Biomarker validation for intraductal papillary mucinous neoplasms of the pancreas

描述(由申请人提供)：成功的癌症筛查的一个关键部分是确定介入将导致延长生存或治愈的病变。切除的IA期胰腺癌(最早可识别的病变，占所有胰腺癌的1%)患者的五年存活率约为35%。正因为如此，目前的胰腺癌筛查范例将继续失败，直到发现可治愈的胰腺癌或开发出更好的系统治疗方法。胰腺导管内乳头状黏液性肿瘤(IPMN)是一种囊性肿瘤，是胰腺癌唯一的放射学可识别的前驱病变，是胰腺癌发生前介入治疗的机会。目前的实验室、内窥镜和成像技术无法区分低风险(低级别异型增生)和高风险(高级别异型增生)的IPMN。正因为如此，临床决策非常有争议，需要高危疾病的标志物。这项多机构研究的目标是(具体目标1)验证一组我们发现在识别高危IPMN方面高度可靠的蛋白质标记物(MMP9、IL-4、sFASL、CA72.4)。最近的分析已经确定了两种不同的蛋白质标志物模型(sFASL/IL-4和MMP9/CA72.4)，它们本身对高危疾病的准确率(AUC)为86%。我们将在一组多机构的囊液样本(n=150)上验证这些标记物 抗体珠阵列。然后，我们将把这些标记物(具体目标2)结合到最近开发的基于临床和放射学因素的术前预测模型(诺模图)中。该模型将根据三个参与机构开发的多机构数据集开发。这一分子临床病理图随后将在一大组登记参加前瞻性多机构试验的患者身上进行验证(具体目标#3)。在IPMN患者中识别高危异型增生标志物的价值怎么强调都不为过。开发一种准确区分低风险和高风险IPMN的术前测试，将使高风险病变的患者在出现不治之症之前接受切除，并使低风险病变的患者避免手术，并免除他们切除胰腺的体力、情感和经济成本。

DESCRIPTION (provided by applicant): A critical component to successful cancer screening is the identification of a lesion for which intervention will result in prolonged survival or cure.The five-year survival of patients with resected stage IA pancreas cancer (the earliest identifiable lesion and <1% of all pancreatic cancer) is approximately 35%. Because of this, current screening paradigms for pancreatic cancer will continue to fail until a curable pancreatic cancer can be identified or until better systemic therapies can be developed. Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are cystic tumors that represent the only radiographically identifiable precursor lesion of pancreatic cancer and represent an opportunity for intervention prior to the development of pancreatic cancer. Current laboratory, endoscopic, and imaging technologies are unable to distinguish between IPMN that is at low-risk (low-grade dysplasia) or at high-risk (high-grade dysplasia) of becoming malignant. Because of this, clinical decision making is very controversial and markers of high-risk disease are needed. The goal of this multi-institutional research effort is to (specific aim #1) validate a group of protein marker (MMP9, IL-4, sFASL, CA72.4) that we have found to be highly reliable in identifying high- risk IPMN. Recent analyses have identified two separate models of protein markers (sFASL/IL-4 and MMP9/CA72.4) that by themselves had accuracy rates (AUC) of 86% for high-risk disease. We will validate these markers on a multi-institutional set of cyst fluid samples (n=150) utilizing antibody bead array. We will then incorporate these markers (specific aim #2) into a recently developed preoperative prediction model (nomogram) based on clinical and radiographic factors. This model will be developed from a multi- institutional dataset developed by the three participating institutions. This molecular-clinicopathologic nomogram will then be validated (specific aim #3) on a large group of patients enrolled into a prospective multi-institutional tria. The value of identifying markers of high-risk dysplasia in patients with IPMN cannot be overstated. Development of a preoperative test to accurately discriminate between low-risk and high-risk IPMN would allow patients with high-risk lesions to undergo resection prior to the development of an incurable disease, and enable patients with low-risk lesions to avoid operation and spare them the physical, emotional, and financial costs of pancreatectomy.