A Clinical Validation Center for Early Detection of Pancreatic Cancer

 描述(由申请人提供)：在美国，PDAC的早期检测是一个最优先考虑的领域，也是促进公共卫生的一个未得到满足的需求。某些亚组的患者，如粘液性胰腺囊肿患者，进展为PDAC的风险更高，但即使在这些队列中，也存在过度诊断的可能性，这突显了能够准确区分侵袭性和惰性囊肿的生物标记物的必要性。我们的EDRN临床验证中心(CVC)由MD Anderson(MDACC)、犹他大学和印第安纳大学组成，其长期目标是实施一个多机构框架，从各种明确定义的胰腺病理患者中收集最高质量的生物标本，以便进行符合EDRN定义的第二阶段和第三阶段研究设计的PDAC早期发现的生物标记物验证研究。具体地说，CVC将前瞻性地招募至少600名早期(切除)PDAC患者，至少300名手术切除的不同组织学和不同程度的不典型增生的胰腺囊性病变患者，至少400名良性胰腺疾病(包括慢性胰腺炎、良性囊肿、低恶性潜能的内分泌肿瘤)，至少300名未切除的胰腺囊性病变但无进展证据的患者，以及至少300名非胰腺疾病的对照患者，以获取这些受试者的血浆和血清样本用于生物标志物验证研究。此外，我们将获取所有胰腺囊性病变患者的囊液样本，包括手术切除和内窥镜成像。根据EDRN原则，这些生物标记物将用于促进与其他生物标记物的合作，以发现和验证生物标记物。我们CVC中产生的初步数据已经确定了一组过度表达的自身抗体和抗原(ERBB2、TNC、ESR1、CACNA1D和CDKN2AIP)，它们显著改善了诊断和诊断前队列中的CA19-9 AUC。我们将使用弗雷德·哈钦森癌症研究中心(FHCRC)开发的能够量化血浆中抗原和自身抗体的混合阵列平台，并使用该平台完成三项符合探针的生物标记物研究：研究1将是EDRN定义的第三阶段研究，来自WHI和PLCO队列的诊断前PDAC样本(n=158)和匹配对照(n=158)，随后是EDRN定义的早期(可切除)PDAC(N=300)与慢性胰腺炎(N=300)和非胰腺疾病对照(N=300)的第二阶段病例对照研究；研究2将是在PLCO诊断前PDAC样本(n=160)和匹配对照(n=160)中进行的EDRN定义的3期研究；研究3将是EDRN定义的2期病例对照研究，研究对象是伴有高度不典型增生或癌症的胰腺囊性肿瘤(N=150)与经手术证实的低度不典型增生和非粘液性囊性病变的胰腺囊性肿瘤(N=150)，以及低风险囊性病变(N=150)。

 DESCRIPTION (provided by applicant): Early detection of PDAC is an area of highest priority and an unmet need for advancing public health in the United States. Certain sub-groups of patients, such as those with mucinous pancreatic cysts are at higher risk for progression to PDAC, but even in these cohorts, there is potential for over-diagnosis, underscoring the need for biomarkers that can accurately distinguish aggressive versus indolent cysts. The long term goal of our EDRN Clinical Validation Center (CVC), comprised of MD Anderson (MDACC), University of Utah and Indiana University, is to implement a multi-institutional framework for collecting the highest quality biospecimens from patients with a variety of well-defined pancreatic pathologies in order to conduct biomarker validation studies for early detection of PDAC that conform to EDRN-defined Phase 2 and Phase 3 study design. Specifically, this CVC will prospectively recruit at least 600 patients with early stage (resected) PDAC, at least 300 patients with surgically resected pancreatic cystic lesions of varying histology and grades of dysplasia, at least 400 benign pancreatic diseases (including chronic pancreatitis, benign cysts, endocrine tumors of low malignant potential), at least 300 patients with non-resected pancreatic cystic lesions that have follow up of 2 years or greater without evidence for progression, and at least 300 control patients with non- pancreatic diseases, in order to obtain plasma and serum samples from these subjects for biomarker validation studies. Additionally, we will obtain cyst fluid samples from all patients with pancreatic cystic lesions, both surgically resected and those being followed by endoscopic imaging. In accordance with the EDRN principles, these biospecimens will be utilized in facilitating collaborations with other BDLs, for biomarker discovery and validation studies. Preliminary data generated in our CVC has identified a focused panel of overexpressed autoantibodies and antigens (ERBB2, TNC, ESR1, CACNA1D and CDKN2AIP) that significantly improves CA19-9 AUC in both diagnostic and pre-diagnostic cohorts. We will use a hybrid array platform developed at Fred Hutchinson Cancer Research Center (FHCRC) that is capable of quantifying both antigens and autoantibodies from plasma, and use this platform to complete three PRoBE compliant biomarker studies: Study 1 will be an EDRN-defined Phase 3 study in pre-diagnostic PDAC samples (n=158) and matched controls (n=158) from WHI and PLCO cohorts, followed by an EDRN-defined Phase 2 case control study of early stage (resectable) PDAC (N = 300) versus chronic pancreatitis (N = 300) and non-pancreatic disease controls (N=300); Study 2 will be an EDRN-defined Phase 3 study in PLCO pre-diagnostic PDAC samples (n=160), and matched controls (n=160); and Study 3 will be an EDRN-defined Phase 2 case control study of pancreatic cystic neoplasms with high-grade dysplasia or cancer (N =150) versus pancreatic cystic neoplasms with surgically confirmed low-grade dysplasia and non-mucinous cystic lesions (N=150), as well as low-risk cyst with adequate follow up that are followed without surgery (N=150).