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. 2017 Jul;146(1):153-160.
doi: 10.1016/j.ygyno.2017.04.012. Epub 2017 Apr 26.

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer

Jennifer Taylor Veneris  1 , Kathleen M Darcy  2 , Paulette Mhawech-Fauceglia  3 , Chunqiao Tian  2 , Ernst Lengyel  4 , Ricardo R Lastra  5 , Tanja Pejovic  6 , Suzanne D Conzen  7 , Gini F Fleming  8
Affiliations

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer

Jennifer Taylor Veneris et al. Gynecol Oncol. 2017 Jul.

Abstract

Objective: To investigate the association of tumor glucocorticoid receptor (GR) expression and patient outcome in ovarian cancer.

Methods: GR expression was evaluated by immunohistochemistry using tissue microarrays of specimens from 481 patients with ovarian cancer and 4 patients with benign conditions. Low GR expression was defined as an intensity of 0 or 1+ and high GR as 2+ or 3+ in >1% of tumor cells. Analyses were performed to evaluate the relationship of GR expression with clinical characteristics, progression-free survival (PFS) and overall survival (OS).

Results: GR protein was highly expressed in 133 of 341 (39.0%) tumors from patients who underwent upfront cytoreduction surgery followed by adjuvant chemotherapy. High GR expression was more common in serous tumors (p<0.001), high grade tumors (p<0.001), and advanced stage tumors (p=0.037). Median PFS was significantly decreased in cases with high GR (20.4months) compared to those with low GR (36.0months, HR=1.66, 95% CI 1.29-2.14, p<0.001). GR remained an independent prognostic factor for PFS in multivariate analysis. OS was not associated with GR status.

Conclusions: These data suggest that high GR expression correlates with poor prognosis and support the hypothesis that modulating GR activity in combination with chemotherapy may improve outcomes.

Keywords: Epithelial ovarian cancer; Glucocorticoid receptor; Hormone receptor; Survival; Tumor markers.

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Conflict of interest statement

Conflict of interest statement

SDC and The University of Chicago have been issued patents on methods of measuring GR expression in TNBC and using GR antagonists in TNBC, which while not directly related to this work on ovarian cancer, could be considered broadly relevant. The spouse of JTV is an employee of Abbott Laboratories.

Figures

Fig. 1
Fig. 1
Representative GR staining of tissue microarrays. (A) A representative case with negative GR staining (0 intensity in 0% of tumor cell nuclei) by IHC. (B) A high power magnification of the case shown in panel A. A region of lymphocytes with positive nuclear GR staining adjacent to negative tumor is present (brown, dashed outline). (C) A representative case with 3+ nuclear GR staining in >75% tumor cell nuclei. (D) A high power magnification of the case shown in panel C. Photomicrographs were taken with 10× magnification (A, C) or 40× magnification (B, D).
Fig. 2
Fig. 2
GR expression varies with histologic subtype and stage. (A) High GR expression varies significantly with histologic subtypes in invasive ovarian cancer. Serous ovarian cancer (Serous), endometrioid cancer (EC), clear cell cancer (CC), mucinous cancer (Mucinous), Carcinosarcoma (CS). Other includes mixed epithelial histology. (B) A trend of increasing GR is observed with increasing invasiveness in 481 ovarian cancer cases. Borderline tumors (Bd), early stage (stage I/II) treated with surgery alone (EarlyS), early stage treated with surgery and adjuvant chemotherapy (EarlySCT), advanced stage (stage III/IV) treated with surgery and adjuvant chemotherapy (AdvSCT), advanced stage treated with neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy (NeoSCT). Clinical characteristics for cases in panels A and B are shown in Supplemental Table S1. (C) Line plot of intensity of nuclear GR staining in tumor cells from specimen collected pre- and post-neoadjuvant chemotherapy in paired samples. 15 of 18 (83%) cases had high GR expression (intensity 2+ or 3+) pre-chemotherapy and post-chemotherapy (p = 0.583, not significant). Three cases exhibited low GR expression (0 or 1+ staining) both pre- and post-neoadjuvant chemotherapy. The 15 cases with high GR expression exhibited 2+ or 3+ staining both pre- and post-neoadjuvant chemotherapy.
Fig. 3
Fig. 3
High GR expression correlates with decreased PFS but not OS in Cohort 1. (A) Kaplan-Meier plot of PFS and (B) OS of cases with high GR (2+ or 3+ staining, black solid line) versus low GR expression (0 or 1+ staining, dashed line) in Cohort 1. (C) Kaplan-Meier plot of PFS and (D) OS in the 206 advanced stage (FIGO stage III/IV) high grade (Grade 2/3) serous cases (advanced HG-SOC) of Cohort 1. (E) Kaplan-Meier plot of PFS in early stage (FIGO stage I/II) cases from Cohort 1. (F) Kaplan-Meier plot of PFS in a separate group of 42 early stage (FIGO stage I/II) cases from Cohort 2 of the TMA. In the online version, high GR expression appears in red and low GR expression appears in green.
Fig. 4
Fig. 4
Forest plots demonstrate a trend toward increased hazard for progression for high GR expression in all subgroups. (A) Forest Plot of unadjusted hazard ratios (HR) for PFS (A) and OS (B) for the following subgroups: Early stage (Early), advanced stage (Advanced), Grade 1, Grade 2, Grade 3, serous ovarian cancer (Serous), endometrioid cancer (EC), clear cell cancer (CC), mucinous cancer (Mucinous), other histologies (Other), no gross residual disease (No Gross), any gross residual disease (Gross), or all patients (All) in Cohort 1 (n = 341). Forest plots present unadjusted hazard ratio (black box) with 95% confidence intervals (black lines). HR greater than one indicates a decreased survival for cases with high GR expression compared to low GR expression. Numbers of cases in each subgroup are as shown in Table 1. Selected adjusted and unadjusted HR are shown in Supplemental Table S5.
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