Validation of biomarkers for risk prediction and early diagnosis of Pancreatic Adenocarcinoma

摘要 胰腺癌(PDAC)，总的5年生存率为11%，是最常见的第三大肿瘤 美国癌症死亡的原因，尽管只占所有恶性肿瘤的2%。只有少数人 的患者(约11%)被诊断为“局部性”疾病(I或IIA)，这种疾病的5年存活率约为 40%在无结节、边缘阴性的胰腺切除术中。一个明显的战略，以改善 低存活率的方法是在局部发现PDAC，从而使其处于更可治愈的阶段。由于正在放映 PDAC的总体人口是不可行的，目前的努力集中在确定以下人群的子集 增加了PDAC开发的风险。目前，开发PDAC的人中只有25%是 胰腺癌监测的候选对象。约10%的人有很强的家族史或 家族史和生殖系突变的组合与PDAC的发展风险相关。另一个 约15%的人患有胰腺囊性肿瘤，包括IPMN和MCNs。无法预测 粘液囊肿的恶变，从而确定应该手术切除的囊肿 需要适当的监视。尽管制定了关于处理囊性病变的多种共识指南， 要确定哪些粘液囊肿会发生恶变仍具有挑战性。在.期间 在之前的融资周期中，我们确定并评估了包含粘蛋白(MUC4， MUC5AC)、粘蛋白相关糖表位(StrA)、TGM2、THSP2、TIMP2和自身抗体 在旨在检测可切除的PDAC的盲法病例对照队列中得到验证。初步突变图谱分析 胰腺囊液(I期和II期)确定了一个独特的小组(PancreaSeq)，它有助于确定恶性 有患胰腺囊肿的风险。当前临床验证中心(CVC)的目标是进一步验证这些 专家小组(S)以符合前瞻性标本收集、回顾-盲化-评估(探针)的方式 目前或潜在的早期发现或诊断PDAC的高危个体队列。 AIM 1将验证囊性病变患者的囊液和血液生物标记物，以确定晚期 前驱病变和鉴别低度不典型增生和无致死潜能。在这个目标中，我们将验证 候选生物标记物，包括PancreaSeq突变面板(3期)、炎性标记物(2期)和 囊液(高特异性)和血清样本(高特异性)中的粘蛋白(MUC4、MUC5AC、StrA)(3相) 敏感性)，以在监视成像过程中识别间歇性恶性肿瘤。目标2将评估以下各项的性能 优化生物标记物组合(S)用于遗传易感性患者恶性疾病的早期检测 接受PDAC发展和新发糖尿病和慢性胰腺炎患者的监测， 定义为在首次诊断后两年内，与一般患者相比，他们面临的风险显著增加 患有未诊断的PDAC的人群。影响：拟议的研究将验证阿司匹林的临床效用 有望用于PDAC早期检测和胰腺囊性病变风险分层的生物标记物小组， 可用于IV期临床效用研究。

Abstract Pancreatic adenocarcinoma (PDAC), with an overall 5-year survival of 11%, is the 3rd most common cause of cancer deaths in the United States, despite accounting for only 2% of all malignancies. Only a minority of patients (~11%) are diagnosed with “localized” disease (I or IIA), which has a 5-year survival rate of about 40% in setting of a node-negative, margin negative pancreatic resection. An obvious strategy for improving the dismal survival would be to detect PDAC when localized and thus at a more curable stage. Since screening the general population for PDAC is not feasible, current efforts have focused on identifying a subset of the people at an increased risk for PDAC development. Currently, only up to 25% of individuals who develop PDAC are candidates for pancreatic cancer surveillance. About 10% are individuals with a strong family history or a combination of family history and germline mutations associated with the risk of PDAC development. The other ~15% are individuals with cystic neoplasms of the pancreas, including IPMNs and MCNs. The inability to predict the malignant transformation of mucinous cysts and thus identify the cysts that should be surgically removed requires appropriate surveillance. Despite developing multiple consensus guidelines on managing cystic lesions, it is still challenging to determine which mucinous cysts will undergo malignant transformation. During the previous funding cycle, we identified and evaluated novel serum biomarker panels comprising mucins (MUC4, MUC5AC), mucin-associated glycoepitopes (STRA), TGM2, THSP2, TIMP2, and autoantibodies that were validated in a blinded case-control cohort aimed at detecting resectable PDAC. Preliminary mutational profiling of pancreatic cyst fluid (phase I and II) identified a unique panel (PancreaSeq) that helped define the malignant risk of pancreatic cysts. The goal of the current Clinical Validation Center (CVC) is to validate further these panel(s) in a prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) compliant manner in cohorts of high-risk individuals who are current or potential candidates for early detection or diagnosis of PDAC. Aim 1 will validate cyst fluid and blood-based biomarkers in patients with cystic lesions to identify advanced precursor lesions and differentiate low-grade dysplasia and no lethal potential. In this aim, we will validate candidate biomarkers, including PancreaSeq mutational panel (Phase 3), inflammatory markers (Phase 2), and mucins (MUC4, MUC5AC, STRA) (Phase 3) in the cyst fluid (high specificity) and serum samples (high sensitivity) to identify interval malignancy during surveillance imaging. Aim 2 will evaluate the performance of optimized biomarker panel(s) for early detection of malignant disease in patients with a hereditary predisposition undergoing surveillance for PDAC development and in patients with new-onset diabetes and chronic pancreatitis, defined as within two years of initial diagnosis, who are at a significantly increased risk compared to the general population for having an undiagnosed PDAC. Impact: The proposed studies will validate the clinical utility of promising biomarker panels for early detection of PDAC and risk stratification of pancreatic cystic lesions, which can be used in phase IV clinical utility studies.