PROJECT SUMMARY/ABSTRACT Mortality from endometrial cancer, the most common gynecologic malignancy in the United States, increased by 2% per year between 2010 and 2014, one of the few cancers to demonstrate rising mortality rates. The most powerful prognostic factor affecting endometrial cancer mortality is stage, which details the extent to which the primary tumor has spread beyond the uterus. Over time, staging criteria have evolved as new clinical data have emerged; however, one potentially important mode of spread not incorporated in endometrial cancer stage criteria is transtubal spread, which occurs when endometrial cancer cells are exfoliated through the fallopian tubes into the abdominal cavity. Despite the recognition that endometrial cancer cells have the capacity for cellular detachment and transtubal transportation, and that this mechanism co-occurs with other aggressive tumor characteristics, we lack empirical data on the prognostic impact of transtubal spread and whether this relationship is modified by other tumor characteristics. The overarching goals of the proposed study are to determine precise estimates of the relationship between intraluminal tumor cells (ILTCs) — an objective measure of transtubal spread — and clinical outcomes, and to assess whether incorporation of this tumor feature improves predictive accuracy. To achieve our goals, we will pool resources from five large academic hospitals. We will collect digital images of archived fallopian tube slides and conduct a pathology review to determine ILTC presence in 1,429 endometrial cancer patients. This information will be merged with existing clinical data to determine the relationship between ILTCs and survival outcomes according to histological subtype and stage (Aim 1). We will also examine whether the addition of ILTCs improves prognostic accuracy (Aim 2). Results from our published pilot data lead us to expect that ILTC presence will be associated with survival, particularly among women diagnosed with serous tumors or stage I tumors. Moreover, we expect to observe greater accuracy in prediction of survival outcomes once stage has been revised to incorporate ILTC status. This investigation will be the first well-powered analysis of the impact of transtubal spread on endometrial cancer prognosis. Our results have high translational potential for refining stage criteria and improving risk stratification, in order to better guide post-operative treatment decisions and reduce endometrial cancer mortality.