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)来比较安全性、可行性和阳性率。 两种卵巢癌筛查策略的预测价值(PPV)，一种是联合使用CA125和HE4 第一行屏幕，另一条引入HE4作为第二行屏幕。年龄在35岁至80岁之间的女性符合以下条件 根据有记录的BRCA1或BRCA2突变或提示 遗传易感性；将每半年对800名这样的妇女进行登记和筛查。50-80岁的女性 如果他们根据之前开发的OvCaRisk模型具有较高的风险，则有资格；400或 妇女将每年进行登记和筛查。我们将使用之前的 开发了参数经验贝叶斯(PEB)纵向算法(高于对应的阈值 90%、95%或99%的特异度)来利用标记物的升高作为疾病、现象的信号 这一点已经有了很好的记录。我们的目标是两个方面都有10%的积极预测值， 对应于每检测到10次手术的比率。在目标1中，我们将记录规定的协议 手术程序和检测到的恶性肿瘤，以排除手术与恶性肿瘤的比率 大于20。在目标2中，我们将记录对一线和二线屏幕的遵从性，并测试空 假设两个分支之间的遵从性没有差异。在目标3中，我们将记录对 健康相关生活质量(HRQOL)并检验以下零假设：1)对HRQOL的影响没有不同 两只胳膊和两只胳膊对癌症的影响在做和不做的女性之间没有区别 体验一次假阳性的第一行屏幕。我们的目标是，这次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个月内使用新标记物进行筛查的临床实施 好几年了。我们已经与雅培诊断公司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、锡达斯-西奈、斯坦福和希望之城)将参加，以及 所有卵巢孢子机构均可参加。数据还将支持成本分析- 使用每种策略进行筛查的有效性，以及实施全面疗效的成本估计 如果将来需要进行这样的审判，就必须进行审判。 相关性(请参阅说明)： 该项目将首次引入HE4作为早期检测和诊断标记物 临床试验。我们将加强和评估比目前用于筛查HIGH的更好的策略。 冒险的女人。通过结合数据，可以在不需要另一项大型试验的情况下实施临床 来自这项研究和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.