TPS5643 Background: Uterine leiomyosarcomas (uLMS) are rare, accounting for less than five percent of all malignant uterine neoplasms. Approximately 85% of women present with clinical stage I disease (i.e., disease limited to the uterus and cervix). NCCN guidelines for stage I uterine confined disease currently recommend observation; however, recurrence risk of uLMS overall is quite high at 50-70% within the first two years. The estrogen receptor (ER) is expressed in 40-87% of leiomyosarcomas. Because of this high expression, estrogen may act as a growth factor that stimulates cell proliferation and tumor growth. Subsequently, there have been several evaluations for the use of aromatase inhibitors as single agent therapy for uLMS. These trials have each shown varying degrees of clinical activity. We hypothesize that by decreasing systemic estrogen using an aromatase inhibitor we will prolong the time to recurrence for patients with this disease. Methods: This is a GOG Foundation led phase II randomized controlled trial comparing letrozole (2.5mg PO daily) to observation in newly diagnosed patients with uterine confined stage I uLMS. Forty patients will be randomized 1:1. Patients will be eligible post operatively if they have no measurable disease and will be required to be estrogen receptor (ER) positive, as defined by ³ 10% expression by immunohistochemistry (IHC). No stratification methods will be applied. The primary endpoint of the trial is investigator-assessed progression free survival. Exploratory translational evaluation will occur to 1) correlate response to letrozole based on IHC hormone receptor status, 2) evaluate gene expression signatures of hormone receptor activity, tumor biology, and tumor microenvironment in relation to response to letrozole, and 3) evaluate the contribution of single nucleotide polymorphism rs3820282 to tumor biology and response to letrozole. GOG 3088 activated in January of 2024 and expects to enroll across 20 US sites. Clinicaltrials.gov Identifier: NCT05649956. Clinical trial information: NCT05649956 .