Abstract Introduction: Women with atypical hyperplasia (AH) or well-differentiated endometrioid endometrial carcinoma (EEC) who wish to retain fertility and/or with severe comorbidities that preclude surgery, are treated with progestin. Previously, we reported FGFR2c was associated with aggressive tumour behaviour and poor survival outcome in EEC. The purpose of this study was to estimate the response rate of Levonorgestrel IUD treatment and determine the association of FGFR2b and FGFR2c expression with outcome in women with AH/borderline histology (BL) and EEC treated with progestin. Method: BaseScope RNA ISH and immunohistochemistry assays were deployed to detect (FGFR2b and FGFR2c mRNA) and (FGFR2 protein and progesterone receptors), respectively in 89 diagnostic biopsies of patients with AH/BL and EEC treated with progestin. Kaplan Meier Curve and Cox regression model analyses were performed to evaluate the predictive value of FGFR2b and FGFR2c in this cohort. Results: The complete resolution rate (CRR) and overall response rate (ORR) at any time point in the whole cohort were 26/82 (32%) and 35/82 (43%), respectively. When stratified by histologic diagnosis CRR was 47.5% and 17% and ORR 63% and 24% for AH/BL and EEC, respectively. The recurrence rate was 28.7%. FGFR2c expression was documented in 12/72 (15%) cases. Both univariable and multivariable Cox regression analyses showed women with FGFR2c expression were 5-fold more likely to progress compared with FGFR2b positive women (HR 5.4, P<0.0001) and (HR, 5, P<0.001), respectively. Conclusion: Progestin treatment is less effective in patients with EEC. Notably, FGFR2c expression appears to be strongly associated with progestin treatment failure. Citation Format: Asmerom Sengal, Deborah Smith, Rebecca Rogers, Cameron Snell, Elizabeth Williams, Pamela Pollock. FGFR2 isoform switching strongly associates with progestin treatment failure in atypical hyperplasia and well-differentiated endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO033.