Linking Markers of Steroid Metabolism, Cell Cycle and Microenvironment to Gleason Score: Towards the Development of a Prognostic Panel
Elsa Li Ning Tapia, Jeri Kim, Eleni Efstathiou, Xuemei Wang, Ina Prokhorova, Ivan Gorlov, Christopher Amos, Patricia Troncoso. University of Texas MD Anderson Cancer Center, Houston, TX
Background: A move from the morphologically founded Gleason grading system to a biologically based classification of prostate cancer (PCa) is needed to support “marker-driven therapy”, particularly given the emergence of promising molecularly targeted agents and our improved understanding of PCa biology. Although prognostic molecular markers for PCa have not been established, several lines of evidence link cell cycle alterations, steroid hormone metabolism, and PI3K signaling with disease progression. As an initial effort towards the broader goal of developing a therapeutically relevant classification system for PCa, we determined the association between candidate markers and Gleason grade (GG) in untreated PCa.
Design: We evaluated radical prostatectomy specimens that contained low-grade (LG) (Gleason score 6, N=45) and high-grade (HG) (Gleason score 8 or 9, n=51) peripheral zone PCa from patients who had not undergone hormonal therapy. Tissue microarrays were constructed to include areas of Gleason grades 3 and 4 derived from LG and HG tumors, respectively. Gleason grade 4 included tumors with fused (n=30) or cribriform glands (n=21). Eleven markers (Death receptor Fas, VEGF, HIF-1A, pAKT, androgen receptor, estrogen receptor alpha, estrogen receptor beta, BMP6, SRD5A2, and UBE2C) were evaluated immunohistochemically, and the percentage of immunoreactive tumor or stromal cells was recorded. Repeated-measure logistic regression models using the GEE method were fit to assess the association between marker expression and tumor grade.
Results: On multivariate analysis, three markers (ER-beta, SRD5A2, and UBE2C) were expressed significantly more frequently in HG than in LG tumors, and one (VEGF) was significantly less expressed in HG tumors. Estrogen receptor alpha expression was significantly lower in the tumor-associated stromal cells of the cribriform glands than of the fused glands (p<0.0001) on multivariate analysis.