p53, p21 and mdm2 expression vs the response to radiotherapy in transitional cell carcinoma of the bladder

Abstract

Objective To identify, in a retrospective study, possible molecular markers predictive of radioresponsiveness in patients with transitional cell carcinoma (TCC) of the bladder. Patients and methods Patients with T2±T4a TCC treated with preoperative radiotherapy and cystectomy were included in the study if their cystectomy specimen was pT3b (in 42) or pT0 (in 17). Because treatment schedules changed over time, radiotherapy was given either as 2 Gyr23 over 4±5 weeks with cystectomy 4±5 weeks later (in 23), or as 4 Gyr5 during 1 week with cystectomy in the following week (in 36 patients).Protein expression of p53, mdm2 and p21 (CDKN1 A/WAF1/CIP1/SDI1) was assessed immunohistochemically in biopsies taken before radiotherapy. Results There was no difference in protein expression when comparing all patients with pT0 and pT3b.However, for patients receiving 46 Gy, increased p53 expression (but not p21 or mdm2) predicted the absence of residual tumour (P=0.005): six of seven patients with >50% p53 expression had pT0 in the cystectomy specimen, whereas 10 of 12 patients with f 5% expression had pT3b. Over-expression of p53 correlated with longer overall (P=0.045) and cancer-speci®c survival (P=0.020). Conclusion The expression of mdm2 or p21 did not predict radioresponsiveness in patients with TCC of the bladder. The role of p53 remains unclear; the view that p53 over-expression confers radioresistance in bladder cancer is not supported.

MRE11 Expression Is Predictive of Cause-Specific Survival following Radical Radiotherapy for Muscle-Invasive Bladder Cancer

“…Whereas we found no correlation for ATM, RAD50, NBS1 and H2AX, we found the opposite effect for MRE11. In two independent test and validation cohorts (the second prospectively acquired) with similar 3-year CSS rates (61.8% and 65.1%), comparable to those of other centers (13,15,17,(21)(22)(23)(24), our data show that low tumor MRE11 protein expression level is an independent factor associated with worse CSS following radical radiotherapy for bladder cancer. Although not validated, similar results have been reported in breast cancer (9), with high expression of MRN complex proteins associated with improved prognosis and better outcome following adjuvant radiotherapy.…”

“…More than 80% are in exons 5 to 8 (coding the p53 DNA binding domain); more than 75% of these are missense mutations. Both TP53 mutations and p53 protein expression by immunohistochemistry have been studied in tumors clinically, but no clear association has been shown between the two (11) and the literature on tumor p53 immunohistochemistry expression and radiotherapy outcomes is conflicting (11)(12)(13)(14)(15)(16)(17)(18).…”

Retinoblastoma protein expression is an independent predictor of both radiation response and survival in muscle-invasive bladder cancer

“…T stage has previously been demonstrated to be predictive for the outcome in bladder cancer subjected to radical radiotherapy (Sengelov and von der Maase, 1999). However, when cohorts receiving preoperative radiotherapy have been examined, correlations have been less consistent (Pollack et al, 1997b;Rotterud et al, 2001). In this context, it is important to realise that the supposed benefit from preoperative radiotherapy lies in an effect on micrometastatic spread at the time of surgery and not in the eradication of the primary tumour.…”

MDM2 and Human Malignancies: Expression, Clinical Pathology, Prognostic Markers, and Implications for Chemotherapy

“…Although there are many reports of MDM2 expression being related to a worse response to treatment, there have been a few that contradict these results. Rotterud and colleagues noted no significant role for MDM2 in the radioresistance of tumors in 59 patients with transitional cell carcinoma of the bladder [92]. Another study of colorectal cancer samples found no correlation between MDM2 expression and the response to chemotherapy [93].…”