P53 IMMUNOHISTOCHEMICAL AND GENETIC ALTERATIONS ARE ASSOCIATED AT HIGH-INCIDENCE WITH POST-IRRADIATED LOCALLY PERSISTENT PROSTATE CARCINOMA

Purpose: Several reports have shown that cells with p53 mutations disp lay increased resistance to ionizing radiation, a treatment often used clinically for localized prostate carcinoma. Materials and Methods: T otals of 18 post-irradiated locally recurrent prostatic carcinoma spec imens and 25 (no radiation) stage D1 node-positive (TxN+M0) primary pr ostatic carcinoma specimens were tested for p53 immunoreactivity by im munohistochemistry. Of the 18 post-radiation locally recurrent prostat ic carcinomas 10 were further analyzed by single strand conformational polymorphism to assess the validity of using this immunohistochemistr y approach in irradiated tissue for detecting p53 alterations. Specime ns showing p53 alterations by single strand conformational polymorphis m were subjected to nucleotide sequence analysis or tested for loss of heterozygosity at a locus within the p53 gene. Results: Of the 25 sta ge TxN+M0 prostatic carcinomas without radiation 5 (20%) were immunore active (consistent with the reported incidence of positive immunoreact ivity in clinical/surgical stage TxN+M0 primary prostatic carcinomas). In contrast, 13 of 18 post-radiation locally recurrent prostatic carc inoma specimens (72%) were immunoreactive. Multivariate logistic regre ssion analysis showed no dependence of p53 immunoreactivity to grade, stage or androgen status in the post-radiation locally recurrent prost atic carcinoma group, while 8 of 10 hormone naive prostatic carcinoma specimens (80%) were immunoreactive. The temporal relationship between p53 alterations and radiotherapy was assessed. Pre-irradiation prosta tic carcinomas available from 5 patients with immunoreactive post-radi ation locally recurrent disease were analyzed and all were immunoreact ive. Conclusions: p53 Alteration in localized prostatic carcinoma is u ncommon. Our study confirms others in that even aggressive locally adv anced nonirradiated primaries (stage TxN+M0) contain only a 20% incide nce of p53 alterations. However, our study demonstrates that p53 alter ations are found in the preponderant majority of post-radiation locall y recurrent prostatic carcinoma specimens. Limited evaluation of pretr eatment prostatic carcinoma biopsies uniformly documented the presence of p53 alterations before ionizing radiation, thereby demonstrating t hat p53 alteration was already present and was not radiation-induced o r only correlated with late stage disease. This finding suggests a pot ential for p53 immunoreactivity to be used as a pretreatment marker th at might predict local treatment failure with ionizing radiation. Larg e scale prospective trials would appear warranted to evaluate conclusi vely the potential prognostic applicability of p53 pre-screening befor e enrollment in definitive radiotherapy.