RETINOBLASTOMA PROTEIN EXPRESSION AND RADIATION RESPONSE IN MUSCLE-INVASIVE BLADDER-CANCER

Purpose: The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage, In this report we ex amine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4-6 weeks later by radical cystectom y, The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also descri bed, Methods and Materials: Immunohistochemical staining of pRB and p5 3 in paraffin-embedded tumor sections using WL-1 anti-RE and DO1 anti- p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively, There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease, The median age was 62 years and follow-up for those living was 85 months, Results: Staini ng for PRE Was negative in 30% of the cases, Correlations were observe d between pRB negativity and high pretreatment apoptosis level (p = 0. 06), locally advanced clinical stage (p = 0.01), increased clinical-to -pathologic downstaging (p = 0.014), and more pathologic complete resp onses (Path-CRs; p = 0,019),Several other factors were tested and were not associated with pRB status, including p53 expression, RE status w as the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression, Despite these signifi cant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed, Restriction of the analyses to S tage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p = 0.02), The overexpression of p53 also correlated with d istant metastasis freedom and overall survival in Stage T3b patients, Patient outcome was best when RE negative and p53 negative staining we re seen, Conclusion: Our results indicate that loss of RE function as measured by immunohistochemical staining is the strongest correlate of radiation response thus far recognized, Loss of RE expression also pr edicted for poor outcome in Stage T3b patients, which appeared to comp liment the finding of normal p53 expression, While normal RE protein e xpression is usually associated with better patient outcome, other ser ies have not examined patients treated with radiotherapy, The absence of pRB may be a useful marker for selecting patients for bladder prese rvation with radiotherapy, particularly when wild-type p53 is present. (C) 1997 Elsevier Science Inc.