Do molecular biomarkers have prognostic value in primary T1G3 bladder cancer treated with bacillus Calmette-Guerin intravesical therapy?

摘要

Objectives: We examined whether altered protein expression for 7 potential biomarkers, including p53, pRb, PTEN, Ki-67, p27, FGFR3, and CD9, could predict tumor recurrence and progression in patients treated with bacillus Calmette-Guerin (BCG) therapy for primary stage T1 grade 3 (T1G3) bladder cancer (BC).Materials and methods: The study included 61 patients with primary T1G3 BC who were treated with 6 weekly intravesical BCG instillations after clinically complete transurethral resection of bladder tumor between 1990 and 2007. All patients had proper muscle tissue in their specimen. Protein expression for 7 molecular biomarkers before BCG therapy was analyzed by immunohistochemistry based on tissue microarray methodology, and the percentage of positive cells was determined quantitatively in a blind fashion. Survival analysis was performed using Kaplan-Meier curves and Cox regression to determine the effect of each marker on recurrence-free survival (RFS) and progression-free survival (PFS) after BCG therapy. Results: Overall 5-year RFS and PFS rates were 56.0% and 84.5%, respectively, with a median follow-up of 60.0 months (range 6-217). The altered expression for each marker were noted in 53.3% for p53, 73.3% for pRb, 63.8% for PTEN, 40.0% for Ki-67, 66.1% for p27, 37.3% for FGFR3, and 47.5% for CD9, respectively. No significant association was found between altered marker status and clinicopathologic characteristics. While increased p53 expression was associated with progression after BCG therapy (5-year PFS rates: 90.7% in p53 < 10% vs. 78.7% in p53 > 10%, P = 0.0495), no single marker was associated with RFS and PFS after BCG therapy in univariate and multivariate Cox regression analysis. Similarly, in subgroup analysis according to tumor size, multiplicity, and morphology, no single marker was associated with RFS and PFS. No difference was noted in molecular marker status between BCG responders and nonresponders. Conclusions: Our findings indicate that immunohistochemical analysis for 7 potential molecular markers has no predictive value for recurrence and progression in primary T1G3 BC treated with BCG therapy. Large prospective studies are needed to validate the prognostic molecular markers in primary T1G3 BC.