Estrogen and progesterone receptor status and outcome in epithelial ovarian cancers and low malignant potential tumors

doi:10.1016/j.ygyno.2009.05.045

Gynecologic Oncology

Volume 114, Issue 3, September 2009, Pages 480-485

https://doi.org/10.1016/j.ygyno.2009.05.045 Get rights and content

Abstract

Objective

Receptors for estrogen (ER) and progesterone (PR) are prognostic indicators for a variety of endocrine tumors including breast and endometrial. This study was conducted to determine if ER and PR expression patterns are predictive of outcome in patients with epithelial ovarian cancer (EOC) or ovarian low malignant potential (LMP) tumors.

Methods

ER and PR protein levels were assessed by immunohistochemistry in 45 LMP and 89 EOC samples. Patterns of ER/PR expression (individually and combinations of ER−/PR−, ER+/PR−, ER−/PR+, and ER+/PR+) were correlated with standard prognostic factors of overall survival (OS) in this patient population.

Results

For patients with EOC, the 5-year OS per ER−/PR+, ER+/PR−, ER+/PR+, and ER−/PR− expression was 83%, 79%, 61%, and 48%, respectively, and these differences were statistically significant. In multivariate analyses, ER/PR expression patterns were found to be independent predictors of OS, as were the classical prognostic factors of grade, stage, debulking, and chemotherapy response to treatment. In patients with mucinous LMP tumors, ER and PR were absent. Because no LMP patients died of disease during the studied period, no correlation analysis with OS could be performed.

Conclusions

Patterns of ER/PR expression provide prognostic information in EOC. Additional studies evaluating hormonal inhibition may help personalize the therapy of patients with ovarian cancer.

Introduction

The “incessant ovulation” hypothesis postulates that repetitive cycles of ovulation-induced trauma followed by repair of the ovarian surface epithelium, without pregnancy-induced rest periods or use of contraception, contribute to ovarian cancer development [1], [2]. This reparative process is controlled in normal ovaries by a variety of hormones, cytokines, growth factors and their receptors, acting in networks of autocrine and/or paracrine regulatory systems. Imbalance of these networks may contribute to the development of EOC. Steroid hormones, primarily estrogen and progesterone have been implicated in ovarian carcinogenesis [3]. Estrogens are major regulators of growth and differentiation in normal ovaries. The association between estrogen and cancer is linked to the mutagenic properties of estrogen and its derivatives in ovarian normal epithelial cells [[4], [5], [6]; rev. in 3]. In contrast, progesterone and its receptors exert protective effects by (1) decreasing the exposure to high levels of estrogen and suppressing ovulation; (2) antagonizing the growth-promoting effect of estrogen; and (3) inducing cell differentiation and apoptosis [3], [7]. Loss of heterozygosity at the 11q23.3–24.3 region which contains the PR gene has been associated with an elevated risk for ovarian cancer and poorer prognosis [8], [9]. Because high expression of ER and PR has been reported in EOC samples [10], [11], [12], [13], [14], [15], [16], we hypothesized that expression patterns of ER and PR may be related to tumor behavior, prognosis, or both.

Section snippets

Clinical specimens

This study was reviewed and approved by the Human Research Review Committee of the University of New Mexico Health Sciences Center. Formalin-fixed, paraffin embedded tumor specimens obtained from 134 patients diagnosed with LMP (n = 45) or EOC (n = 89) tumors, treated at the University of New Mexico Cancer Center between March 1996 and June 2005, were retrieved from the Human Tissue Repository. Sample size was constrained by the case availability. Eligible cases had to have a surgical debulking and

Patient characteristics

Of the 134 patients included in this study, 47.7% were non-Hispanic whites, 34.3% Hispanics, 15.7% Native Americans, 1.5% Blacks, and 0.8% Asians. The median age was 54.1 ± 14.3 years (range, 17–87 years). All patients underwent standard surgical staging. This included hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy (total if diseased), systematic pelvic and para-aortic lymphadenectomy, and resection of as much visible tumor as was technically possible. All LMP patients

Discussion

The strength of our study resides in the homogenous patient population treated with optimal debulking procedures, full surgical staging, modern chemotherapy with platinum-based combinations, and the long follow-up of 60 months. The limitation lies in the retrospective aspect and the limited number of patients.

