Biomarkers of Prostate Cancer Radiation Outcome

描述(由申请人提供)：越来越多的证据表明，前列腺癌的分子变化使其对放射治疗的反应较差，并与相当大比例的治疗失败有关。这些变化的某些生物标记物已被确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，即当今最常被诊断的患者类型，此类信息要少得多。 放射治疗肿瘤学小组的多机构随机试验RTOG 94-08主要集中在这一重要的有利到中等风险组患者，比较了接受或不接受4个月雄激素消融治疗的放疗。来自这项试验的875名患者的诊断肿瘤标本已由RTOG存档，并将提供给这里建议的研究。这提供了一个独特的机会，在适当选择的生物标记物和临床结果之间进行相关性研究，具有以前没有的统计能力。 研究中的生物标记物是根据与辐射和/或雄激素剥夺反应有关的预测有用的流行范围和途径来选择的。这项拟议研究的具体目的是：1)用免疫组织化学方法检测94-08年度RTOG临床试验的治疗前诊断活检标本中P53、Bcl-2、Bax、MDM2和Ki-67的水平；2)以单因素和多因素的方式分析这些标志物与临床结果(无生化和转移失败)之间的相关性；以及3)检测这些分子标志物的预测价值是否受到两个治疗小组之一的短期雄激素剥夺治疗的影响。将采用人工和计算机辅助的免疫组织化学染色分析。 如果成功，这项拟议的研究将定义在预测早期到中期风险前列腺癌患者的重要群体在接受或不接受雄激素治疗的情况下对辐射反应的临床有用的生物标记物，将提供对辐射或雄激素缺乏抵抗机制的洞察，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记物相关途径的生物/分子干预。

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 Diagnostic tumor specimens from 875 patients from this trial have been archived by RTOG and will be made available for the study proposed here.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