Prognostic effect of mammalian target of rapamycin pathway in prostate adenocarcinoma

Aim: Prostate cancer is the most frequent type of cancer in the world and it's incidence is increasing. Even though this cancer can be managed by active surveillance for a group of patients, it is not a proper way for other group of patients that show more aggressive features. Many researches conduct to find out for new treatment methods based on immunotherapy. Recent researches show that mammalian target of rapamycin (mTOR) cascade may be an alternative for prostate cancer's treatment. Experimental and clinical studies shows that mTOR inhibitors have anti-angiogenic and growth inhibitory characteristic on several types of cancer. However, the studies on mTOR pathway changes for prostate cancer patients have not been detailed. In this study, mTOR signaling pathway proteins (AKT, p-mTOR, 4E-BP1, p-P70S6K, PIK3CA) and several proteins that affect this pathway (PTEN, Stathmin-1, Cyp4z1, E-cadherin, Hey2) were studied by immunohistochemistry. Immunohistochemical data were compared with pathologic prognostic parameters and biochemical recurrence. Material& method: 389 prostate carcinoma patients were included in the study diagnose between 2003 and 2013. Tissue micro-array blocks were prepared from tumor areas. AKT, p-mTOR, 4E-BP1, p-P70S6K, PTEN, Stathmin-1, Cyp4z1, E-cadherin, Hey2 immunhistochemical stains were applied to the sections prepared from these blocks. Staining extent of >0% but <10% was graded as 1, ≥10% but <50% as 2, and ≥50% as 3. Weak intensity of staining was graded as 1, moderate intensity as 2, and strong intensity as 3. Immunoreactivity score and staining intensity scores were multiplied by each other. Final staining scores of 0-9 were obtained. Total staining scores were grouped. 0-3 score was considered weak expression (negative staining). 4-9 score was considered strong expression (positive staining). Immunhistochemical results were statistically compared with prognostic parameters. In the analysis, Independent groups t test for continuous variables, Pearson's chi- square test for discontinuous variables were applied. Statistical significance in this study was set at P≤0.05. Correlation of immunostaining with biochemical relapse was done using a Cox regression model (%95 confidence interval). Results: There was statistically significant correlation between Gleason score, surgical margin positivity, pT stage, tumor volume and biochemical recurrence. There was no significant relationship between tertiary pattern, vascular invasion, perineural inasion, lymph node involvement and biochemical recurrence. Statistical significance was found between immunohistochemical score p-P70S6K, PTEN with pT stage and Gleason score. Statistical significance was found between Stathmin-1 and Gleason score and perineural invasion. The results indicate that AKT-1 positivity decreased the risk of biochemical recurrence (x0.357, 64.3%) statistically. Conclusion: In our study, statistically there was a significant relation between the biochemical recurrence with Gleason score, surgical margin positivity, pT stage and tumor volume. However, there was no significant relation between the biochemical recurrence with tertiary pattern, vasculary invasion, perineural invasion, lymph node involvement. Since there was statistically significant relationship between two prognostic parameters Gleason score and pT stage, with proteins p-P70S6K, PTEN and Stathmin-1 which have impact on mTOR pathway, these proteins and AKT expression that was found to be related with biochemical recurrence are suggested to have prognostic impact on prostate carcinoma.