Biomarker validation for intraductal papillary mucinous neoplasms of the pancreas

描述（申请人提供）：成功的癌症筛查的一个关键组成部分是确定一个病变，对该病变进行干预将延长生存期或治愈。IA期胰腺癌（最早可识别的病变，占所有胰腺癌的1%）切除患者的五年生存率约为35%。正因为如此，目前的胰腺癌筛查模式将继续失败，直到可以确定可治愈的胰腺癌或直到可以开发更好的全身治疗。胰腺导管内乳头状粘液性肿瘤（IPMN）是胰腺癌的囊性肿瘤，是唯一可通过放射学检查识别的前驱病变，并代表了在胰腺癌发展之前进行干预的机会。目前的实验室、内窥镜和成像技术无法区分IPMN是低风险（低度异型增生）还是高风险（高度异型增生）。正因为如此，临床决策是非常有争议的，需要高风险疾病的标志物。这项多机构研究工作的目标是（具体目标#1）验证一组蛋白质标志物（MMP 9、IL-4、sFASL、CA 72.4），我们发现这些标志物在鉴定高风险IPMN中高度可靠。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MMP 9/CA 72.4），它们本身对高危疾病的准确率（AUC）为86%。我们将利用多机构的一组囊液样本（n=150）验证这些标记物， 抗体珠阵列。然后，我们将这些标志物（具体目标#2）纳入最近开发的基于临床和放射学因素的术前预测模型（列线图）。该模型将根据三个参与机构开发的多机构数据集开发。然后将在入组前瞻性多机构试验的一大组患者中验证该分子-临床病理学列线图（具体目标3）。在IPMN患者中识别高危异型增生标志物的价值不能被夸大。发展一种术前测试，以准确区分低风险和高风险的IPMN将使高风险病变的患者在发展为不治之症之前接受切除术，并使低风险病变的患者避免手术，使他们免于胰腺切除术的身体，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.