Early Detection of Ovarian Cancer Using Uterine Lavage and Duplex Sequencing

应用子宫灌洗和双链测序技术早期检测卵巢癌 全世界每年发现近25万例卵巢癌新发病例，其中大多数 这些妇女将死于他们的疾病。如果早期发现，手术治愈率超过90%，但目前 大多数病例是在癌症已经扩散的晚期发现的。因此，我们最 卵巢癌的一个紧迫问题是缺乏工具来识别早期疾病， 化疗可以完全治愈。临床早期检测是一项重大挑战， 症状通常很少且模糊。已经开发了几种成像和分子方法，但正如- 然而，还没有一种筛查方法能够很好地预防死亡，所以目前还没有一种方法 指南推荐的，也不是FDA批准的。一个迫切的、未得到满足的需求仍然存在。在这份提案中，我们概述了一个 我们计划在3年内开发并推出一种创新的早期检测产品，我们相信它将 成为有史以来第一个具有足够灵敏度和特异性的卵巢癌筛查工具，以挽救生命， 成为预防保健的一部分。该测试是基于一种微创子宫灌洗装置 和五分钟的临床程序，以采样卵巢肿瘤脱落到输卵管和子宫的DNA 腔然后通过最准确的DNA测序技术--双链测序法对收集的样本进行分析。 现有的技术，以检测肿瘤衍生突变的低水平特征，以推断存在或 没有癌症。我们的团队成员开创了这些专有技术中的每一项; 联合诊断的可行性得到了强有力的初步研究的支持。在这个快速通道的第一阶段， 应用，我们将进一步完善我们的收集和测序程序，以促进工业规模的步骤 部署，并将正式验证分析性能。在第二阶段，我们将进行两个平行的情况- 对不同但同样重要的人群进行对照研究。在目标1中，我们将重点关注平均风险妇女， 这些公司仅在美国就拥有超过5000万的潜在未满足市场。在一个大的队列中，我们将 验证诊断性能和临床实用性，重点是最大限度地提高灵敏度和特异性 通过严格的统计建模和协变量调整。在目标2中，我们将重复此过程，但对于 患有遗传性卵巢癌易感条件的妇女，特别强调识别 极早期肿瘤最终交付的产品将是一个强大的，具有成本效益和实用性的 可实施的实验室开发测试（LDT）准备用于商业部署。卵巢癌的治疗 夺走了我们中成千上万女性的生命;我们从根本上认为这是不必要的，不可接受的， 我们的团队和技术比世界上任何其他公司都更有优势，可以开始改变。

Early Detection of Ovarian Cancer Using Uterine Lavage and Duplex Sequencing Nearly a quarter of a million new cases of ovarian cancer are identified every year worldwide and the majority of these woman will die from their disease. When detected early, surgical cure rates exceed 90%, but currently most cases are detected at an advanced stage when the cancer has already disseminated. As such, our most pressing problem in ovarian cancer is a lack of tools to identify early stage disease when resection plus chemotherapy can achieve a complete cure. Clinical early detection poses a significant challenge because symptoms are often few and vague. Several imaging and molecular approaches have been developed but, as- of-yet, no screening method has ever performed well enough to prevent deaths, so none are currently guideline-recommended, nor FDA approved. An urgent, unmet need remains. In this proposal we outline a plan to develop, and bring to market within 3 years, an innovative early detection product, which we believe will be the first ever ovarian cancer screening tool with sufficient sensitivity and specificity to save lives and to become a routine part of preventative care. The test is based on a minimally-invasive uterine lavage device and five-minute clinic procedure to sample DNA shed by ovarian tumors into the fallopian tubes and uterine cavity. The collected sample is then analyzed by Duplex Sequencing, the most accurate DNA sequencing technology in existence, to detect the low-level signature of tumor-derived mutations to infer the presence or absence of cancer. Members of our team pioneered each of these proprietary technologies; the premise and feasibility of the combined diagnostic are supported by strong preliminary studies. In Phase I of this Fast Track application we will further refine steps in our collection and sequencing procedures to facilitate industrial-scale deployment and will formally validate analytical performance. In Phase II we will carry out two parallel case- control studies on distinct, but equally important populations. In Aim 1 we will focus on average risk women, who encompass a potential unmet market of more than fifty million in the US alone. In a large cohort we will validate diagnostic performance and clinical utility, with a focus on maximizing sensitivity and specificity through rigorous statistical modeling and covariate adjustment. In Aim 2 we will repeat this process, but for women with a heritable ovarian cancer-predisposing condition, with the specific emphasis on identifying extremely early stage tumors. The final product to be delivered will be a robust, cost effective and practically implementable Laboratory Developed Test (LDT) ready for commercial deployment. Ovarian cancer regularly takes the lives of thousands of women among us; we fundamentally believe this is unnecessary, unacceptable and something that our team and technology is positioned better than any other in the world to begin changing.