ABNORMAL BCL-2 AND PRB EXPRESSION ARE INDEPENDENT CORRELATES OF RADIATION RESPONSE IN MUSCLE-INVASIVE BLADDER-CANCER

The objective of this study was to determine whether the overexpressio n of bcl-2, a key protein governing the apoptotic response to radiatio n, adds to pRb status in estimating the propensity for radiation respo nse in patients with muscle-invasive bladder cancer, Archival formalin -fixed, paraffin-embedded, pretreatment bladder tumor samples were ava ilable in 109 of 301 patients treated preoperatively with 50 Gy in 25 fractions followed by radical cystectomy 4-6 weeks later, Radiation re sponse was assessed by clinical-to-pathological tumor downstaging or u pstaging, Altered expression of bcl-2 (47% of 107 patients), p53 (56% of 109 patients), and pRb (30% of 98 patients) was assessed by immunoh istochemical staining, Morphological criteria were used to calculate t he percentage of apoptotic cells, bcl-2 staining correlated with tumor grade; all grade 2 tumors (n = 7) displayed normal bcl-2 expression ( negative staining), No correlations between bcl-2 staining and pretrea tment apoptosis levels, p53 staining, and pRb staining were observed, In terms of the radiation response parameters, univariate analyses rev ealed that bcl-2 overexpression was the only factor associated with up staging, The main predictor of downstaging was the loss of pRb express ion (negative staining), Multivariate logistic regression confirmed th ese findings and also showed that normal pRb expression (positive stai ning) was significantly related to upstaging, Patient outcome was adve rsely affected by bcl-2 overexpression, because these patients experie nced significantly increased actuarial local failure rates, No differe nce in distant metastasis or survival rates by bcl-2 staining was seen , The strongest independent correlates of radiation response thus far identified in muscle-invasive bladder cancer are from bcl-2 and pRb im munohistochemical staining, The overexpression of bcl-2 and the normal expression of pRb seem to thwart the apoptotic response to radiation via independent mechanisms, Abnormalities in the expression of protein s that regulate apoptosis may prove to establish a molecular phenotype to characterize which patients should receive radiotherapy.