How Can We Screen for Pancreatic Cancer and its Precursors?
Individuals with invasive pancreatic cancer or high-grade dysplasia can be identified based on a specific DNA mutation in pancreatic juice samples from the duodena, according to the June issue of Clinical Gastroenterology and Hepatology. Tests for mutant TP53 might be developed to improve the diagnosis of and screening for pancreatic cancer and its precursors.
One way to reduce pancreatic cancer mortality could be to identify tumor precursors, while they are still treatable. The most common precursors to pancreatic adenocarcinoma are microscopic, pancreatic intraepithelial neoplasias (PanINs) and larger cystic precursor neoplasms called intraductal papillary mucinous neoplasm (IPMNs). These are generally asymptomatic and are identified only incidentally or by screening.
Markers are needed to accurately distinguish early invasive pancreatic cancers and high-grade dysplasia (PanIN-3 and IPMNs with high-grade dysplasia) from lesions with low-grade dysplasia, so physicians can determine management and surveillance strategies. The tumor protein 53 (TP53) gene is mutated in approximately 75% of invasive pancreatic cancers, with a similar prevalence in familial and sporadic pancreatic cancers.
Mitsuro Kanda et al. therefore looked for TP53 mutations in pancreatic juice samples from 180 participants in the US multicenter Cancer of the Pancreas Screening (CAPS) trials, comparing their findings with the eventual diagnosis, based on surgery or fine-needle aspiration.
They found that detection of TP53 mutations in duodenal samples of pancreatic juice identified 67.4% of patients with pancreatic ductal adenocarcinomas and 50% with high-grade lesions (PanIN-3 and high-grade IPMN). TP53 mutations were not identified in duodenal samples from 58 controls or 55 individuals without evidence of advanced lesions (see figure).
Kanda et al. also analyzed frozen section samples from a different set of patients, and found TP53 mutations in 9.1% of intermediate-grade IPMNs, 17.8% of intermediate-grade PanINs (PanIN-2), 38.1% of high-grade IPMNs, 47.6% of PanIN-3, and 75% of 20 invasive ductal adenocarcinomas (one cancer had 2 mutations). No TP53 mutations were detected in low-grade PanINs (PanIN-1) or IPMNs.
One participant of the trial did not have any evidence for a mass based on imaging analyses, but a duodenal sample of pancreatic juice was found to have a TP53 mutation. Thirteen months after the initial screening examination, this patient was found to have a pancreatic ductal adenocarcinoma that contained the same TP53 mutation, indicating the limitations of current imaging tests in screening for pancreatic cancer.
In an editorial that accompanies the article, Manoop S. Bhutani et al. state that the study shows a promising role for TP53 mutation analysis in identifying patients with pancreatic cancer and earlier lesions. However, because of the overall low sensitivity of the analysis, it can’t be used alone for screening purposes—it is most likely to be used in conjunction with imaging techniques such as endoscopic ultrasound and magnetic resonance imaging.
Bhutani et al. add that in addition to screening duodenal samples of pancreatic juice for TP53 mutations, analyses of other biomarkers (mutations in DNA, secreted proteins and glycoproteins, and microRNAs), and incorporation of other technologies might increase our ability to identify patients at highest risk for pancreatic cancer.
More information on Pancreatic Cancer
Read the article online. Kanada M, Sadakari Y, Borges M, et al. Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. Clin Gastroenterol Hepatol 2013;11:719-730.e5
Read the accompanying editorial. Bhutani M, Thosani N, Suzuki R, et al. Pancreatic cancer screening: what we do and do not know. Clin Gastroenterol Hepatol 2013;11:731–733