1或2突变）和/或强烈的家族史，绝经前女性的一个子集患乳腺癌的风险显著升高。对高危妇女有效的乳腺癌预防（药物或手术）是激素干预;在高危妇女中预防乳腺癌的最强有力的基础是通过激素干预。然而，手术和药物预防都有严重的负面长期后果，许多妇女可能无法接受。我们提出了一种预防性运动干预措施，可以解决相同的激素问题，但严重的副作用较少，不会对生活质量产生负面影响。运动训练也有许多公认的积极的健康益处，超出了本文的假设。这些妇女非常积极地降低风险。因此，即使风险的改变是微不足道的（例如，与较小的肿瘤大小，乳腺癌的延迟发作，或乳腺密度降低，这将提高早期筛查的成功率相一致），风险增加的女性应该知道他们可以合理地期望从定期锻炼中降低乳腺癌风险。拟议的剂量反应试验的总体目标是在160名乳腺癌终身风险> 18%的女性中确定5个月低或高剂量运动对已知与乳腺有丝分裂活动相关的变量的影响。运动剂量的选择接近目前的公共卫生指南，以促进健康（每周150分钟）和体重控制（每周300分钟）。待检验的主要假设是，运动训练将导致雌激素暴露量的显着减少，并以剂量反应的方式。雌激素暴露的测量是一个特别的创新相比，以前的研究已经检查了运动对雌激素的影响，拟议的工作。在运动训练干预之前和之后的2个月经周期内收集每日现场尿样，主要结局将是通过雌激素曲线下面积评估的总激素暴露。研究指标包括已知的有丝分裂原（例如，多个月经周期的每日尿雌激素和孕激素;雌激素代谢物;其他性类固醇激素），以及MRI扫描的纤维腺体组织体积（作为乳腺有丝分裂活性的替代品）。还将评估身体组成和脂肪因子的变化。结合正在进行的低风险女性平行试验（WISER研究）的数据，拟议的工作将提供有关乳腺癌常见风险因素（雌激素，雌激素代谢，其他性类固醇激素，脂肪因子和身体成分）水平差异或缺乏差异的新信息，以及运动训练对这些结果的影响的比较。 公共卫生相关性：WISER Sister是一项随机对照试验，将显著增加对160名风险显著增加的年轻女性（18-35岁）进行5个月运动训练以降低乳腺癌风险因素（包括雌激素和MRI乳腺成像）的潜力的了解。结合正在进行的低风险女性平行试验（WISER研究）的数据，拟议的工作将提供有关乳腺癌常见风险因素（雌激素，MRI乳腺密度，雌激素代谢，其他类固醇激素，脂肪因子和身体成分）水平差异或缺乏差异的新信息，以及运动训练对这些结果的影响的比较。WISER Sister研究将160名乳腺癌风险升高的年轻女性随机分为3个相等大小的组：等待列表控制，低剂量运动（每周150分钟，以接近当前公共卫生建议的运动促进一般健康）和高剂量运动（每周增加到300分钟，以接近公共卫生建议的体重控制）。

DESCRIPTION (provided by investigator): A subset of premenopausal women is at significantly elevated risk for breast cancer due to specific genetic traits (e.g. BRCA1 or 2 mutations) and or strong family history. Effective breast cancer prevention available for high-risk women (drugs or surgery) are hormonal interventions; the strongest basis for breast cancer prevention among high risk women is through hormonal intervention. However, both surgical and drug based prevention have serious negative long term consequences that may not be acceptable to many women. We propose a preventive exercise intervention for increased risk women that might address the same hormonal issues, yet have fewer serious side effects and not impact negatively on quality of life. Exercise training also has many well established positive health benefits beyond those hypothesized herein. These women are highly motivated to reduce their risk. Therefore, even if the alteration in risk is marginal (e.g. consistent with smaller tumor size, delayed onset of breast cancer, or reduced breast density that would improve the success of early screening), women at increased risk deserve to know what they can reasonably expect from regular exercise with regard to reducing breast cancer risk. The overarching goal of the proposed dose response trial is to establish the effects of 5 months of low or high dose exercise on variables known to be associated with breast mitotic activity, among a cohort of 160 women with a > 18 percent lifetime risk for breast cancer. The exercise doses were chosen to approximate the current public health guidelines for health promotion (150 minutes weekly) and weight control (300 minutes weekly). The primary hypothesis to be tested is that exercise training will result in a significant decrease of estrogen exposure, and in a dose response manner. The measurement of estrogen exposure is a particular innovation of the proposed work compared to prior studies that have examined the effects of exercise on estrogens. Daily spot urinary samples will be collected over 2 menstrual cycles before and after the exercise training intervention and the primary outcome will be total hormone exposure as assessed by estrogen area under the curve. Study measures include known mitogens (e.g. daily urinary estrogen and progesterone over multiple menstrual cycles; estrogen metabolites; other sex steroid hormones), as well as fibroglandular tissue volume from MRI scans (as a surrogate of breast mitotic activity). Changes in body composition and adipokines will also be assessed. In combination with data from an ongoing parallel trial in low risk women (the WISER study), the proposed work will provide novel information regarding differences, or lack thereof, in levels of commonly accepted risk factors for breast cancer (estrogens, estrogen metabolism, other sex steroid hormones, adipokines, and body composition), as well as comparisons of the effects of exercise training on these outcomes. PUBLIC HEALTH RELEVANCE: WISER Sister is a randomized controlled trial that will add significantly to understanding the potential for five months of exercise training to reduce breast cancer risk factors (including estrogens and MRI breast imaging) in 160 young women (aged 18-35) with significantly increased risk. In combination with data from an ongoing parallel trial in low risk women (the WISER study), the proposed work will provide novel information regarding differences, or lack thereof, in levels of commonly accepted risk factors for breast cancer (estrogens, breast density from MRI, estrogen metabolism, other steroid hormones, adipokines, and body composition), as well as comparisons of the effects of exercise training on these outcomes. The WISER Sister study will randomize 160 young women with elevated breast cancer risk into 3 equal sized groups: wait list control, low dose exercise (150 minutes weekly, to approximate the current public health recommendations for exercise for general health promotion), and high dose exercise (building to 300 minutes weekly, to approximate the public health recommendations for weight control).