Biomarkers of Prostate Cancer Radiation Outcome

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DESCRIPTION (provided by applicant): There is increasing evidence that prostate cancers have molecular alterations that render them poorly responsive to radiation therapy and that are associated with a significant proportion of treatment failures. Certain biomarkers for these alterations have been identified as being prognostic for clinical outcome in high grade, locally advanced prostate cancer, but there is far less such information available for favorable or intermediate risk patients, the type of patient most frequently diagnosed today. The Radiation Therapy Oncology Group's multi-institutional randomized trial RTOG 94-08, focused primarily upon this important favorable-to-intermediate risk group of patients, comparing radiation therapy with or without 4 months of androgen ablation therapy. Diagnostic tumor specimens from 875 patients from this trial have been archived by RTOG and will be made available for the study proposed here. This provides a unique opportunity to carry out correlative studies between appropriately selected biomarkers and clinical outcome, with a statistical power not previously available. Study biomarkers have been selected based upon prognostically useful prevalence ranges and pathways linked to radiation and/or androgen deprivation response. The specific aims of this proposed study are to: 1) immunohistochemically measure the levels of p53, Bcl-2, bax, mdm2 and Ki-67 in pre-treatment diagnostic biopsy specimens from the RTOG clinical trial 94-08; 2) analyze correlations between these markers and clinical outcomes (freedom from biochemical and metastatic failure) in univariate and multivariate fashion, taking conventional prognosticators such as stage, grade and PSA into account; and 3) examine whether the predictive value of these molecular markers is influenced by the use of short term androgen deprivation therapy in one of the two treatment arms. Both manual and computer assisted analyses of immunohistochemical staining will be employed. If successful, this proposed study will define biomarkers that are clinically useful in predicting response to radiation with or without androgen deprivation therapy in the important group of early-to-intermediate risk prostate cancer patients, will provide insight into mechanisms of resistance to radiation or androgen deprivation and will guide the design of future clinical trials that could include biologic/molecular interventions directed against these biomarker-associated pathways.