Abstract 3157: Expression of progesterone receptor and p4EBP1 as molecular predictors of response to progestin treatment in endometrial adenocarcinoma and complex atypical hyperplasia
Authors: Penner Kristine , Wadehra Madhuri , Steinhardt Angela , Hogue Claire , Cass Ilana , Walsh Christine , Holschneider Christine , Braun Jonathan , Dorigo Oliver 
Published: June 2012

Abstract
Objective: Progestin therapy is a fertility-sparing treatment option for women with complex atypical hyperplasia (CAH) or low grade endometrial adenocarcinoma (Grade 1 EA). However, no biological markers have yet been identified that reliably predict response to treatment. Expression of progesterone receptor and activation of the PI3K/Akt/mTOR pathway have been hypothesized to impact the effectiveness of progestin treatment. We investigated whether the expression of progesterone receptor isoforms PR-A and PR-B, and of pAkt and p4EBP1 as indicators of PI3K/Akt/mTOR pathway signaling in pretreatment biopsy specimens predict the response of patients with CAH and Grade 1 EA to progestin treatment.
Methods: Premenopausal women with CAH or Grade 1 EA who underwent progestin therapy for a minimum of 8 weeks were identified. Pre-treatment endometrial biopsy specimens and matched second specimens obtained while on progestin treatment were stained by immunohistochemistry for expression of PR-A, PR-B, pAkt and p4EBP1. The H-score (staining intensity × % of cells) was determined for tumor cells and stroma. T tests were used to compare mean H-scores. Standardized resolution ratios (SRR) were calculated to assess relationship with resolution.
Results: 38 subjects were identified with a median age of 36 years (range 23-48). On initial sampling, pathology showed G1EAC in 35% and CAH in 65% of subjects. 50% of subjects had documented resolution to normal histopathology with a median time to resolution of 7 months. Staining for PR-A, PR-B, pAkt and p4EBP1 was found to be positive in 84%, 87%, 84%, and 24% of all patients. The H-score was significantly higher in tumor tissue compared to stromal tissue (p&lt;.0003) for all four markers. PR-A and PR-B expression was significantly decreased in the second specimen under progestin treatment for subjects both with and without resolution (p&lt;.00001). In contrast, pAkt expression decreased significantly after treatment only in subjects with resolution (p = .02). Expression of p4EBP1 did not change significantly with treatment (p = .24). Strong positive PR-A or PR-B staining in tumor tissue of pretreatment biopsies showed a positive correlation with resolution (SRR=1.95, CI 1.15-3.18; SRR = 2.37, CI 1.25-4.13, respectively). In addition, p4EBP1 positivity was associated with resolution (SRR = 2.3, CI 1.48-3.52). Expression of pAkt did not correlate significantly with resolution (SRR = 1.5, CI 0.66-3.29).
Conclusions: Our data suggest that the response of premenopausal women with CAH or Grade 1 EA to progestin treatment is significantly correlated with expression of PR-A, PR-B or p4EBP1 in pre-treatment tumor tissue. We propose that the expression of PR-A, PR-B and p4EBP1 may serve as valuable molecular predictors of response to progestin therapy in CAH and Grade 1 EA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3157. doi:10.1158/1538-7445.AM2011-3157