Using Markers to Improve Pancreatic Cancer Screening

使用标记物改善胰腺癌筛查

• 批准号: 8692702
• 负责人: Michael G. Goggins
• 金额: $ 40.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692702
• 关键词: Age; Biological Assay; Cancer Etiology; Cancer Patient; Carcinoma in Situ; Cessation of life; Clinical; Clinical Trials; Cyst; Cyst Fluid; Data; Detection; Diagnosis; Diagnostic; Disease; Dysplasia; Endoscopy; Enrollment; Evaluation; Excision; Family; Future; Gene Mutation; Goals; Image; In Situ Lesion; Individual; Irrigation; Juice; KRAS2 gene; Lesion; Lesion by Stage; Liquid substance; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Microscopic; Mucinous Neoplasm; Mutation; Neoplasms; Pancreas; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Papillary; Patients; Population; Premalignant; Prevalence; Recording of previous events; Research; Resected; Risk; Sampling; Specimen; TP53 gene; Testing; Time; Tumor Markers; Ultrasonography; advanced disease; aged; base; chronic pancreatitis; cohort; diagnostic accuracy; disorder control; high risk; improved; molecular marker; mortality; mutant; neoplastic; pancreatic juice; pancreatic neoplasm; prospective; public health relevance; screening

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.

描述（由申请人提供）：胰腺导管腺癌是美国癌症死亡的第四个主要原因，也是最致命的癌症之一。由于大多数胰腺癌患者患有晚期疾病，以检测可治愈的早期病变，因此需要筛查个体。在我们的胰腺筛查（CAPS）临床试验的癌症中，我们根据家族史或基因突变状态筛查了约500名患有胰腺癌风险的人。我们发现〜5-10％的病变需要切除（癌症，囊肿内部乳头状粘液性肿瘤（IPMNS）），〜10-30％的囊肿需要进行监测。病变的患病率随着年龄的增长而增加，尤其是60岁以上。在我们的早期CAP试验中，我们在40岁时开始筛查40岁，现在年龄在50岁时，我们现在怀疑筛查在以后开始时可能会更有效（55岁）。尽管我们可以鉴定囊肿，但我们无法可靠地识别出非常早期的浸润性癌症或微观胰腺内肿瘤（PANINS），这是胰腺癌最常见的前体。需要精确的标记来识别这些病变，这些病变可以可靠地在胰液中可靠地检测到，可用于胰腺筛查。最近，我们发现约99％的低级Panins港口突变，可以在胰管灌洗中检测到的突变（“胰汁”）。我们发现，在胰腺癌患者中检测到内窥镜超声检查期间非侵入性收集的胰汁中的TP53突变，并且在疾病控制或疾病控制中，患有癌症或侵入性癌症患者接受胰腺癌筛查的患者，或患有低级患者的胰腺癌。因此，果汁分析有可能提供准确的癌症或高级Panin的证据。为了进一步评估胰果汁分析的实用性，我们提出：目标＃1：确定胰液中检测到的突变的诊断准确性，作为胰腺肿瘤的指标。我们将使用NextGen测序来寻找胰腺癌，慢性胰腺炎或正常胰腺患者的突变。目标＃2：确定Panin突变对接受胰腺切除的患者中胰液突变的贡献。我们将确定患者Panin的签名突变，并在其前胰液中寻找这些突变。目标＃3：比较接受胰腺囊肿评估的前瞻性患者中囊肿流体与胰液中突变的患病率。目标＃4：确定接受胰腺筛查的高危个体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风险队列（年龄> 55岁），并继续监视接受过上限试验的患者。