Precision Medicine Approach to Prostate Cancer Active Surveillance

摘要：前列腺癌（PCa）每年导致28,000多人死亡，是2012年男性癌症死亡的第二大原因。今年将有超过24.1万例PCa的新诊断，其中大多数选择初级治疗方法，如放疗或手术，这伴随着潜在的副作用和随后健康相关生活质量的下降。前列腺特异性抗原（PSA）筛查的广泛使用导致了深刻的分期迁移，大多数新诊断病例临床定位和低分级。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PCa的比例估计在15-84%之间。在大量PSA筛查试验发表后，PSA筛查实践的变化很小，预计即使在最近的美国预防服务工作组（USPSTF）建议之后，患者仍将继续推动前列腺癌筛查，其他指南仍促进知情决策。鉴于筛查检测的前列腺癌通常是惰性病程，主动监测(AS) -或仔细监测癌症，最常见的是PSA动力学和连续活检，并根据这些参数进行选择性干预-是一种新兴的前列腺癌初始管理替代方案，似乎不太可能威胁到质量或生命长度。对于那些低级别、小体积的恶性肿瘤患者来说，AS是一种管理策略，他们被仔细随访，并根据明显的进展进行治疗。然而，大多数AS策略要求连续活检以确定是否有疾病进展，这些活检有潜在的并发症，如感染。补充可靠的生物标志物来预测疾病进展将极大地增强这种方法的吸引力。我们假设疾病侵袭性和预后的生物标志物可以在早期前列腺癌中被询问，这些生物标志物将可靠地预测前列腺癌的进展和/或分期和分级。我们的目标是在本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志物来确定侵袭性疾病的存在或进展。这项由Genomic Health开发的基于活检的多基因定量RT-PCR检测，Oncotype DX前列腺癌检测，在前列腺癌患者的多变量模型中区分侵袭性和惰性癌症。我们将使用PASS队列（n=1000名男性）来完成这项研究，这是北美最大的、前瞻性的、多地点的AS研究。我们还将利用下一代DNA测序技术评估AS男性侵袭性PCa的新兴组织生物标志物，并评估活检样本的TMPRSS2:ERG和PTEN状态，并确定与侵袭性PCa的关系。

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.