The primary objectives of this research are to continue screening studies in a cohort of workers occupationally exposed to benzidine to both develop a bladder cancer screening approach as well as to reduce the number of deaths and serious morbidity associated with bladder cancer in this cohort. This approach to bladder cancer screening and risk control may have broad application in occupationally exposed workers and in high risk individuals such as smokers over the age of 55 in the general population. We propose to continue to screen and monitor a cohort of approximately 2,000 Chinese workers exposed to benzidine to identify confirmed and presumptive cases of bladder cancer and conduct a risk factor analysis. In a pilot study and in a 2-year bladder cancer screening program we have detected bladder cancer in its earliest stages prior to detection by conventional cytologic criteria using a biomarker profile consisting of G-actin, a marker for early differentiation changes, the p300 tumor-related antigen detected with M344 monoclonal antibody, and abnormal DNA ploidy detected by the presence of cells with >5C DNA. To date, we have screened 1686 exposed male workers and 388 unexposed male controls matched for age and smoking. Preliminary statistical analysis of the results from workers in two of the cities using the previously defined panel of biomarkers using both khi2 and Logistic Regression, identified highly significant correlations ( p < 0.05 to 0.001) were found with duration of benzidine exposure, pack-years smoked, and urinary stasis associated with benign prostatic hypertrophy, all of which are also risk factors for bladder cancer. The currently employed weighted exposure index and hematuria did not correlate with the biomarkers. The current proposed program is designed to assess the bladder cancer risk of exposed individuals and validate using a panel of biomarkers for risk assessment. The ultimate aim is to devise a strategy that will detect persons likely to develop dangerous, invasive disease early enough to alter potentially unfavorable outcomes and release those at little elevated risk. The detection window during which this can be achieved with conventional screening techniques is very narrow, but can be widened with new tests based upon detecting the emerging malignant phenotype rather than waiting for frank cancer. The original screening is estimated to stratify the approximately 2000 subjects and controls into Group 1-negative for all biomarkers (1500 subjects); Group 2- positive for one marker (400 subjects) and Group 3 - positive for two or more markers (100 subjects). In the current proposal Group 1 will be screened every 3 years, Group 2 every year, and the highest risk Group 3 every 6 months. Concomitantly, patients will undergo routine urinalysis, Papanicolaou cytology, and physical examinations including updating occupational and smoking history and for urologic symptoms. Additional markers will be investigated with this group to determine if more specific markers for emerging aggressive disease can be identified. Potential examples include epidermal growth factor receptor and one or more oncogene proteins (e.g., p185-neu/erbB2). The end result will be a risk assessment and monitoring strategy for effective cancer control.
