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. The outcomes of the FPC cohorts are summarized on the basis of the genetic basis for susceptibility for pancreatic ductal adenocarcinoma (PDAC; eg, CDKN2a/p16-Leiden mutations carriers are one cohort, BRCA/PALB2 mutation carriers are a second cohort, 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. The PDAC surveillance programs were run at multispecialty centers of dedicated expertise. The significant improvement in outcomes may be lost if surveillance was to be performed outside of such centers. The authors observe that the detection rate of cancer or its immediate precursor lesion ranged from 2% 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 surveillance protocols can be refined so that they are more cost-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 other centers. The cumulative incidence of cancer increased with age; it may be possible to shift the starting age slightly upward to 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 A previous cost-effectiveness 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 assess other factors that could mitigate cancer risk upward, 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 in protocol is similar to that seen in FPC surveillance programs throughout the world.⁹ It is difficult to know whether differences in detection rates of PanIN3 and stage IA disease depend on the imaging strategy. It is clear that early detection was present using all of the protocols in these three centers. Future studies are needed that can sort out whether a specific surveillance protocol outperforms another; this underscores the need to tolerate different approaches in surveillance strategies so that comparisons can be forthcoming.

Overall, the findings reported by Vasen et al¹ represent a remarkable and encouraging step forward for better management of PDAC, a disease that has not had a significant improvement in survival in the last 50 years. While it is possible that lead time bias might play a role in these outcomes, it is difficult to say whether the concept of lead time bias is applicable to pancreatic cancer, where the disease quickly metastasizes and is uniformly lethal. Are these findings applicable to sporadic pancreatic cancer? Although genetic susceptibility to pancreatic cancer leads to multifocal neoplasia throughout the pancreas, the molecular basis for the familial versus sporadic pancreatic tumorigenesis is the same.^10,11 Thus, the results by Vasen et al¹ can impact our thinking about pancreatic cancer in the general population in several ways. First, the data support the idea that earlier detection of pancreatic cancer can significantly improve outcomes. Second, targeting high-risk individuals is one strategy for detecting disease in asymptomatic patients. The authors are to be commended for identifying a pathway for earlier detection of pancreatic neoplasia in asymptomatic high-risk patients. These findings emphasize the difficulty in trying to catch PDAC at the highest precancer stage (eg, PanIN3 or intraductal papillary mucinous neoplasm with high-grade dysplasia) and the need to keep surveillance at centers of expertise. This long-term prospective study also highlights the prognostic value and clinical need for developing better biomarkers and molecular imaging tests for the earlier detection of PDAC.