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

Abstract

Background Ovarian cancer is a lethal disease comprised of distinct histopathological types. There are few established biomarkers of ovarian cancer prognosis, in part because subtype-specific associations may have been obscured in studies combining all subtypes. We examined whether progesterone receptor (PR) and estrogen receptor (ER) protein expression were associated with subtype-specific survival in the international Ovarian Tumor Tissue Analysis (OTTA) consortium. Methods PR and ER were assessed by central immunohistochemical analysis of tissue microarrays for 2933 women with invasive epithelial ovarian cancer from 12 study sites. Negative, weak, and strong expression were defined as positive staining in <1%, 1–50%, and ≥50% of tumor cell nuclei, respectively. Hazard ratios (HRs) for ovarian cancer death were estimated using Cox regression stratified by site and adjusted for age, stage, and grade. Results PR expression was associated with improved survival for endometrioid (EC; p<0·0001) and high-grade serous carcinoma (HGSC; p=0·0006), and ER expression was associated with improved EC survival (p<0·0001); no significant associations were found for mucinous, clear cell, or low-grade serous carcinoma. EC patients with hormone receptor (PR and/or ER) positive (weak or strong) versus negative tumors had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·33; 95% CI, 0·21–0·51; p<0·0001). HGSC patients with strong versus weak or negative tumor PR expression had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·71; 95% CI, 0·55–0·91; p=0·0061). 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 determine whether hormone receptor status predicts response to endocrine therapy, and can guide personalized treatment for ovarian cancer. Funding Carraressi Foundation, US National Institutes of Health, National Health and Medical Research Council of Australia, UK National Institute for Health Research, and others.

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

“…Molecularly, our data also support previous pre-clinical data that showed that the mechanisms of tumor progression in women with estrogen exposure occur as a result of direct tumor growth via VEGF induction and indirect growth via MAPK signaling in the tumor microenvironment [15][16][17][18]. However, a recent study including 1,742 women with HGSOC did not find that estrogen receptor expression itself was a significant predictor of survival [8]. This discrepancy implies the possibility of an unknown factor linking estrogen signaling and progression of HGSOC.…”

“…Generally, the incidence of ovarian cancer starts to elevate in the peri-menopausal period, a time in which circulating estrogen levels tend to rise relative to the earlier reproductive stages, as shown in recent meta-analysis of observational data [6]. HGSOC, the most common histologic subtype of ovarian cancer and known to have aggressive tumor biology, expresses estrogen receptor in 60-85% of the samples [7,8]. Estrogen replacement therapy has been related to increased ovarian cancer incidence and mortality related to disease [9][10][11][12].…”

“…Mechanistically, two molecular pathways have been proposed to explain ovarian cancer growth, metastasis, and progression related to estrogen: (i) tumor production of vascular endothelial growth factor (VEGF) via estrogen receptor signaling (direct pathway); and (ii) increased tumor-endothelial cell migration via mitogen-activated protein kinases (MAPK) signaling (in direct pathway) [15][16][17][18]. In contrast, a recent large-size multicenter consortium study concluded that estrogen receptor expression in HGSOC did not impact survival outcomes [8]. This discrepancy between population-based and translational studies strongly suggests that there is a possibility of an unproven factor linking estrogen and ovarian cancer.…”

Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

“…PGR was selected for validation. It is expressed in most SBT (37) and in approximately 30% of serous EOC (38) and had the largest fold change in comparing paired samples. Consistent with expression array results, immunohistochemistry of progesterone receptor A and B (PRA and PRB) in 10 FFPE samples of SBT-EOC revealed strong differential expression in SBT versus invasive regions for both progesterone receptor isoforms (Fig.…”

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

“…Most of these patients also participated in previous OTTA studies 18, 19, 20, and all studies received ethics board approval for tumor profiling. TMAs were constructed containing 1–6 cores of 0.6–1.0 mm in diameter from formalin‐fixed paraffin embedded tissue representing tumor from each patient.…”