Prognostic factors in stage T1 grade 3 bladder cancer survival: The role of G1-S modulators (p53, p21Waf1, p27kip1, cyclin D1, and cyclin D3) and proliferation index (ki67-MIB1)

Objective: To determine the prognostic value of a subset of regulators of the transition from G1-to-S phase of cell cycle in stage T1 grade 3 bladder cancers. Methods: Fifty-one such cases were investigated to determine the significance on patient's survival of p53, p21 Waf1, p27Kip1, Cyclin D1, Cyclin D3, and ki67-MIB1 (proliferation index). The statistical analysis included Kaplan-Meier methodology with Log-rank test and Cox' proportional hazard analysis. Results: Tumor size (p = 0.0034), and the labeling index of ki67-MIb1 (p = 0.0034), p53 (p = 0.0332), p27kip1 (p = 0.0059) and Cyclin D1 (p = 0.0103) were associated to disease-free survival. Progression-free survival was related to tumor size (p < 0.0001), ki67 (p = 0.0163), p53 (p = 0.0041), p27kip1 (p = 0.0161), Cyclin D1 (p < 0.0001) and Cyclin D3 (p < 0.0001). Patient's overall survival was associated to Cyclin D3 (p < 0.0001), p53 (p = 0.0017), p21Waf1 (p = 0.0142), Cyclin D1 (p < 0.0001), ki67-MIB1 (p = 0.0450), and tumor size (p = 0.0296). Down-regulation of p27kip1 and Cyclin D3 over-expression (disease-free), over-expression of p53, Cyclin D1 and Cyclin D3 (progression-free), and over-expression of Cyclin D3 (overall survival) were independent predictors by Cox's multivariate analysis. Down-regulation of p27kip1 (p < 0.001, R.R. 0.997, 95%C.I. 0.995-0.999), and over-expression of Cyclin D1 (p < 0.001, R.R. 1.009, 95%C.I. 1.004-1.014) and Cyclin D3 (p = 0.005, R.R. 1.013, 95%C.I. 1.004-1.022) were the main independent predictors. Conclusion: Down-regulation of p27kip1 and over-expression of Cyclin D1 and Cyclin D3 might be relevant predictors of survival in stage T1 grade 3 bladder cancers, thus selecting a group of patients at higher risk of malignant behavior. (C) 2003 Elsevier B.V. All rights reserved.