Mayo Clinic Prospective Resource for Biomarker Validation and Early Detection of Pancreatic Cancer

胰腺导管腺癌(PDAC)通常在晚期被发现，因为没有肿瘤。 筛查策略，伴随着低存活率。及早发现PDAC将产生积极影响 存活率，目前在符合条件的高危个体(HRI)中进行筛查，这些高危个体由家族史和种系定义 突变状态被认为是最佳实践。这项建议的总体目标是利用在 最后一个资助期，以显著增强我们开发和验证诊断性能的能力 新的血液蛋白和甲基化DNA(MDM)生物标志物用于PDAC的早期检测 符合标本采集和回溯性盲法评价(探查)的方法。我们假设一个 结合蛋白质、MDM和CA19-9可以准确地识别HRIS中的早期PDAC。我们将评估 我们的方法在PDAC早期阶段和诊断前阶段的性能特征，并确定 使用HRIS将针对临床翻译进行优化的方法作为早期检测工具。二十多年来， 梅奥诊所未来的生物样品资源已经积累起来，使用标准化的高质量程序， 来自数千名PDAC患者的注释良好的生物标本，包括那些在 胰腺癌易感基因，家族性胰腺癌家族的高危成员，患者 高危胰腺疾病患者和健康对照组。我们亦已在 我们的中心。在那些面临生物群落风险的人中，我们纵向跟踪了他们20多年， 突发事件PDAC案例的发展，使我们能够利用新的方法来应对挑战和 更好地设计探头第三阶段研究。根据我们在上一次赠款期间的调查结果，我们现在专注于定制 用于探针第二阶段研究和表征性能的样本，以改进第三阶段研究。我们的方法 将使我们能够评估，例如，针对预期使用的HRI设置的生物标记物表达的可变性，以及 生物标记物表达的暂时性，以提高检测早发性PDAC的能力。我们的具体目标是： 1)从适合于PCDC的血样产品和胰腺囊液中获得正式的生物样品集 生物标志物研究；2)利用我们过去的知识和经验，开发新的生物标志物小组，使用 量身定制的第二阶段设计，并纳入协变量以改进检测(年龄、性别、种族、吸烟、个人 糖尿病病史、诊断时的症状)以优化检测；以及3)评估所需的性能 这些参数将为在HRIS监测环境中成功设计PDAC第三阶段研究提供信息。 我们的多学科团队致力于继续领导和贡献PCDC组织，以 推进胰腺癌的早期发现。我们的项目利用了现有的基础设施和生物样品 梅奥诊所和宾夕法尼亚大学的胰腺癌和其他胰腺疾病银行，它 将扩大从患者那里收集新的预期血液和胰腺囊液，为PCDC做出贡献 签名协议队列和PCDC中央生物库。

Pancreatic ductal adenocarcinoma (PDAC) is typically detected at late stage due to absence of a cancer screening strategy, with concomitant poor survival rates. Detection of PDAC at an early stage positively impacts survival, and currently screening in eligible high-risk individuals (HRIs) defined by family history and germline mutation status is considered best practice. The overall goal of this proposal is to use knowledge gained during the last grant period to considerably enhance our ability to develop and validate the diagnostic performance of new blood protein and methylated DNA (MDM) biomarkers for early detection of PDAC, using prospective specimen collection and retrospective blinded evaluation (PRoBE) compliant methods. We hypothesize that a combination of proteins, MDMs, and CA19-9 will accurately identify early stage PDAC in HRIs. We will assess the performance characteristics of our approaches in early stage and pre-diagnostic phase of PDAC and identify approaches that are optimized for clinical translation as an early detection tool using HRIs. For over two decades, Mayo Clinic’s prospective biospecimen resources have accrued, using standardized high-quality procedures, well-annotated biospecimens from thousands of PDAC patients including those with germline mutations in pancreas cancer susceptibility genes, high risk members in familial pancreatic cancer kindreds, patients with high-risk pancreatic conditions, and healthy controls. We have also launched the PCDC Signature Protocols at our center. Among those at risk with biospecimens who we have followed longitudinally over two decades, incident PDAC cases have developed, enabling us to utilize novel approaches to address the challenges and better design PRoBE phase 3 studies. Based on our findings in the last grant period, we now focus on tailoring samples for PRoBE phase 2 studies and characterizing performance to improve phase 3 studies. Our approach will allow us to assess, for example, variability in biomarker expression for intended use HRI settings, and temporality of biomarker expression to improve the ability to detect early onset PDAC. Our Specific Aims are to: 1) Accrue formal biospecimen sets from blood sample products and pancreatic cyst fluid suitable for PCDC biomarker studies; 2) Leverage our past knowledge and experience to develop new biomarker panels using tailored phase 2 designs and incorporating covariates to refine detection (age, sex, race, smoking, personal history of diabetes mellitus, symptoms at diagnosis) to optimize detection; and 3) Evaluate needed performance parameters that will inform the design of a successful phase 3 study for PDAC in a surveillance setting of HRIs. Our multidisciplinary team is committed to continue its leadership and contribution to the PCDC organization to advance the early detection of pancreatic cancer. Our project leverages existing infrastructures and biospecimen banks of pancreatic cancer and other pancreatic diseases at Mayo Clinic and University of Pennsylvania, and it will extend new prospective collections of blood and pancreatic cyst fluid from patients, contributing to PCDC Signature Protocol cohorts and a PCDC central biorepository.