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Unfavorable Prognosis in Advanced Serous Ovarian Cancer May Be Linked to Estrogen Receptor Beta Isoform

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Key Points

  • This study is reportedly the first to analyze the subcellular expression of estrogen receptor beta isoforms in advanced serous ovarian cancers.
  • Patients who had cytoplasmic estrogen receptor beta 2 expression had significantly worse 5-year outcomes than did those who did not (28% vs 60%).
  • The significant connection between cytoplasmic estrogen receptor beta 2 and chemoresistance has clinical implications for the development of newer interventions.

Anomalies in the cytoplasmic expression of estrogen receptor beta 2 appear to be associated with poorer outcomes in patients with advanced serous ovarian cancer, according to the results of a study reported by Ciucci et al in Gynecologic Oncology. This isoform may represent an independent unfavorable prognostic marker and/or a marker predicting chemoresistance in women with this type of ovarian cancer.

Clinical data seem to implicate estrogen as a major player in ovarian cancer, with a large number of ovarian tumors expressing estrogen receptor beta. In contrast to estrogen receptor alpha, which appears to be involved in cell survival and proliferation, the natural function of estrogen receptor beta seems to be that of a tumor suppressor.

Study Details

To shed light on the prognostic role of estrogen receptor beta in ovarian cancer, the investigators examined the pattern of expression of the full-length estrogen receptor beta (estrogen receptor beta 1) and two estrogen receptor beta splice variant isoforms (estrogen receptor beta 2 and 5) in 56 patients with advanced serous ovarian cancer. They then correlated the pattern of expression with clinicopathologic parameters and with response to chemotherapy.

A glimpse at the demographics of this study population showed a median age of 54 years. Thirty-five patients (63%) underwent complete resection. In addition, all patients were treated with platinum-based chemotherapy, and approximately 90% also received paclitaxel. Median follow-up was 47 months. A total of 16 patients were found to be chemoresistant, and 40 patients were chemosensitive.

Poorer Outcomes With Estrogen Receptor Beta 2 Expression

In their cohort, estrogen receptor beta 2 was mainly localized in the cytoplasm, whereas estrogen receptor beta 1 and 5 were predominantly expressed at the nuclear level. Nearly 60% of the tumors showed a medium level of estrogen receptor beta 1 nuclear staining without cytoplasmic immunoreactivity. When cytoplasmic immunoreactivity was present, it was of low intensity. About 45% of patients showed a cytoplasmic reaction of medium intensity. Furthermore, chemoresistant patients seemed to demonstrate cytoplasmic estrogen receptor beta 2 expression more often than chemosensitive patients (P = .03).

Turning to the association between immunohistochemical results and survival data, the investigators found that the median overall survival was 47 months. Based on the univariate survival analysis, the only molecular marker that was significantly associated with a shorter overall survival was cytoplasmic estrogen receptor beta 2 expression (P = .0006). The 5-year survival rate was lower for patients who expressed this isoform than for those who did not (28% vs 60%).

Similar findings were revealed for disease-free survival. Again, the only molecular marker that was significantly associated with a shorter disease-free survival was cytoplasmic estrogen receptor beta 2 expression (median of 14 months vs 23 months in negative patients; P = .04). In addition, for those who expressed this isoform, the 5-year recurrence rate was about 88%, compared with 65% for those who did not.

In the subset of platinum-sensitive patients, cytoplasmic estrogen receptor beta 2 expression maintained its unfavorable role. Those who expressed this isoform had a shorter median overall survival than those who did not (53 months vs undefined; P = .004). Again, the 5-year survival rate reflected this negative association: 43% for those who expressed cytoplasmic estrogen receptor beta 2 and 72% for those who did not.

Finally, the investigators identified a statistically significant association between cytoplasmic estrogen receptor beta 2 immunoreactivity and chemoresistance. They suggested that the mitochondrial antiapoptotic action of this isoform may contribute to chemotherapy resistance in ovarian cancer.

Clinical Implications

This is reportedly the first study to analyze the subcellular expression of estrogen receptor beta and its isoforms in advanced serous ovarian cancer. Although the investigators admitted that their cohort is small and the functional role of cytoplasmic estrogen receptor beta is far from clear, the prognostic role of estrogen receptor beta 2 in advanced serous ovarian cancer is promising. Its immunohistochemical assessment at the time of surgery might help to identify candidates for clinical trials of new interventions.

The investigators remarked, “One of the striking observations of this study was the strong statistical association of cytoplasmic estrogen receptor beta 2 immunoreactivity with reduced survival, a finding also reported in familial and sporadic breast cancers.”

Daniela Gallo, PharmD, of the Catholic University of the Sacred Heart, Rome, is the corresponding author of the article in Gynecologic Oncology.

The authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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