Randomized Controlled Trial Novel Markers Predict Malignancy Elevated-Risk Women

我们建议进行一项随机对照试验（RCT），以比较安全性、可行性和积极性。 两种卵巢癌筛查策略的预测值（PPV），一种是使用CA 125和HE 4作为联合筛查策略。 第一行屏幕，另一个引入HE 4作为第二线屏幕。年龄在35-80岁之间的妇女，如果 根据BRCA 1或BRCA 2的记录突变或提示以下情况的家系， 遗传易感性; 800名这样的妇女将被登记，每半年进行一次筛查。50-80岁妇女 如果根据先前开发的OvCaRisk模型，他们的风险升高，则符合资格; 400个此类 妇女将每年登记和接受筛查。我们将使用先前的 开发的参数经验贝叶斯（PEB）纵向算法（高于对应于 90%、95%或99%特异性），以利用标记物的升高作为疾病的信号， 这是有据可查的我们将两组的阳性预测值定为10%， 对应于每检测到一种癌症进行10次手术的比率。在目标1中，我们将记录方案指示的 手术操作和检测到的恶性肿瘤，以排除手术与恶性肿瘤的比例 大于20。在目标2中，我们将记录与第一和第二行屏幕的一致性，并测试null 假设两组之间的顺应性没有差异。在目标3中，我们将记录 健康相关生活质量（HRQOL），并检验零假设：1）对HRQOL的影响无差异 2）对癌症担忧的影响在做和不做的女性之间没有差异 经历一次假阳性的一线筛查。我们的目标是，这项随机对照试验的结果与 正在进行的大型疗效试验将导致在5年内使用新标志物进行临床筛查 年我们与Abbott Diagnostics和金丝雀基金会合作，加快翻译速度。 四个临床中心（瑞典医学癌症，雪松西奈，斯坦福大学和希望之城）将参与， 将提供给所有卵巢孢子机构的参与。数据还将支持成本分析- 使用每种策略进行筛查的有效性，以及进行全面疗效评估的成本估计 如果将来需要进行这样的审判， 相关性（参见说明）： 该项目将首次在前瞻性研究中引入HE 4作为早期检测和诊断标志物。 临床试验我们将谴责和评估比目前用于筛查高- 风险女人通过结合数据，无需另一项大型试验即可进行临床实施 与正在进行的疗效试验的报告。

We propose to conduct a randomized controlled trial (RCT) to compare safety, feasibility and positive predictive value (PPV) of two ovarian cancer screening strategies, one using CA125 and HE4 together as a first-line screen, the other introducing HE4 as a second-line screen. Women aged 35-80 will be eligible if they are at elevated risk based on a documented mutation in BRCA1 or BRCA2 or a pedigree suggestive of inherited susceptibility; 800 such women will be enrolled and screened semi-annually. Women aged 50-80 will be eligible if they have elevated risk based on a previously developed OvCaRisk model; 400 such women will be enrolled and screened annually. We will interpret serum markers using the previously developed parametric empirical Bayes (PEB) longitudinal algorithm (above a threshold corresponding to 90%, 95% or 99% specificity) to take advantage of rise in a marker as a signal of disease, a phenomenon that has been well documented. We will target a positive predictive value of 10% in both arms, corresponding to a ratio of 10 surgeries per cancer detected. In Aim 1 we will document protocol-indicated surgical procedures and malignancies detected in order to rule out a ratio of surgeries to malignancies greater than 20. In Aim 2 we will document compliance with first- and second-line screens and test the null hypothesis that compliance does not differ between the two arms. In Aim 3 we will document effects on health-related quality of life (HRQOL) and test the null hypotheses that 1) effects on HRQOL do not differ between the two arms and 2) effects on cancer worry do not differ between women who do and do not experience a false-positive first-line screen. Our goal is that the results of this RCT together with results of ongoing large efficacy trials will lead to clinical implementation of screening using novel markers within 5 years. We have partnered with Abbott Diagnostics and the Canary Foundation to accelerate translation. Four clinical centers (Swedish Medical Cancer, Cedars-Sinai, Stanford and City of Hope) will participate, and participation will be offered to all Ovarian SPORE institutions. Data will also support analyses ofthe cost- effectiveness of screening using each strategy, and estimation of the costs of conducting a full-scale efficacy trial should such a trial be required in the future. RELEVANCE (See instructions): This project will introduce HE4 as an early detection and diagnostic marker for the first time in a prospective clinical trial. We will denhonstrate and evaluate better strategies than are currently used for screening high- risk women. Clinical implementation may follow without the need for another large trial, by combining data from this study with reports from ongoing efficacy trials.