A central problem in ovarian cancer is late diagnosis which causes the 5-year survival rate to plummetbelow 50%. Ovarian cancer symptoms are vague and nonspecific and current screening is generally noteffective. Because ovarian cancer is so deadly risk-reducing salpingo-oophorectomy (RRSO) is oftenrecommended for women at high risk; however RRSO has fertility and health consequences. It is nowbelieved that ovarian high-grade serous carcinoma (HGSC) may begin in the fallopian tubes (FTs) as seroustubal intraepithelial carcinoma (STIC) and that precancerous changes are detectable before metastasis to theovary and peritoneal cavity occurs. Our preliminary data indicate that there are significant changes in serumprotein biomarkers in HGSC cases 12-84 months prior to diagnosis. Further we have also shown that changesoccur in multispectral fluorescence image markers of normal and cancerous ovaries and FTs and that we canbuild a thin falloposcope suitable for traversing the uterus and FT for imaging and cell collection. We will address the unmet clinical need for a minimally invasive test for STIC and early (stage I/II) ovariancancer. Currently no methods enable the detection of ovarian HGSC with a lead time of more than 12 months.Overall our work will meet the need to detect aggressive cancers at the earliest possible stage. Our initialtarget population is women at high risk for ovarian cancer who wish to delay or avoid RRSO. We will combineblood screening for protein markers with a minimally invasive falloposcopy for optical imaging and FT cellcollection. Our procedure will be tested in a study of women at high risk undergoing bilateral salpingo-oophorectomy with hysterectomy which will enable us to obtain and compare test results to gold standardhistology. The specific aims are to: 1) Develop and validate biomarkers that detect STIC and early epithelial ovarian cancer. We will improveupon our existing cut-off based algorithm with newly-discovered markers as well develop a velocity-basedbiomarker algorithm. The algorithm that detects disease 12-84 months prior to diagnosis will be confirmed inan independent blinded set of clinical blood samples. 2) Develop endoscopic imaging and pathomics markers. We will improve our prototype falloposcopesystem with higher resolution multispectral imaging and improved cell collection ability. We will developimaging and karyometric markers from the FT images and the cells collected and perform a pilot in vivo study. 3) Develop an actionable clinical strategy for early detection of epithelial ovarian cancer. A study will beperformed in women at high risk who are planning a RRSO. Those who test positive from our blood testdeveloped in Specific Aim 1 will have their tissue undergo a falloposcopy. Imaging and pathomics data will beused to develop a classifier which will be compared to gold standard histology findings of normal FT STIC oroccult HGSC.