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

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 OOR is lower in this cohort than previously reported. Future work to validate these findings in an independent multi-institutional cohort is needed.

Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma

“…Previously, we reported that the expression of FGFR2c splice isoform was associated with aggressive tumor characteristics and poor survival outcome [ 11 ] as well as progestin treatment failure in a separate cohort of women [ 20 ]. In this former study, tumors with expression of FGFR2c were compared to all those not expressing FGFR2c (including those that had lost both FGFR2b and FGFR2c expression) [ 11 ].…”

“…We employed the BaseScope RNA ISH assay that has been previously developed, optimized, and validated by our laboratory to detect the FGFR2b and FGFR2c isoforms [ 11 , 20 ]. In brief, we utilized custom‐designed probes from Advanced Cell Diagnostic (ACD) (Newark, CA, USA): (1) a human‐specific probe (1ZZ) (BA‐Hs‐FGFR2‐tv2‐E7E8) that targets an exon 7–8 junction (NM_022970.3, 1,578–1,622 bp) to detect the ‘FGFR2b’ epithelial isoform and (2) a human‐specific probe (BA‐Hs‐FGFR2‐tv1‐E7E9) that targets an exon 7–9 junction (NM_000141.4, 1,580–1,619 bp) to detect the ‘ FGFR2c mRNA’ mesenchymal isoform.…”

Protective Effects of Irbesartan, an Angiotensin Receptor Blocker with PPARγ Agonistic Activity, against Estradiol Benzoate-Induced Endometrial Hyperplasia and Atypia in Female Rats via Modulation of TNFα/Survivin Pathway

“…Endometrial carcinoma is the most common gynecological malignancy, and EH is its precursor [ 1 ]. There is a strong relationship between the renin–angiotensin system and AngII receptors’ overexpression, and initiation and progression of EH and EC.…”

“…The hyperplastic changes originate from the uterine endometrial glands with an increase in the gland-to-stroma ratio compared with the regular endometrium. Unfortunately, about 40% of EH patients with atypia develop carcinoma, the most common fatal gynecological malignancy [ 1 ]. The revised 2014 WHO classification divides EH into two categories: (1) hyperplasia without atypia and (2) atypical hyperplasia, based upon the presence or absence of cytological atypia [ 2 ].…”

Assessing Post-Treatment Pathologic Tumor Response in Female Genital Tract Carcinomas: An Update

“…Recently, it has been shown that abnormal mismatch repair (MMR) protein expression can predict poor response to progestins and/or higher rate of recurrence in young women with AH or FIGO 1 carcinoma ( 51 ). Finally, other authors reported that another biomarker, FGFR2c, appears to be strongly associated with progestin treatment failure, with low overall response rate to levonorgestrel intrauterine device treatment ( 52 ).…”