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

Abstract

The objective of the study was to investigate the predictive value of various clinical, biochemical, and histopathological parameters, with special emphasis on the expression of the retinoblastoma protein (pRB), on the radiation response in bladder cancer. In order to obtain a truly objective response measure, patients receiving preoperative radiotherapy followed by cystectomy were studied. Pretreatment tumour samples and clinical data from 108 consecutive patients were collected. End points were complete response (CR) to radiotherapy, relapse-free survival time and overall survival time. Expression of pRB was assessed by immunohistochemical staining as present or absent. Complete response to radiotherapy was obtained in 42 of 106 evaluable patients (40%). Predictive for CR to radiotherapy, in univariate analysis, was transurethral resection (as opposed to biopsy), B-haemoglobin, no upper urinary retention, and loss of pRB staining. Loss of pRB staining was the strongest independent predictor of radiation response in multivariate logistic regression analysis and absence of upper urinary retention was the only other significant factor. Loss of pRB was the only parameter showing statistically significant, independent association with relapse-free survival, whereas B-haemoglobin was also independently associated with overall survival. Loss of pRB expression seems to indicate a phenotype displaying enhanced radiosensivity and may be of benefit by denoting patients who would selectively benefit from a treatment schedule containing radiotherapy.

Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer

“…This is inconsistent with previous fi ndings [ 9,15,16 ] , where Rb was found to be a predictive marker for outcome after radiotherapy. A reason for this could be that we used another antibody and staining protocol, or that the tissues were handled using different fi xation protocols.…”

“…Full-slide sections were scored under the microscope. Thresholds used: p16 > 10% was considered positive [ 14 ] ; Rb was negative when no staining of carcinoma cell nuclei was observed (positive control staining of stromal cell nuclei) [ 15,16 ] ; Ki67 > 20% positive carcinoma cell nuclei was considered high [ 16,17 ] ; p53 > 20% was considered positive [ 9,16,17 ] ; TIP60 and MRE11 were scored on a continuous scale and the lowest quartile considered ' low ' [ 18 ] . pATM-positive carcinoma cell nuclei were scored on a continuous scale and the optimal threshold value defi ned by receiver operating characteristic curve.…”

Tailoring to RB: tumour suppressor status and therapeutic response

“…Specific loss of RB is associated with improved response to cytotoxic therapeutics in bladder cancer152,153, and recently published studies have demonstrated that although hyperphosphorylation of RB does not affect the response to cytotoxic agents in breast cancer, RB loss is directly associated with improved outcome with chemotherapy132. In this study the effect of RB status was independent of p53 and other pathophysiological markers in multivariate analyses.…”

Targeting the RB-pathway in Cancer Therapy

“…This finding has been further corroborated by gene expression profiling that revealed a statistically significant impact of an RB loss-of-heterozygosity signature on improved therapeutic response (32). In bladder cancer, tumors lacking RB have been shown to display an improved response to radiation (33). The aforementioned radiosensitivity of HPV-positive head and neck cancers, which are defective in RB function, would represent another tumor type supporting the concept (24, 27).…”