Survival times in patients with bladder cancer are highly variable, even in patients whose tumor is categorized for stage and grade based on histopathology. We and others have reported that elevated debrisoquine recovery ratio levels (DBRR) and reduced dapsone recovery ratio (DPRR) were significant risk factors for aggressive bladder disease. We have sought to evaluate whether or not these novel phenotypic trait measures are prognostic indicators of survival which could be of value in guiding clinical decisions. In a preliminary study, a panel of cytochrome P450 (CYP) enzyme phenotypic markers were evaluated as potential predictors of survival time in patients with superficial (Ta, T1, CIS)(n=44) and invasive (T2, T3, T4) transitional cell bladder cancer (n=43). At the time of diagnosis, each subject received a cocktail of three oral drugs simultaneously:mephenytoin (100mg), debrisoquine (10mg) and dapsone (100mg) as in vivoprobes of CYP2C19, CYP2D6 and CYP3A, respectively. All cases were followed until death or up to 311 months, depending on which occurred first. Patients with superficial disease were followed with 3-monthly review cystoscopies to screen for the presence of recurrence and progression. Patients with invasive tumors were followed after radiotherapy or cystectomy as appropriate clinically. For each drug, the metabolic ratios were determined and phenotypic poor metabolizers (n=4) were excluded from the survival analysis. Invasive bladder cancers with below median CYP2D6 mediated DBRR (<0.56) had an increased median survival time compared to the median survival in patients with above median DBRR (39.5 months (95% CI 14-145) vs. 12 months (95% CI 7-32), p<0.02). Conversely and independently, there was a subgroup of invasive bladder cancers with improved survival identified in this instance by above median DPRR (>0.524) in comparison to a DPRR below the median (37.5 months (95% CI 23-) vs. 14 months (95% CI 5-39), p<0.04). Significant differences in survival times were not detected among superficial bladder cancer cases even when stratified by grade. A further subset analysis of the invasive group revealed a seven-fold increase in median survival in cases with the combination of the low-risk phenotype (both low DBRR and high DPRR). The present study suggests that the invasive bladder tumors associated with high CYP2D6 and low CYP3A activity have a different pathophysiology and natural history based on these novel phenotypic traits. Studies in a larger population incorporating additional phenotypic and genotypic biomarkers of disease susceptibility and outcome are ongoing. Supported in part by 2R01 CA 59834.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA