WISER Sister

描述(由研究人员提供)：由于特定的遗传特征(例如BRCA1或2突变)和或强烈的家族史，绝经前妇女患乳腺癌的风险显著增加。对于高危妇女(药物或手术)，有效的乳腺癌预防是荷尔蒙干预；在高危妇女中，预防乳腺癌的最有力基础是通过荷尔蒙干预。然而，手术和基于药物的预防都会产生严重的负面长期后果，这可能是许多妇女无法接受的。我们建议对高危女性进行预防性运动干预，这可能会解决同样的荷尔蒙问题，但严重副作用较少，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，而不是这里假设的那些。这些女性非常有动力降低她们的风险。因此，即使风险的变化是微乎其微的(例如，肿瘤体积较小、乳腺癌发病延迟或乳房密度降低将提高早期筛查的成功率)，风险较高的女性也应该知道，在降低乳腺癌风险方面，她们可以通过定期锻炼获得合理的期望。拟议的剂量反应试验的首要目标是在160名乳腺癌终生风险为18%的女性队列中，确定5个月的低剂量或高剂量运动对已知与乳房有丝分裂活动相关的变量的影响。选择的运动量与当前的公共卫生指南大致相同，包括促进健康(每周150分钟)和控制体重(每周300分钟)。需要检验的主要假设是，运动训练将导致雌激素暴露的显著减少，并以剂量反应的方式出现。与之前研究运动对雌激素影响的研究相比，雌激素暴露的测量是拟议工作的一个特别创新。在运动训练干预前后的两个月经周期内，每天采集现场尿样，主要结果是总激素暴露，根据曲线下的雌激素面积进行评估。研究措施包括已知的有丝分裂原(例如，多个月经周期的每日尿雌、孕激素；雌激素代谢物；其他性类固醇激素)，以及来自MRI扫描的纤维腺组织体积(作为乳房有丝分裂活动的替代指标)。还将评估身体成分和脂肪因子的变化。结合正在进行的低风险女性平行试验(WISER研究)的数据，这项拟议的工作将提供有关乳腺癌常见危险因素(雌激素、雌激素新陈代谢、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，它将显著增加对160名风险显著增加的年轻女性(年龄18-35岁)进行五个月运动训练以降低乳腺癌风险因素(包括雌激素和MRI乳房成像)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，这项拟议的工作将提供有关乳腺癌常见风险因素(雌激素、MRI乳房密度、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组：轮候名单对照组、低剂量锻炼(每周150分钟，接近目前公共卫生建议的锻炼以促进一般健康)和高剂量锻炼(增加到每周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).