In the Ovarian Tumor Tissue Analysis Consortium Study recently published by Sieh et al,1 tissue microarrays from 2,933 cases of epithelial ovarian carcinoma demonstrated that progesterone receptor (PR) expression and estrogen receptor (ER) expression were associated with significantly improved disease-specific survival in endometrioid adenocarcinoma of the ovary (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21–0.51, P < .0001). In addition, strong PR expression was independently associated with improved disease-specific survival in high-grade serous adenocarcinoma of the ovary (HR = 0.71, 95% CI = 0.55–0.91, P = .0080).
The Consortium Study findings are noteworthy because they provide a molecular validation paradigm of episodic clinical activity attributed to the weak estrogen tamoxifen in some patients with ovarian carcinoma. That activity was sufficient to position tamoxifen in a randomized phase III trial against thalidomide (Thalomid) for biochemical-recurrent disease.2 In that study, the antiangiogenic properties of thalidomide did not outperform tamoxifen.
Growing Body of Literature
More important, the report from the Ovarian Tumor Tissue Analysis Consortium is timely and joins the ranks of a growing body of literature attesting to both the prognostic value of the steroid hormone receptors in distinct histologic subtypes of ovarian carcinoma and the therapeutic potential of targeting these receptors.
In 2013, Zhao et al performed a meta-analysis that included 35 studies.3 In overall survival analyses, the pooled hazard ratio for elevated PR levels reached 0.88 (95% CI = 0.82–0.95), indicating that increased PR expression could be associated with improved survival.
Earlier this year, using a novel cell culture assay, Diep et al demonstrated a molecular link between PR expression and induction of Forkhead-box transcription factor–dependent cellular senescence.4
Taking into consideration the Consortium Study findings, it appears that clinical priming of this pathway using PR agonists may provide a useful strategy to induce irreversible cell-cycle arrest in endometrioid and high-grade serous ovarian carcinomas.
Argenta et al have also just reported the results of a phase II study using the ER antagonist fulvestrant (Faslodex) in patients with recurrent disease.5 Clinical benefit via stable disease, partial response, or complete response was experienced by half of the study group and ER-a expression was also associated with clinical benefit. Like the Consortium Study findings, these confirm that ovarian cancer includes a subset of tumors with sensitivity to estrogen pathway blockade.
Prospective validation is required for any molecular phenomena indicating that prognostic steroid hormone biomarkers can serve as pathway targets that might affect survival outcomes. One important avenue that should be explored is whether the frequency of ER and PR in endometrioid ovarian carcinomas segregates the risk of lymph node metastases and distant spread just as cellular and tumor grade does in endometrioid adenocarcinoma of the uterus.6 ■
Dr. Tewari is Director of Research, Division of Gynecologic Oncology, University of California, Irvine.
Disclosure: Dr. Tewari reported no potential conflicts of interest.
1. Sieh W, Köbel M, Longacre TA, et al: Hormone-receptor expression and ovarian cancer survival: An Ovarian Tumor Tissue Analysis Consortium study. Lancet Oncol 14:853-862, 2013.
2. Hurteau JA, Brady MF, Darcy KM, 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 119:444-450, 2010.
3. Zhao D, Zhang F, Zhang W, et al: Prognostic role of hormone receptors in ovarian cancer: A systematic review and meta-analysis. Int J Gynecol Cancer 23:25-33, 2013.
4. Diep CH, Charles NJ, Gilks CB, et al: Progesterone receptors induce FOXo1-dependent senescence in ovarian cancer cells. Cell Cycle 12:1433-1449, 2013.
5. Argenta PA, Um I, Kay C, et al: Predicting response to the anti-estrogen fulvestrant in recurrent ovarian cancer. Gynecol Oncol. Jul 30, 2013 (early release online).
6. Monk BJ: Personal communication to K.S. Tewari. August 20, 2013.