Precision Medicine Approach to Prostate Cancer Active Surveillance

描述(由申请人提供)：前列腺癌主动监测项目摘要：前列腺癌(PCA)每年导致超过28,000人死亡，是2012年男性癌症死亡的第二大原因。今年将有超过241,000例新诊断的前列腺癌，大多数选择基本治疗，如放射或手术，相关的潜在副作用和随后的健康相关生活质量下降。前列腺特异性抗原(PSA)筛查的广泛使用导致了深刻的阶段性迁移，大多数新诊断的病例都是临床上局限于局部的低级别病例。这种阶段迁移导致诊断的数量远远超过致命病例的数量，即过度诊断那些如果不治疗就永远不会进展或对患者造成伤害的癌症。根据隐匿性或潜伏性疾病的定义，过度诊断的前列腺癌的比例估计在15%-84%之间。在大型PSA筛查试验公布后，PSA筛查做法发生了极小的变化，预计即使在最近美国预防服务工作组(USPSTF)提出建议后，患者仍将继续推动PCa筛查，而其他指南仍然促进知情决策。考虑到筛查检测到的PCa的过程通常是无痛的，主动监测(AS)--或对癌症的仔细监测，最常见的是PSA动力学和连续活检，并根据这些参数选择干预--是一种新兴的PCa初始治疗方案，似乎不太可能威胁到生活质量或生存时间。对于那些低级别、低体积的恶性肿瘤，AS是一种管理策略，他们被仔细跟踪，并根据明显的进展进行治疗。然而，大多数AS策略要求进行连续活检以确定是否有疾病进展，并且这些活检有潜在的并发症，如感染。补充AS可靠的生物标志物以预测疾病进展将极大地增强这一方法的吸引力。我们假设疾病侵袭性和预后的生物标志物可以在早期PCa中被询问，并且这些生物标志物将可靠地预测PCa的进展和/或分期不足和分级。我们的目标是在这项提案中阐明这一挑战。我们将确认一组新的基于组织的生物标记物，以确定侵袭性疾病的存在或进展。这一新的、基于活检的多基因定量RT-PCR分析是由基因组健康，Oncotype DX前列腺癌分析开发的，在前列腺癌患者的多变量建模中区分侵袭性和惰性癌症。我们将使用PASS队列(n=1000人)来实现这一点，这是北美最大的、预期的、多地点AS研究。我们还将使用下一代DNA测序评估新出现的基于组织的生物标志物在男性AS侵袭性PCa中的作用，还将评估活检样本TMPRSS2：ERG和PTEN的状态，并确定与侵袭性PCa的相关性。

DESCRIPTION (provided by applicant): Precision Medicine Approach to Prostate Cancer Active Surveillance Project Summary: Prostate cancer (PCa) accounts for over 28,000 deaths per year and was the second-greatest cause of cancer death among men in 2012. There will be over 241,000 new diagnoses of PCa this year with the majority opting for primary curative therapies, such as radiation or surgery, with associated potential side effects and subsequent declines in health related quality of life. Widespread use of prostate-specific antigen (PSA)-screening has led to profound stage migration, with the majority of newly diagnosed cases being clinically localized and of low grade. Such stage migration has resulted in the number of diagnoses far outnumbering the number of lethal cases, i.e. over diagnosis of those cancers that would never progress or cause harm to the patient if left untreated. Estimates of the proportion of over diagnosed PCa range from 15-84%, depending on the definition of occult or latent disease. PSA screening practices have changed minimally after publication of large PSA screening trials, and it is expected that even after the recent United States Preventive Services Task Force (USPSTF) recommendations, patients will continue to drive PCa screening, and other guidelines still promote informed decision-making. Given the often indolent course of screen-detected PCa, active surveillance (AS) - or careful monitoring of the cancer, most often with PSA kinetics and serial biopsy, with selected intervention based on these parameters - is an emerging initial management alternative for PCa that appears unlikely to threaten quality or length of life. AS is a management strategy for those with low-grade, low volume malignancy, who are followed carefully and treated with curative intent based on apparent progression. However, most AS strategies call for serial biopsies to determine whether there is disease progression, and these biopsies have potential complications such as infection. Supplementing AS with reliable biomarkers to predict disease progression would greatly enhance the appeal of this approach. We hypothesize that biomarkers of disease aggressiveness and prognosis can be interrogated in early stage PCa and that these biomarkers will reliably predict PCa progression and/or under-staging and grading. We aim to elucidate this challenge in this proposal. We will confirm a novel panel of tissue-based biomarkers to determine the presence of or progression to aggressive disease. This novel, biopsy-based multi-gene quantitative RT-PCR assay developed by Genomic Health, Oncotype DX Prostate Cancer Assay, discriminates aggressive from indolent cancer on multivariate modeling of prostate cancer patients. We will accomplish this using the PASS cohort (n=1000 men), the largest, prospective, multi- site AS study in North America. We will also evaluate emerging tissue-based biomarkers for aggressive PCa in men on AS using Next Generation DNA sequencing and will also assess on biopsy samples TMPRSS2:ERG and PTEN status and determine associations with aggressive PCa.