ArticlesHormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study
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
References (50)
- et al.
Expression of progesterone receptor is a favorable prognostic marker in ovarian cancer
Gynecol Oncol
(2005) - et al.
Prognosis and hormone receptor status in older and younger patients with advanced-stage papillary serous ovarian carcinoma
Gynecol Oncol
(2009) - et al.
Recruitment of newly diagnosed ovarian cancer patients proved challenging in a multicentre biobanking study
J Clin Epidemiol
(2011) - et al.
Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma
Hum Pathol
(2008) - et al.
Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): a Gynecologic Oncology Group Study
Gynecol Oncol
(2010) - et al.
Estrogen receptor alpha and Sp1 regulate progesterone receptor gene expression
Mol Cell Endocrinol
(2003) - et al.
Global cancer statistics
CA Cancer J Clin
(2011) - et al.
Rethinking ovarian cancer: recommendations for improving outcomes
Nat Rev Cancer
(2011) - et al.
Ovarian carcinoma subtypes are different diseases: implications for biomarker studies
PLoS Med
(2008)
Hormone response in ovarian cancer: time to reconsider as a clinical target?
Endocr Relat Cancer
St Gallen 2011: summary of the consensus discussion
Breast Care (Basel)
Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: from the ‘MALOVA’ ovarian cancer study
Oncol Rep
Steroid hormone receptors and long term survival in invasive ovarian cancer
Cancer
Prognostic significance of estrogen receptor alpha and beta expression in human serous carcinomas of the ovary
Arch Gynecol Obstet
Evaluation of a hormone receptor-positive ovarian carcinoma subtype with a favourable prognosis by determination of progesterone receptor and oestrogen receptor 1 mRNA expression in formalin-fixed paraffin-embedded tissue
Histopathology
Estrogen receptor 1 mRNA is a prognostic factor in ovarian carcinoma: determination by kinetic PCR in formalin-fixed paraffin-embedded tissue
Endocr Relat Cancer
Expressions of estrogen and progesterone receptors in epithelial ovarian cancer: a clinicopathologic study
Int J Gynecol Cancer
Prognostic role of hormone receptors in ovarian cancer: a systematic review and meta-analysis
Int J Gynecol Cancer
Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer
Int J Cancer
Association of two common single-nucleotide polymorphisms in the CYP19A1 locus and ovarian cancer risk
Endocr Relat Cancer
Genetic polymorphisms in the Paraoxonase 1 gene and risk of ovarian epithelial carcinoma
Cancer Epidemiol Biomarkers Prev
Hormone therapy and the impact of estrogen intake on the risk of ovarian cancer
Arch Intern Med
Different risk factor profiles for mucinous and nonmucinous ovarian cancer: results from the Danish MALOVA study
Cancer Epidemiol Biomarkers Prev
Assessment of hepatocyte growth factor in ovarian cancer mortality
Cancer Epidemiol Biomarkers Prev
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