The prognosis and treatment of LMP differ from that of invasive EOC [19], [20]. LMP tumors account for 10% to 20% of all epithelial ovarian malignancies and the 10-year overall survival

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

We would like to thank C. Martinez and A. Meisner (UNM Human Tissue Repository) for providing tissue samples and clinical data; Karen Buehler (Tricore), for technical support with the IHC assays; the Biostatistics Shared Resource of the Cancer Center, and Fernando Valenzuela (UNM, Albuquerque) for reviewing the manuscript and the anonymous reviewers for their insightful comments.

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Citation Excerpt :
Several studies have assessed the prognostic value of endocrine receptor expression in ovarian cancer, concluding that expression of PR is prognostically favorable, whereas the results on ERα and ERβ are contradictory. Likewise, the association with other clinical risk factors is variable [12–17]. A review and meta-analysis by Zhao et al. including in total 35 studies, of which 23 considered the prognostic value of ER, did not find any evidence of an effect of ER on prognosis [18].
Background and Aims: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival in epithelial ovarian cancer. Methods: Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer in an independent data set, hypothesizing that the expression levels and prognostic impact may differ between the subtypes. Results: Expression of PR or AR protein was associated with improved 5-year progression-free (P = .001 for both) and overall survival (P < .001 for both, log-rank test). ERα and ERβ did not provide prognostic information. Patients whose tumors coexpressed PR and AR had the most favorable prognosis, and this effect was retained in multivariable analyses. Analyses of the corresponding genes using an independent data set revealed differences among the molecular subtypes, but no clear relationship between high coexpression of PGR and AR and prognosis. Conclusions: A favorable outcome was seen for patients whose tumors coexpressed PR and AR. Gene expression data suggested variable effects in the different molecular subtypes. These findings demonstrate a prognostic role for PR and AR in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer.
Analysis of the contribution of immunologically-detectable HER2, steroid receptors and of the "triple-negative" tumor status to disease-free and overall survival of women with epithelial ovarian cancer
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Citation Excerpt :
For patients with EOC, the 5-year overall survival per ER−/PR+, ER+/PR−, ER+/PR+, and ER−/PR− expression set was 83%, 79%, 61%, and 48%, respectively, and these differences were statistically significant. In multivariate analyses, ER/PR expression patterns were found to be independent predictors of overall survival (Arias-Pulido et al., 2009). This concept has been recently and further addressed by Lenhard et al. (2012) in a study which evaluated the expression of estrogen receptor alpha and beta (Erα/Erβ), and progesterone receptor A and B (PR-A/PR-B).
We assessed associations between steroid receptors including: estrogen-alpha, estrogen-beta, androgen receptor, progesterone receptor, the HER2 status and triple-negative epithelial ovarian cancer (ERα-/PR-/HER2-; TNEOC) status and survival in women with epithelial ovarian cancer. The study included 152 women with primary epithelial ovarian cancer. The status of steroid receptor and HER2 was determined by immunohistochemistry. Disease-free and overall survival were calculated and compared with steroid receptor and HER2 status as well as clinicopathological features using the Cox Proportional Hazards model. A mean follow-up period of 43.6 months (interquartile range = 41.4 months) was achieved where 44% of patients had serous tumor, followed by mucinous (23%), endometrioid (9%), mixed (9%), undifferentiated (8.5%) and clear cell tumors (5.3%). ER-alpha staining was associated with grade II–III tumors. Progesterone receptor staining was positively associated with a Body Mass Index ≥ 25. Androgen receptor positivity was higher in serous tumors. In stand-alone analysis of receptor contribution to survival, estrogen-alpha positivity was associated with greater disease-free survival. However, there was no significant association between steroid receptor expression, HER2 status, or TNEOC status, and overall survival. Although estrogen-alpha, androgen receptor, progesterone receptor and the HER2 status were associated with key clinical features of the women and pathological characteristics of the tumors, these associations were not implicated in survival. Interestingly, women with TNEOC seem to fare the same way as their counterparts with non-TNEOC.
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Papadimitriou et al. reported that ER and PR expression status did not correlate with response to letrozole [31], and del Carmen et al. found that the time to treatment termination in patients with ER −/PR − disease was longer than that in patients with ER +/PR + disease [20]. Other researchers have investigated the utility of ER and/or PR expression as a prognostic biomarker in ovarian cancer patients [37–43]. Only 2 of these studies restricted the sample to serous carcinomas of any histologic grade [42,43]; the others included all ovarian cancer types and histologic grades.
To determine whether hormonal therapies have efficacy in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum.
We searched departmental databases for patients with histologically-confirmed, evaluable, recurrent low-grade serous ovarian or peritoneal carcinoma who received hormonal therapy at our institution between 1989 and 2009. We retrospectively reviewed patients' medical records for demographic, disease, hormonal therapy, and estrogen receptor and progesterone receptor expression data. We used the Response Evaluation Criteria in Solid Tumors version 1.1 to determine patients' responses to hormonal therapy. Because patients could have received more than one evaluable hormonal therapy regimen, we chose to define the outcome metric as “patient-regimens.” Median time to disease progression (TTP) and overall survival (OS) were also calculated. Regression analysis was also performed.
We identified 64 patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Patients' median TTP and median OS were 7.4 and 78.2 months, respectively. Patients received 89 separate hormonal patient-regimens, which produced an overall response rate of 9% (6 complete responses and 2 partial responses). Sixty-one percent of the patient-regimens resulted in a progression-free survival duration of at least 6 months. Patient-regimens involving ER +/PR + disease produced a longer median TTP (8.9 months) than patient-regimens involving ER +/PR − disease did (6.2 months; p = 0.053). This difference approached but did not reach statistical significance.
Hormonal therapies have moderate anti-tumor activity in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Further study to determine whether ER/PR expression status is a predictive biomarker for this rare cancer subtype is warranted.
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^☆: Supported in part by the National Cancer Institute R01 CA118743 (ERP, HOS); NIH/NCI P30 CA118110, University of New Mexico School of Medicine; Dedicated Health Research Funds from the University of New Mexico School of Medicine (RAC grants C-2291-T to HAP, and C-2279 to HOS); a grant from the Stranahan Foundation (ERP); and by the DHHS/PHS/NIH/ NCRR/GCRC Grant # 5M01 RR00997, Clinical and Translational Science Center, University of New Mexico Health Sciences Center.

