Phosphorilated S6 Expression Status Predicts Progression and Disease Specific Survival in Urothelial Carcinoma Following Cystectomy
L Schultz, R Albadine, J Hicks, AM De Marzo, M Schoenberg, GJ Netto. Johns Hopkins University, Baltimore, MD
Background: Bladder urothelial carcinoma (UrCa) continues to carry an unacceptably high rates of mortality and morbidity with 10-years survival rate of 40-50%. Identifying novel molecular prognostic factors and targets of therapy is therefore crucial. mTOR pathway plays a pivotal role in establishing cell shape, polarity, migration and proliferation.
Design: Tissue microarrays (TMA) were constructed from 144 archival cystectomies (14 pTis/pTa, 16 pT1, and 111 pT2-4 cases) performed at our hospital (1994-2002). They included 121 invasive UrCa and 12 UrCa with divergent aggressive differentiation (sarcomatoid, squamous and undifferentiated). Triplicate tumor and paired benign urothelium were spotted from each specimen. TMA spots were categorized as to presence of invasion. Standard immunohistochemistry analysis for mTOR pathway members PTEN, c-MYC, p27, phos Akt, phos S6, and 4-EBP1 was performed. Markers were evaluated for pattern of staining, percent of positive cells and intensity (0 to 3+ score). A final H-score was generated for each marker as a product of intensity x extent of immunoexpression.
Results: Mean patient age at cystectomy was 68 y; M:F ratio was 4:1 and mean length of follow-up was 82.6 months (1-182). Forty-nine (36%) pts received intravesical BCG/mitomycin and 13 (9%) received neoadjuvant radio/chemotherapy. In our cohort, disease progression rate was 42% (25% local recurrence and 17% distant metastases). Overall survival (OS) and disease specific survival (DSS) rates were 60% and 68%, respectively. PTEN showed loss of expression in 35% of UrCa. On univariate analysis, all markers showed lower expression in invasive UrCa compared to benign urothelium with the exception of 4-EBP1 (higher in UrCa). PTEN, p27, phos Akt, phos S6 and 4-EBP1 expression correlated with pTNM (p< 0.03). C-MYC, p27, and phos Akt expression significantly correlated with divergent aggressive differentiation and presence of invasion in analyzed TMA spot. Phos S6 was predictive of OS (p=0.01), DSS (p=0.008) and progression (p=0.05) with higher expression levels predicting favorable outcome. On multivariate analysis phos S6 remained an independent predictor of DSS (p=0.006) after adjusting for clinical stage, pTNM, invasive TMA spot histology and divergent aggressive differentiation.
Conclusions: We found an overall downregulation of mTOR pathway members in our cohort of bladder cancers. Phos S6 was an independent predictor of DSS on univariate and multivariate analysis.
Category: Genitourinary (including renal tumors)
Tuesday, March 23, 2010 2:00 PM
Platform Session: Section A, Tuesday Afternoon