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

胰腺导管腺癌（PDAC）通常在晚期发现，因为没有癌症 筛查策略，伴随生存率低。在早期阶段检测PDAC会产生积极影响 生存率，目前在符合条件的高风险个体（HRI）中进行筛查，根据家族史和种系定义 突变状态被认为是最佳实践。本提案的总体目标是利用在 最后一个赠款期，以大大提高我们的能力，开发和验证诊断性能的 新的血液蛋白质和甲基化DNA（MDM）生物标志物，用于PDAC的早期检测，使用前瞻性 样本采集和回顾性盲法评价（PRoBE）合规方法。我们假设 蛋白质、MDM和CA 19 -9的组合将准确地鉴定HRI中的早期PDAC。我们将评估 我们的方法在PDAC的早期和诊断前阶段的性能特点， 作为使用HRI的早期检测工具，为临床翻译优化的方法。二十多年来， 马约诊所的前瞻性生物标本资源已经积累，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，家族性胰腺癌易感基因中的高危成员， 高风险胰腺疾病和健康对照。我们亦已在 我们的中心在那些我们纵向跟踪了二十多年的生物标本的风险中， 事件PDAC案例的发展，使我们能够利用新的方法来应对挑战， 更好地设计PRoBE 3期研究。根据我们在上一个资助期的发现，我们现在专注于定制 用于PRoBE II期研究的样品和表征性能以改进III期研究。我们的方法 将允许我们评估，例如，预期用途HRI设置的生物标志物表达的变异性，以及 生物标志物表达的时间性以提高检测早发性PDAC的能力。我们的具体目标是： 1)从血液样本产品和胰腺囊肿液中采集适用于PCDC的正式生物样本集 生物标志物研究; 2）利用我们过去的知识和经验， 定制的第2阶段设计并纳入协变量以完善检测（年龄、性别、种族、吸烟、个人 糖尿病史、诊断时的症状）以优化检测;以及3）评估所需性能 这些参数将为在HRI监测环境中成功设计PDAC III期研究提供信息。 我们的多学科团队致力于继续发挥领导作用，为PCDC组织做出贡献， 促进胰腺癌的早期发现。我们的项目利用现有的基础设施和生物标本 马约诊所和宾夕法尼亚大学的胰腺癌和其他胰腺疾病的库存， 将扩大对患者血液和胰腺囊肿液的新的前瞻性收集， 签名方案队列和PCDC中央生物储存库。

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.