Using Markers to Improve Pancreatic Cancer Screening

描述（由申请人提供）：胰腺导管腺癌是美国第四大癌症死亡原因，也是最致命的癌症之一。由于大多数胰腺癌患者病情进展较晚，为了发现可治愈的早期病变，需要对个体进行筛查。在我们的胰腺癌筛查（CAPS）临床试验中，我们根据家族史或基因突变状态筛选了约500名患胰腺癌风险增加的个体。我们发现约5-10%的患者有需要切除的病变（癌症、囊肿-导管内乳头状粘液瘤（IPMNs）），约10-30%的患者有需要监测的囊肿。病变的患病率随着年龄的增长而增加，尤其是60岁以上。在我们早期的CAPS试验中，我们在40岁时开始筛查，在50岁时开始筛查，现在我们怀疑在55岁时开始筛查可能更有效。虽然我们可以识别囊肿，但我们不能可靠地识别非常早期的浸润性癌症或显微镜下的胰腺上皮内瘤变（PanINs），这是胰腺癌最常见的前兆。需要准确的标记物来识别这些病变，这些标记物可以在胰液中可靠地检测到，并可用于胰腺筛查。最近，我们发现约99%的低级别PanINs harbor突变，这些突变可以在胰管灌洗液中检测到。我们发现，在内镜超声无创采集的胰腺液中，TP53突变在胰腺癌患者和接受胰腺原位癌或浸润性癌筛查的患者中被检测到，而在疾病对照组或低级别不典型增生患者中未被检测到。因此，果汁分析有可能提供癌症或高级别PanIN的准确证据。为了进一步评估胰液分析的效用，我们提出：目的1：确定在胰液中检测到的突变作为胰腺肿瘤指标的诊断准确性。我们将使用nextgen测序在胰腺癌、慢性胰腺炎或正常胰腺患者中寻找突变。目的2：确定胰切除术患者中PanIN突变对胰液突变的贡献。我们将识别患者PanIN的特征突变，并在术前胰液中寻找这些突变。目的#3：比较在接受胰腺囊肿评估的前瞻性队列患者中囊肿液和胰液突变的患病率。目的4：确定接受胰腺筛查的高危人群中胰腺病变和胰液突变的患病率。我们将招募一个新的老年高危队列（年龄在50 - 55岁之间），并继续对先前参加CAPS试验的患者进行监测。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer death in the USA and one of the deadliest cancers. Since most patients with pancreatic cancer present with advanced disease, in order to detect curable early-stage lesions, one needs to screen individuals. In our Cancer of the Pancreas Screening (CAPS) clinical trials we have screened ~500 individuals at increased risk of developing pancreatic cancer based on family history or gene mutation status. We find ~5-10% have lesions requiring resection (cancers, cysts-intraductal papillary mucinous neoplasms (IPMNs)), ~10-30% have cysts that require surveillance. The prevalence of lesions increases with age, especially over age 60. In our early CAPS trials, we initiated screening at age 40, later at age 50 and we now suspect screening may be more effective when initiated later (age 55). Although we can identify cysts, we cannot reliably identify very early invasive cancer or microscopic pancreatic intraepithelial neoplasias (PanINs) which are the commonest precursor to pancreatic cancer. Accurate markers are needed to identify these lesions, markers that can be reliably detected in pancreatic fluids and can be used for pancreatic screening. Recently, we found ~99% of low-grade PanINs harbor mutations, mutations that can be detected in pancreatic duct lavages ("pancreatic juice"). We found TP53 mutations in pancreatic juice collected non-invasively during endoscopic ultrasound are detected in patients with pancreatic cancer and patients undergoing pancreatic screening with carcinoma in situ or invasive cancer, not in disease controls or those with low-grade dysplasia. Thus, juice analysis has the potential to provide accurate evidence of cancer or high-grade PanIN. To further evaluate the utility of pancreatic juice analysis we propose: Aim #1: To determine the diagnostic accuracy of mutations detected in pancreatic fluid as indicators of pancreatic neoplasia. We will use nextgen sequencing to search for mutations in patients with pancreatic cancer, chronic pancreatitis, or normal pancreata. Aim #2: To determine the contribution of PanIN mutations to pancreatic fluid mutations among patients undergoing pancreatic resection. We will identify signature mutations of patient's PanIN and search for these mutations in their pre-op pancreatic fluid. Aim #3: To compare the prevalence of mutations in cyst fluid vs. pancreatic fluid among a prospective cohort of patients undergoing pancreatic cyst evaluation. Aim #4: To determine the prevalence of pancreatic lesions and pancreatic fluid mutations among high-risk individuals undergoing pancreatic screening. We will enroll a new older-age high-risk cohort (age >55) and continue surveillance of patients enrolled in prior CAPS trials.