Research Project 5: Risk Stratification in Localized Prostate Cancer using Biomarkers in Blood

项目总结/摘要 前列腺癌的主要临床挑战之一是管理筛查检测到的、局部化的前列腺癌。 疾病近年来，“积极监督”（保守管理）的情况急剧增加， 低风险疾病。一个必然的结果是越来越多的关注用于危险分层的算法。虽然 Gleason分级对肿瘤学结果有很强的预测作用，很明显，虽然一些Gleason分级低的男性 活检分级的男性实际上确实患有高风险疾病，但许多Gleason分级较高的男性实际上不会 在生命的自然过程中经历前列腺癌的症状，即使未经治疗。我们有 显示了基于血液中的一组激肽释放酶标志物-总PSA、游离PSA、完整PSA-的统计模型， 和人激肽释放酶2（hK 2）-强烈预测活检中高级别（Gleason评分≥7）癌症的风险。的 在涉及近15，000名男性的多项研究中验证了该面板。我们还证明， 该小组是高度预测的长期风险，远处转移的男性随访多年，没有 筛选我们建议评估专家组的临床作用是否可以从以下决定扩展： 诊断性活组织检查与立即治疗决策和积极监测方案有关。 我们将首先使用来自五个独立队列的数据，三个来自欧洲，两个来自美国，以确定 四种激肽释放酶标志物的组合是否可以预测根治性膀胱切除术中的不利病理 或治疗后肿瘤学结果，如转移。如果是这样的话，面板数据通常可能是 可从诊断活检中获得-可用于帮助决定治疗与保守治疗 管理我们的第二个目标是确定一组标记物是否可以预测活动的结果。 监测活检。如果是这样的话，在低进展风险的男性中使用该面板来避免活检将减少 主动监测方案所需的活组织检查次数，减少发病率，并可能增加 积极监测作为一种管理策略的可接受性。我们还旨在确定 通过添加一种新的标记物，微生物蛋白-β（MSMB）或 根据标记物相关的单核苷酸多态性（SNP）修改测量的标记物水平。

PROJECT SUMMARY/ABSTRACT One of the primary clinical challenges in prostate cancer is the management of screen-detected, localized disease. Recent years have seen a dramatic increase in “active surveillance” (conservative management) of low-risk disease. A corollary has been increased attention to the algorithms used for risk stratification. Although Gleason grade is strongly predictive of oncologic outcome, it is clear that, while some men with low Gleason grade on biopsy do in fact harbor high-risk disease, many men with higher Gleason grade would not in fact experience symptoms of prostate cancer during the natural course of their life even if left untreated. We have shown that a statistical model based on a panel of kallikrein markers in blood – total PSA, free PSA, intact PSA and human kallikrein 2 (hK2) – strongly predicts risk of high-grade (Gleason score ≥7) cancer on biopsy. The panel has been validated in multiple studies involving close to 15,000 men. We have also demonstrated that the panel is highly predictive of the long-term risk of distant metastasis in men followed for many years without screening. We propose to evaluate whether the clinical role of the panel could expand from decisions about diagnostic biopsy to those concerning immediate treatment decision-making and active surveillance protocols. We will first use data from five independent cohorts, three from Europe and two from the US, to determine whether the panel of four kallikrein markers can predict either unfavorable pathology at radical prostatectomy or post-treatment oncologic outcomes such as metastases. If so, the panel – data from which may often be available from the diagnostic biopsy – could be used to help decisions about treatment versus conservative management. Our second aim is to determine whether the panel of markers can predict the result of active surveillance biopsy. If so, using the panel to avoid biopsy in men at low risk of progression would decrease the number of biopsies required by active surveillance protocols, reducing morbidity and potentially increasing the acceptability of active surveillance as a management strategy. We also aim to determine whether the properties of the panel could be improved by either adding a novel marker, microseminoprotein-β (MSMB) or modifying measured marker levels in the light of marker-related single-nucleotide polymorphisms (SNPs.)