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Simple Summary  Women diagnosed with low-grade endometrioid cancer (EEC) and its precursor lesion, atypical hyperplasia (AH) are frequently treated with hormonal therapy including levonorgestrel releasing intrauterine device (LNG-IUD) as an alternative to surgery. Biomarkers that inform which group of patients are more likely to respond to LNG-IUD are not available. The aim of this study was to document the response rate to LNG-IUD therapy in women with AH and EEC and identify potential biomarkers to guide treatment response. The overall response rate (ORR) for the whole cohort was 30/69 (~44%) with a higher ORR seen in AH (64%) compared to EEC (23%). Fibroblast Growth Factor Receptor (FGFR2) isoforms were detected using RNA in situ hybridization. The FGFR2c isoform was expressed in 16.7% of the samples, with those expressing FGFR2c 5-times more likely to have treatment failure. FGFR2 isoform expression could be used to guide treatment decisions following confirmation of this finding in an independent study.    Abstract  Women with atypical hyperplasia (AH) or well-differentiated early-stage endometrioid endometrial carcinoma (EEC) who wish to retain fertility and/or with comorbidities precluding surgery, are treated with progestin. Clinically approved predictive biomarkers for progestin therapy remain an unmet need. The objectives of this study were to document the overall response rate (ORR) of levonorgestrel intrauterine device (LNG-IUD) treatment, and determine the association of FGFR2b and FGFR2c expression with treatment outcome. BaseScope RNA ISH assay was utilized to detect expression of FGFR2b and FGFR2c mRNA in the diagnostic biopsies of 89 women (40 AH and 49 EEC) treated with LNG-IUD. Detailed clinical follow-up was available for 69 women which revealed an overall response rate (ORR) of 44% (30/69) with a higher ORR seen in AH (64%) compared to EEC (23%). The recurrence rate in women who initially responded to LNG-IUD was 10/30 (33.3%). RNA ISH was successful in 72 patients and showed FGFR2c expression in 12/72 (16.7%) samples. In the 59 women with detailed clinical follow-up and RNA-ISH data, women with tumours expressing FGFR2c were 5-times more likely to have treatment failure in both univariable (HR 5.08,  p  < 0.0001) and multivariable (HR 4.5,  p  < 0.002) Cox regression analyses. In conclusion, FGFR2c expression appears to be strongly associated with progestin treatment failure, albeit the ORR is lower in this cohort than previously reported. Future work to validate these findings in an independent multi-institutional cohort is needed.

cancers

Fibroblast Growth Factor Receptor 2 Isoforms Detected via Novel RNA ISH as Predictive Biomarkers for Progestin Therapy in Atypical Hyperplasia and Low-Grade Endometrial Cancer