Molecular clustering based on ERα and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum

Abstract

Assessment of estrogen receptor expression by immunohistochemistry has yielded inconsistent results as a prognostic indicator in ovarian carcinoma. In breast and endometrial carcinomas, panels of estrogen-induced genes have shown improved prognostic capability over the use of estrogen receptor immunohistochemistry alone. For both breast and endometrial cancer, over-expression of estrogen-induced genes is associated with better prognosis. We hypothesized that analysis of a panel of estrogen-induced genes can predict outcome in ovarian carcinoma and potentially differentiate between tumors of varying hormonal responsiveness. From a cohort of 219 women undergoing ovarian cancer surgery from 2004 −2007, 83 patients were selected for inclusion. All patients had advanced stage ovarian/primary peritoneal high-grade serous carcinoma and underwent primary surgical debulking followed by adjuvant treatment with platinum and taxane agents. The expression of ERα and six genes known to be induced by estrogen in the female reproductive tract (EIG121, sFRP1, sFRP4, RALDH2, PR, IGF-1) was measured using qRT-PCR. Unsupervised cluster analyses were used to categorize patients as high or low gene expressors. Gene expression results were then compared to those for estrogen receptor immunohistochemistry. Clusters were compared using chi-square analyses, and Cox proportional hazards were used to evaluate survival outcomes. Median follow-up time was 38.7 months (range 1–68). A cluster defined by EIG121 and ERα segregated tumors into distinct groups of high and low gene expressors. Shorter overall survival was associated with high gene expression (HR 2.84 [1.11–7.30], p=0.03), even after adjustment for other covariates. No difference in estrogen receptor immunohistochemistry expression was noted between gene clusters. In contrast to other hormonally-driven cancers, high expression of ERα and the estrogen-induced gene EIG121 predicts shorter overall survival in patients with high-grade serous ovarian carcinoma. Such a biomarker panel may potentially be used to guide management with estrogen antagonists in this patient population.

Restoration of miR-200c to Ovarian Cancer Reduces Tumor Burden and Increases Sensitivity to Paclitaxel

“…We performed immunohistochemistry for TUBB3 on a cohort of 129 primary high-grade (stage III or IV) serous ovarian carcinomas from MD Anderson Cancer Center (described previously) (25). Patients with tumors with a low tumor TUBB3 score (1; weak staining in 1–10% of tumor) had significantly prolonged survival (average survival 52.73 ± 4.08 months) compared to patients with tumors with high TUBB3 score (3 or 4; moderate to strong staining in more than 10% of tumor (average survival 42.56 ±3.19 months) (Figure 5).…”

“…Formalin-fixed, paraffin embedded slides obtained from 129 surgical specimens from MD Anderson Cancer Center described previously (25) were stained for TUBB3 protein by immunohistochemistry. Tissue was then stained with neuronal class III B-tubulin polyclonal antibody (PRB-435P, Covance, Emeryville, CA).…”

New insights on the role of hormonal therapy in ovarian cancer

“…Despite the correlation of ER expression with improved patient outcome in the studies reviewed above, a recent study in 83 advanced stage ovarian/primary peritoneal high-grade serous carcinomas evaluated expression of ERα by IHC and expression of six genes known to be induced by estrogen in the female reproductive tract by qRT-PCR. ERα expression correlated with poor prognosis [51]. High expression of ER α and estrogen-induced genes was associated with worse overall survival and it was a negative prognostic factor independent of other patient-dependent covariates such as age, race, and BMI.…”

Role of TRAP1 and estrogen receptor alpha in patients with ovarian cancer -A study of the OVCAD consortium

“…However, the importance of ERα expression as therapeutic and prognostic marker in EOC is still controversial [11]. Prognostic significance of ERα expression was recently described as favorable, revealing a significantly longer overall survival [12-14].…”