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.

Survival rates for ovarian cancer are excellent when detected early but are quite poor when detected late, which is often the case. We have shown that non-invasive screening for DNA shed from ovarian cancers by combining uterine lavage and Duplex Sequencing, the most sensitive DNA sequencing technology available, can detect tumors at an early stage when they remain surgically curable. This project proposes to further develop and clinically validate a commercial screening test with the potential to save the lives of women around the world.