Biomarkers of Prostate Cancer Radiation Outcome

描述（由申请人提供）：越来越多的证据表明前列腺癌具有分子改变，使其对放射治疗反应不良，并与相当大比例的治疗失败相关。这些改变的某些生物标志物已被鉴定为高级别局部晚期前列腺癌的临床预后，但对于有利或中等风险患者（当今最常诊断的患者类型），此类信息要少得多。 放射治疗肿瘤学组的多机构随机试验RTOG 94-08主要关注这一重要的可接受至中等风险患者组，比较了放射治疗伴或不伴4个月雄激素消融治疗。来自本试验的875例患者的诊断性肿瘤标本已由RTOG存档，并将用于此处拟定的研究。这提供了一个独特的机会，进行适当选择的生物标志物和临床结果之间的相关性研究，具有以前不可用的统计功效。 研究生物标志物的选择是基于与辐射和/或雄激素剥夺反应相关的临床有用的患病率范围和途径。本研究的具体目的是：1）化学发光法测定来自RTOG临床试验94-08的治疗前诊断活检标本中p53、Bcl-2、bax、mdm 2和Ki-67的水平; 2）分析这些标志物与临床结果之间的相关性（无生化和转移失败）的单变量和多变量方式，考虑到传统的预测因素，如阶段，等级和PSA;和3）检查这些分子标志物的预测值是否受两个治疗组之一中短期雄激素剥夺疗法的使用的影响。将采用人工和计算机辅助免疫组织化学染色分析。 如果成功，这项拟议的研究将确定在早期至中度风险前列腺癌患者的重要群体中，在预测有或没有雄激素剥夺治疗的放射反应方面临床有用的生物标志物，将提供对放射抵抗或雄激素剥夺机制的深入了解，并将指导未来临床试验的设计，其中可能包括针对这些生物标志物的生物/分子干预-相关路径。

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 Diagnostic tumor specimens from 875 patients from this trial have been archived by RTOG and will be made available for the study proposed here.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.