mTOR Pathway in Papillary Renal Cell Carcinoma (PapRCC)
GJ Netto, R Albadine, J Hicks, AM DeMarzo, VE Reuter, M Carducci, P Argani, R Pili, L Schultz. Johns Hopkins University and Memorial Sloan Kettering Cancer Ctr
Background: Dysregulation of mTOR pathway has been demonstrated in several types of solid malignancies. mTOR pathway activation interacts with effectors of cell cycle progression and ultimately regulates protein translation and cell proliferation. Hypoxia modulates mTOR pathway through HIF1α accumulation. Agents targeting mTOR are in various stages of clinical development. We assessed the status of mTOR pathway components in PapRCC and their potential prognostic role.
Design: Standard immunohistochemical analysis was performed for PTEN, phos Akt, p27, c-MYC, 4-EBP1, phosS6, and HIF1 α using tissue microarrays constructed from 54 primary PapRCC treated at our hospital (2004-2006). 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, and was correlated with clinicopathological parameters and outcome on univariate and multivariate analyses.
Results: Median and mean follow up in our cohort was 36 months (range: 2-68). The overall progression rate and disease specific survival rates were 17% and 92%, respectively. Comparing biomarkers expression in paired benign and PapRCC tissue, we found significantly higher expression of phos S6, 4-EBP1 and HIF1 α in PapRCC (p<0.005). In contrast, p27 and phos Akt expression was lower in PapRCC (p<0.03). Loss of PTEN was seen in 44% of PapRCC and was significantly correlated with tumor size (p=0.02) while loss of p27 correlated with Fuhrman grade (p=0.04). Higher 4-EBP1 expression significantly correlated with both pTNM stage (p=0.01) and Fuhrman grade (p=0.02). Higher expression of HIF1α also correlated with pTNM stage (p=0.02) and tumor size (p=0.001). On univariate analysis, only Phos S6 expression levels correlated with outcome. Phos S6 was a significant predictor of disease progression (p=0.03). We also found Phos S6 to be an independent predictor of disease progression on multivariate analysis adjusting for Fuhrman grade, pTNM stage and patient gender (p=0.05).
Conclusions: We found the expression of several members of mTOR pathway to be significantly correlated with clinicopathologic parameters in PapRCC including tumor size, pTNM stage and Fuhrman grade. High expression status of phosS6 was an independent predictor of progression in our cohort of PapRCC. If confirmed, our results support consideration of therapeutically targeting mTOR pathway in PapRCC.
Category: Genitourinary (including renal tumors)
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 141, Tuesday Morning