^☆☆: This work was presented at the 12th Biennial meeting International Gynecologic Cancer Society. Bangkok, Thailand, October 25-28, 2008.

¹: These authors contributed equally to this work.

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Published by Elsevier Inc.

Estrogen and progesterone receptor status and outcome in epithelial ovarian cancers and low malignant potential tumors☆,☆☆

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Clinical specimens

Patient characteristics

Discussion

Conflict of interest statement

Acknowledgments

Lancet

Mol. Cell. Endocrinol.

Obstet. Gynecol.

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

Early events in ovarian epithelial carcinogenesis: progress and problems in experimental approaches

Int. J. Gynecol. Cancer

Estrogen, progesterone and epithelial ovarian cancer

Reprod. Biol. Endocrinol.

Endogenous hormones and ovarian cancer: epidemiology and current hypotheses

Cancer Epidemiol. Biomark. Prev.

Chapter 3: Endogenous estrogens as carcinogens through metabolic activation

J. Natl. Cancer Inst. Monographs

Is estradiol a genotoxic mutagenic carcinogen?

Endocr. Rev.

Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone

J. Natl. Cancer Inst.

Chromosome 11 allele imbalance and clinicopathological correlates in ovarian tumours

Br. J. Cancer

Definition and Refinement of a Region of Loss of Heterozygosity at 11q23.3–q24.3 in Epithelial Ovarian Cancer Associated with Poor Prognosis

Cancer Res.

Loss of ERβ expression as a common step in estrogen-dependent tumor progression

Endocr. Relat. Cancer

Differential Expression of Estrogen Receptor-α and -β Messenger RNAs as a Potential Marker of Ovarian Carcinogenesis

Cancer Res.

Steroid hormone receptors and long term survival in invasive ovarian cancer

Cancer