201 HIF 1 ALPHA AND PHOS S6 ARE INDEPENDENT PREDICTORS OF SURVIVAL IN CLEAR CELL RENAL CELL CARCINOMA (CCRCC)

Article Outline

• INTRODUCTION AND OBJECTIVES
• METHODS
• RESULTS
• CONCLUSIONS
• Copyright

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INTRODUCTION AND OBJECTIVES 

Dysregulation of mTOR pathway has been demonstrated in several types of malignancies. mTOR pathway interacts with effectors of cell cycle progression and ultimately regulates protein translation and cell proliferation. Hypoxia modulates mTOR pathway through accumulation of HIF1. Agents targeting mTOR are in various stages of clinical development. Here we assess the expression of members of mTOR pathway in ccRCC and their potential prognostic role.

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METHODS 

Standard immunohistochemical analysis was performed for PTEN, phos Akt, p27, c-MYC, 4-EBP1, phos S6, and HIF1 using TMAs constructed from 176 pts treated at our hospital (1982-2005). The tumors included 135 primary ccRCC(53.5% pT1, 46.5% pT2-3) and 41 unrelated metastatic lesions. Nuclear and or cytoplasmic expression was assessed for each marker as the percentage of positive cells (extent) and intensity of staining (0 to 3+). A final H-score was calculated in each tumor as the product of intensity x extent. Marker H-score was correlated with clinico-pathological parameters, disease progression and disease specific survival (DSS) on univariate analysis. Immunoexpression of each marker was also correlated with outcome on multivariate analysis adjusting for established prognostic parameters.

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RESULTS 

Disease progression and DSS rates in our cohort were 65% and 49%, respectively. Mean length of follow-up was 55 months (2-231). Primary ccRCC: On univariate analysis, all tested markers significantly correlated with pTNM stage(p<0.03). p27, phosS6, 4-EBP-1 and HIF expression was significantly higher in tumors compared to benign controls (p=0.0000). These markers were also predictors of disease progression (p<0.009) and DSS (p=0.001;p=0.001; p=0.01and p=0.0008 respectively). Additionally, loss of p27 correlated with tumor size (p=0.000) and Fuhrman grade (p=0.03). On multivariate analysis, both elevated phos S6 and HIF1 expression were independent predictors of DSS (p= 0.000 and 0.001, respectively). Metastatic ccRCC: A statistically significantly higher expression of c-myc, phos S6, phos Akt and 4-EBP1 (p<0.01;) was detected in metastatic tumors compared to primary ccRCC.

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CONCLUSIONS 

We found the expression of several members of the mTOR pathway to be significantly correlated with pTNM stage, disease progression and DSS in ccRCC further lending support to therapeutically targeting mTOR pathway in these tumors. HIF1 and phosS6 independently predicted DSS in our cohort.