THE PROGNOSTIC ROLE OF P53, METALLOTHIONEIN, P-GLYCOPROTEIN, AND MIB-1 IN MUSCLE-INVASIVE UROTHELIAL TRANSITIONAL-CELL CARCINOMA

Tissue from primary tumors was analyzed for 118 patients with urotheli al cancer who subsequently received cisplatin-based chemotherapy, Immu nohistochemical staining was performed for nuclear p53 reactivity; for two proposed mediators of drug resistance, metallothionein (MT) and P -glycoprotein; and for the cell proliferation marker MIB-1, For each m arker, immunoreactivity was expressed as a percentage of positively st aining cells, and overall intensity of staining was graded on a scale from 0 to 3, The product of these two measurements was calculated to g enerate a percentage-intensity index. Clinical data were obtained inde pendently via retrospective chart review, Chemotherapy regimens contai ning cisplatin (cisplatin, methotrexate, and vinblastine or methotrexa te, vinblastine, doxorubicin, and cisplatin) were administered for met astatic disease (n = 64), for locally advanced disease (n = 45), or as an adjuvant treatment (n = 9), The overall response rate was 56% amon g 99 evaluable patients, and median survival was 12.7 months, By univa riate analysis, Eastern Cooperative Oncology Group performance status (P = 0.0025), tumor grade (P = 0.03), percentage of MT staining (P = 0 .01), and percentage-intensity index of MT staining (P = 0.04) were si gnificant predictors of response to chemotherapy, The first three of t hese were significant in a multivariate model (P = 0.05, 0.04, and 0.0 4, respectively), By subgroup analysis, the percentage of MT staining predicted for response in metastatic disease (P = 0.03), but not in lo cally advanced disease (P = 0.28), Only performance status was signifi cantly related to overall survival (P = 0.0001, log-rank test) in the whole cohort, Overexpression of MT in the 64 patients with metastatic disease was associated with a shorter survival (P = 0.04), Expression of p53, P-glycoprotein, and MIB-1 did not predict for survival, In con clusion, overexpression of MT is associated with a poorer outcome from chemotherapy, possibly due to cisplatin resistance.