Effect of progestin therapy on steroid receptor status and cellular proliferation in low-grade endometrial adenocarcinoma

Abstract

<h3>Objectives:</h3> Low grade endometrioid endometrial cancer is a hormone sensitive disease however little is known about the role of steroid receptors in the development or treatment of disease. Our objective was to determine if steroid receptor status, or change in receptor status, predicts response to progesterone therapy in women with early stage, low grade endometrial cancer. <h3>Methods:</h3> A retrospective cohort of women was identified who underwent primary progesterone therapy for treatment of grade 1 endometrial adenocarcinoma. Steroid receptor (SR) status as well as Ki-67 expression was assessed with immunohistochemistry on pre- and post-treatment formalin fixed paraffin embedded biopsy specimens. Automated image analysis on digitized immunostained slides was performed. Estrogen Receptor (ER), Progesterone Receptor (PR), Androgen Receptor (AR) and Glucocorticoid Receptor (GR) were scored with an H-score and Ki-67 was reported as percent positive. Clinical and pathologic variables, including response to progesterone therapy were collected. SR levels and clinical characteristics were compared using paired t- and Fischer exact tests. <h3>Results:</h3> Fourteen women were included in this analysis, the majority of whom (13/14) had a progestin IUD for treatment of their carcinoma and the majority (9/14) were non-surgical candidates due to medical co-morbidities. Eight women had resolution of adenocarcinoma and six women did not have a response to therapy. Median treatment duration was 4.8 months (range 3.3 – 9.3). Responders were more likely to be younger and pre-menopausal. Two patients had mismatch repair deficient tumors, neither responded to progestin therapy. Both ER and PR declined significantly after progestin treatment (median H-score pre vs post for ER 183 vs 104, p=0.013; PR 110 vs 40, p<.001). GR levels increased (23 vs 47, p=0.003). AR demonstrated variable response. Neither pre-treatment, post-treatment, nor change in SR levels were associated with response to progestin therapy. Women with a response to therapy had lower Ki-67 levels prior to treatment compared to women who did not respond to therapy (26% vs 39%, p=0.033). <h3>Conclusions:</h3> Both ER and PR levels declined during progestin treatment in primary low grade endometrial adenocarcinoma suggesting a negative feedback loop from PR to ER signaling at the level of protein expression. Neither pre-treatment SR levels, nor change in SR receptor status predicted a response to progestin therapy which suggests more complex context-specific interactions of SRs and their ligands. Pre-treatment cellular proliferation as a biomarker for response to hormonal therapy warrants further study.