Elsevier

The Lancet Oncology

Volume 14, Issue 9, August 2013, Pages 853-862
The Lancet Oncology

Articles
Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

https://doi.org/10.1016/S1470-2045(13)70253-5Get rights and content

Summary

Background

Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.

Methods

12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed.

Findings

2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21–0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55–0·91; p=0·0080), but weak PR expression was not (1·02, 0·89–1·18; p=0·74).

Interpretation

PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.

Funding

Carraresi Foundation and others.

Introduction

Ovarian cancer causes more than 140 000 deaths worldwide every year, and is the most lethal gynaecological malignancy in developed countries.1 Invasive epithelial ovarian cancer has five major histopathological types that are phenotypically, molecularly, and aetiologically distinct: high-grade serous carcinoma (HGSC), low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, and clear-cell carcinoma.2, 3 The association between tumour biomarker expression and survival varies substantially between subtypes, and can be obscured in analyses of all ovarian cancers combined.4 However, the infrequency of histopathological types other than HGSC has precluded robust subtype-specific analyses and hindered efforts to identify biomarkers of ovarian cancer survival.

The progesterone receptor (PR) and oestrogen receptor (ER) mediate the effects of female steroid hormones on proliferation and apoptosis of ovarian cancer cells.5 Immunohistochemical assessment of ER and PR status is routinely done for the clinical management of breast cancer.6 However, whether ER or PR status could successfully guide ovarian cancer prognosis or treatment is unclear. Previous studies have shown that PR7, 8, 9 or ER7, 10 expression is associated with improved ovarian cancer survival, independent of clinical prognostic factors, but these associations have not been consistently replicated.4, 11, 12, 13, 14 The conflicting data are difficult to interpret for several reasons. First, most studies combined all disease subtypes,7, 8, 9, 11, 12, 13 which can obscure subtype-specific associations. Second, the few studies that focused on serous carcinoma10, 14 and other subtypes4 had small sample sizes and low statistical power. Finally, different methods of immunohistochemical analysis and biomarker scoring were used, which could contribute to the heterogeneous results.15

We formed the international Ovarian Tumor Tissue Analysis (OTTA) consortium to overcome the main obstacles that heretofore have prevented the development of clinically useful prognostic biomarkers for ovarian cancer. Here, we examine the association of tumour PR and ER expression with disease-specific survival by central immunohistochemical assessment and subtype-specific analyses in a large population of women with invasive epithelial ovarian cancer.

Section snippets

Participants

12 studies participating in the consortium contributed tissue microarray sections and clinical data to our study (table 1). Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. Patients with ovarian cancer of mixed and other histological types were excluded. For a patient to be eligible for inclusion in our analysis, tissue microarrays for immunohistochemistry analysis and clinical follow-up data had to be

Results

2933 women with ovarian cancer were included in this study (table 2). Of the 1669 patients (57%) who died within 10 years of diagnosis, cause of death was ovarian cancer for 1312 (79%), unrelated to ovarian cancer for 160 (10%), and unknown for 197 (12%; table 3). Information about extent of residual disease after primary cytoreductive surgery was available for 2023 patients (table 3).

PR and ER expression differed substantially between ovarian cancer subtypes (table 3). The proportion of

Discussion

We have shown that patients with endometrioid carcinoma who have hormone-receptor-positive tumours are less likely to die from their disease than are those with hormone-receptor-negative tumours. Furthermore, we established that patients with HGSC whose tumours stain strongly positive for PR have improved survival compared with those whose tumours stain negative or weakly positive for PR. The magnitude of these biomarker effects is similar to the protective effect of germline BRCA mutations on

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