Progress in the Earlier Detection of Pancreatic Cancer.

The difficulty of performing pancreatic cancer surveillance in patients genetically susceptible to familial pancreatic cancer (FPC) cannot be emphasized enough. The stakes are quite high because precursor lesions are difficult to detect with current imaging, it is challenging to distinguish incipient neoplasia from lower grade or nonneoplastic cystic lesions, and the outcomes can be lethal if an incipient neoplasia is missed. In the article that accompanies this editorial, 1 the authors, who represent three centers in two countries, have done an outstanding job of using clinical acumen and the tools at hand to improve cancer outcomes in these high-risk patients. The surveillance tools used in this study included magnetic resonance imaging, magnetic resonance cholangiopancreatography, and/or endoscopic ultrasound. The centers varied in the use of imaging tests, with one center routinely performing both tests on an annual basis. Theoutcomes oftheFPCcohortsaresummarized onthebasis of the genetic basis for susceptibility for pancreatic ductal adenocarcinoma (PDAC; eg, CDKN2a/p16-Leiden mutations carriers are onecohort,BRCA/PALB2mutationcarriersareasecondcohort,and the third cohort was composed of heterogeneous patients with FPC, in whom the genetic basis for the disease remains unknown). The goal of the surveillance was to identify early-stage PDAC or neoplastic precursor lesions in asymptomatic individuals and determine whether this, in turn, would change the prognosis of PDAC. Surveillance of these FPC patients detected both early-stage PDAC and high-risk neoplastic precursor lesions. Thirteen of 178 of the CDKN2a mutation carriers were diagnosed with PDAC, but the majority of these patients had significant upstaging of their disease through the surveillance, leading to a cancer resection rate of 75%. Thirty-four percent of the CDKN2a patients had T1N0M0 (stage IA) disease. In contrast, for sporadic PDAC, the rates of resection and the percentage of patients diagnosed at stage IA disease are 20% and 4%, respectively. Not surprisingly, the 5-year survival rates were substantially better in the CDKN2a patients who underwent surveillance (24%) versus the survival rate typically seen in sporadic PDAC (4% to 7%). Pancreatic cancer also developed in the other cohorts; two cancers occurred in the FPC cohort (one adenocarcinoma and one neuroendocrine), whereas a stage IA PDAC was detected in the BRCA/PALB2 cohort. Asymptomatic incipient PDAC (pancreatic intraepithelial neoplasm 3 [PanIN3] and/or intraductal papillary mucinous neoplasm with high-grade dysplasia) was detected in four of the patients with FPC. PanIN3 is a rare finding in the general population and is almost always found in the setting of pancreatic cancer. 2,3 Animal models of PDAC and case reports of patients with PanIN3 who subsequently developed pancreatic cancer suggest that it is likely that these neoplastic lesions would have progressed to cancer over time. 4 If this is the case, surgery for these patients (all of whom are alive 16 to 55 months postoperatively) could be curative. The report offers insights into strategies for earlier cancer detection and provides a platform to address key questions for the future.ThePDACsurveillanceprogramswererunatmultispecialty centers of dedicated expertise. The significant improvement in outcomesmaybelostifsurveillancewastobeperformed outsideof suchcenters.Theauthorsobservethatthedetectionrateofcanceror itsimmediate precursor lesion ranged from2% to 7%depending on the cohort studied and the center’s surveillance protocol. Could this detection rate be improved over time? It seems reasonable that with further study risk stratification could be improved and that surveillanceprotocolscanberefinedsothattheyaremorecost-effective. The age at which surveillance starts would be one consideration. Surveillance started at age 45 years in one center (Leiden, the Netherland) and at age 40 or 10 years earlier than the youngest age of diagnosis in the family in the other centers (Marburg, Germany, and Madrid, Spain). The mean age at diagnosis of PDAC was 58 years in Leiden, and PDAC was detected at age 68 and 53 years at the othercenters. The cumulative incidence of cancer increased withage;itmaybepossibletoshiftthestartingageslightlyupwardto improve yield. The type of mutation involved in susceptibility may also be of value in risk stratification. The CDKN2a mutation carriers had a much higher cancer rate than the BRCA/PALB2 mutation carriers. This observation reflects what is already known about these genetic syndromes from epidemiologic studies. 5,6 Ap revious costeffectiveness analysis of surveillance in patients with FPC suggests that patients who have a lifetime incidence of PDAC that exceeds 15% would be the most cost-effective to screen. 7 Although the lifetime risk of PDAC in CDKN2a carriers (16%) exceeds that of BRCA/PALB2 carriers (approximately 5%), we should not forego surveillance in all of these lower risk patients. It is important to assessotherfactorsthatcouldmitigatecancerriskupward,including a personal history of diabetes, the number of family members with PDAC, and smoking history. 8 A composite risk assessment that includes environmental factors, number of family members with cancer, known mutational status, and presence of diabetes could all aid in targeting surveillance for the highest risk patients. Lastly, the imaging protocols varied at the different centers, including various algorithms with endoscopic ultrasound and/or magnetic resonance imaging/magnetic resonance cholangiopancreatography; this variation