Correlation and prognostic significance of p53, A21(WAF1/CIP1) and Ki-67 expression in patients with superficial bladder tumors treated with bacillusCalmette-Guerin intravesical therapy

Purpose: We determine if, before intravesical bacillus-Calmette Guerin (BCG ) therapy, p53, p21(WAF-1-CIP1) (a critical downstream effector of p53 path way of cell growth control, inhibiting cyclin dependent kinases) and the ce ll proliferation marker Ki-67 (MIB-1) could be used as prognostic markers o f response to BCG in patients with superficial bladder tumors. Materials and Methods: The study included 47 patients with superficial blad der tumors at high risk for recurrence or progression treated with 6 weekly intravesical BCG instillations. We analyzed p53, p21 and Ki-67 on paraffin embedded samples by immunohistochemistry and the percentage of positive ce lls was determined in a blinded fashion. Quantitative immunostaining was an alyzed in relation to time to recurrence and progression using univariate o r multivariate analysis and the Kaplan-Meier method. Results: During a mean followup of 24.6 months 23 of the 47 patients (48.9% ) presented with tumor recurrence and 10 (21.2%) had later progression to i nvasive disease. A p21 over expression (greater than 10%) was observed in 2 3 tumors (48.9%) and positively correlated with p53 (p = 0.0097) but not wi th Ki-67 (p = 0.327). Of the tumors 18 (38.2%) were p53 and p21 negative. A mong p21 positive tumors 15 (65.2%) were p53 and p21 positive, suggesting t hat p21 may also be regulated by p53 independent pathways. However, p53 did not act as a predictor of recurrence or progression. In contrast, using Ka plan-Meier curves p21 over expression (greater than 10%) and Ki-67 at a 25% cutoff were associated with shorter recurrence-free survival (both p = 0.0 2 log rank test) but they did not predict additional information about risk of progression. However, multivariate analysis failed to demonstrate any i ndependent prognostic value for p21 or Ki-67 in contrast to tumor stage. Conclusions: Our results indicate that p21(WAF-1-CIP1) seems to be regulate d by p53 independent pathways in superficial bladder cancer. The present st udy did not indicate an independent prognostic significance in patients tre ated with BCG for p53, p21(WAF-1-CIP1) or Ki-67 markers. Larger prospective studies are needed to evaluate further the independent value of these biol ogical markers in superficial bladder cancer management.