P53 STATUS AND PROGNOSIS OF LOCALLY ADVANCED PROSTATIC ADENOCARCINOMA- A STUDY BASED ON RTOG-8610

Background: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and ar e associated with advanced disease. Purpose: We assessed the prognosti c value of identifying abnormal p53 protein expression in the tumors o f patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blocka de before and during the radiation therapy. Methods: The study populat ion consisted of a subset of patients entered in Radiation Therapy Onc ology Group protocol 8610 (''a phase III trial of Zoladex and flutamid e used as cytoreductive agents in locally advanced carcinoma of the pr ostate treated with definitive radiotherapy''). Immunohistochemical de tection of abnormal p53 protein in pretreatment specimens (i.e., needl e biopsies or transurethral resections) was achieved by use of the mon oclonal anti-p53 antibody DO7; specimens in which 20% or more of the t umor cell nuclei showed positive immunoreactivity were considered to h ave abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival we re evaluated in univariate (logrank test) and multivariate (Cox propor tional hazards model) analyses, Reported P values are two-sided. Resul ts: One hundred twenty-nine (27%) of the 471 patients entered in the t rial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patient s. Statistically significant associations were found between the prese nce of abnormal p53 protein expression and increased incidence of dist ant metastases (P =.04), decreased progression-free survival (P =.03), and decreased overall survival (P =.02); no association was found bet ween abnormal p53 protein expression and the time to local progression (P =.58). These results were independent of the Gleason score and cli nical stage. A significant treatment interaction was detected with res pect to the development of distant metastases: Among patients receivin g both radiation therapy and hormone therapy, those with tumors exhibi ting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P =.001); for patients treated wit h radiation therapy alone, the time to distant metastases was unrelate d to p53 protein expression status (P =.91). Conclusions: Determinatio n of p53 protein expression status yields significant, independent pro gnostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with loca lly advanced prostate cancer who are treated primarily with radiation therapy. Implications: The interaction of radiation therapy plus hormo ne therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone th erapy act, at least in part, by the induction of apoptosis (a cell dea th program) and suggests that this mechanism may be blocked in patient s whose tumors have p53 mutations.