Clinical significance of Mullerian inhibiting substance type II receptor (MISIIR) expression in epithelial ovarian cancer Free

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Objectives: MISIIR is a member of the transforming growth factor beta (TGF-B) family that is expressed by some ovarian cancers. Mullerian inhibiting substance (MIS) is the natural ligand for MISIIR. Ligand-receptor biding can induce apoptosis and act synergistically with cytotoxic agents in vitro. Little has been published about the effects of MISIIR expression on the biologic behavior of epithelial ovarian cancer (EOC). We hypothesized that expression of MISIIR in vivo impacts the clinical behavior of EOC and the response to chemotherapy. We sought to determine the effect of MISIIR expression on disease free survival (DFS) and overall survival (OS) in EOC.

Methods: Two tissue microarrays (TMAs) were constructed from patients with primary EOC. The first TMA (random) consisted of 59 randomly-chosen patients with serous, clear cell and endometrioid EOC. The second TMA (chemopredictive) consisted of an additional 39 advanced stage, high-grade EOCs, all optimally cytoreduced and treated with platinum-based chemotherapy and defined as poor or good responders. Immunohistochemical (IHC) analysis was performed utilizing a monoclonal anti-MISIIR antibody. Intensity of staining (0 to 3+) was determined by two independent observers; 0/1+ was considered negative and 2+/3+ positive. JMP statistical software was used for statistical analysis.

Results: The random TMA demonstrated MISIIR expression in 59% (35/59) of EOCs. There was no association between MISIIR expression and stage or grade [early vs. late stage (p=0.29, Chi square) or low vs. high grade (p=0.85, Chi square)]. There was no difference in expression between optimally and suboptimally debulked tumors (p=0.21, Fisher exact). DFS was independent of MISIIR expression in univariate (p=0.74, log rank) and multivariate analyses (p=0.47). Using the chemopredictive TMA we first analyzed the lowest and highest quartiles for survival and found no difference in MISIIR expression (25% vs. 22% MISIIR expression in early vs. late recurrence respectively). This was corroborated using time points of 12 and 18 months to first recurrence. Notably, for both TMAs analyzed separately we observed a marked improvement in median OS for MISIIR positive tumors: [(82 months vs. 54 months, random TMA)(60 vs. 41 months, chemopredictive TMA)]. However, in both instances Kaplan-Meier analysis was not statistically significant (p=0.4, log-rank) though power was limited at later time points due to censoring.

Conclusions: MISIIR expression occurs in a high percentage of EOC. Expression is not correlated with grade, stage or cytoreduction status in EOC which would suggest it has broad applicability as a potential target for therapy. We observed a trend toward markedly improved median survival for MISIIR positive cases in 2 independent cohorts but this must be interpreted cautiously until larger cohorts with more patients at later time points are available.