Familial Pancreatic Cancer Kindreds Research Articles

Intraductal Papillary Mucinous Neoplasms in High-Risk Individuals: Incidence, Growth Rate, and Malignancy Risk

In high-risk individuals (HRIs), we aimed to assess the cumulative incidence of intraductal papillary mucinous neoplasms (IPMNs) and compare IPMN growth, neoplastic progression rate, and the value of growth as predictor for neoplastic progression to these in sporadic IPMNs. We performed annual surveillance of Dutch HRIs, involving carriers of germline pathogenic variants (PVs) and PV-negative familial pancreatic cancer kindreds. HRIs with IPMNs were compared with Italian individuals without familial risk under surveillance for sporadic IPMNs. A total of 457 HRIs were followed for 48 (range 2-172) months; the estimated cumulative IPMN incidence was 46% (95% confidence interval, 28%-64%). In comparison with 442 control individuals, IPMNs in HRIs were more likely to grow ≥2.5 mm/y (31% vs 7%; P < .001) and develop worrisome features (32% vs 19%; P= .010). PV carriers with IPMNs more often displayed neoplastic progression (n= 3 [11%] vs n= 6 [1%]; P= .011), while familial pancreatic cancer kindreds did not (n= 0 [0%]; P= 1.000). The malignancy risk in a PV carrier with an IPMN was 23% for growth rates ≥2.5 mm/y (n= 13), 30% for ≥5 mm/y (n= 10), and 60% for ≥10 mm/y (n= 5). The cumulative incidence of IPMNs in HRIs is higher than previously reported in the general population. Compared with sporadic IPMNs, they have an increased growth rate. PV carriers with IPMNs are suggested to be at a higher malignancy risk. Intensive follow-up should be considered for PV carriers with an IPMN growing ≥2.5 mm/y, and surgical resection for those growing ≥5 mm/y.

Mechanisms of development and progression of pancreatic neoplasms.

Pancreatic ductal adenocarcinoma (PDAC) develops via dysplastic changes in the epithelia graded as low- and high-grade with accumulation of molecular alterations. Constitutive activation of mitogen-activated protein kinase (MAPK) contributed by attenuation of DUSP6 plays a key role in sustaining PDAC. Active MAPK induces various molecules that function as effectors to sustain PDAC. AURKA and SON are downstream effectors that contribute substantially to the proliferation and survival of PDAC cells and are potentially useful as therapeutic targets. Active MAPK also promote microRNAs that modulate the proliferation of PDAC cells and are useful as diagnostic markers. Familial pancreatic cancer kindreds in Japan show various germline mutations supposed to increase a pancreatic cancer risk. Intraductal papillary mucinous neoplasms (IPMNs) consist of dilated ducts lined by papillary neoplastic epithelia of various shapes and varying grades of atypia. Various papillae of IPMNs are classified into four subtypes that are associated with clinicopathological features, including patient prognosis. GNAS is a specific driver gene for the development of IPMN through gain-of-function mutations. Tracing of molecular alterations has elucidated the mechanism of progression of IPMN from dysplasia to carcinoma, as well as one type of papillae. Intraductal tubulopapillary neoplasms belong to a distinct class of pancreatic neoplasms.

Risk of Pancreatic Cancer in the Long-Term Prospective Follow-Up of Familial Pancreatic Cancer Kindreds.

A family history of pancreatic cancer is associated with increased pancreatic cancer risk. However, risk estimates for individuals in kindreds with an aggregation of pancreatic cancer (>1 relative) are imprecise because of small samples sizes or potentially impacted by biases inherent in retrospective data. The objective of this study is to determine the age-specific pancreatic cancer risk as a function of family history using prospective data. We compared pancreatic cancer incidence (n = 167) in 21 141 individuals from 4433 families enrolled in the National Familial Pancreatic Cancer Registry with that expected based on Surveillance Epidemiology and End Results data and estimated the cumulative probability of pancreatic cancer using competing risk regression. Familial pancreatic kindred members (kindreds with pancreatic cancer in 2 first-degree relatives [FDRs] or a pathogenic variant) had a standardized incidence ratio of 4.86 (95% confidence interval [CI] = 4.01 to 5.90), and sporadic kindred members (kindreds not meeting familial criteria) had a standardized incidence ratio of 2.55 (95% CI = 1.95 to 3.34). Risk in familial pancreatic cancer kindreds increased with an increasing number of FDRs with pancreatic cancer, with a standardized incidence ratio of 3.46 (95% CI = 2.52 to 4.76), 5.44 (95% CI = 4.07 to 7.26), and 10.78 (95% CI = 6.87 to 16.89) for 1, 2, and 3 or more FDRs with pancreatic cancer, respectively. Risk was also higher among individuals with a family history of young-onset (aged younger than 50 years) pancreatic cancer. Pancreatic cancer risk is strongly dependent on family history, including both the degree of relationship(s) and age of onset of pancreatic cancer in relatives. These risk estimates will help inform the design of early detection studies and the risk and benefit analysis of screening trials.

Long-term yield of pancreatic cancer surveillance in high-risk individuals

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater...

S0025 Patients in Familial Pancreatic Cancer Kindreds Demonstrate Increased High-Risk Radiological Features Compared to Those With Deleterious Germline Variants in a High-Risk Pancreatic Surveillance Program

INTRODUCTION: Recent literature has identified risk factors for neoplastic progression in patients at increased risk of pancreatic ductal adenocarcinoma (PDAC). Solid pancreatic masses, ≥ 3 cysts at baseline, main pancreatic duct dilation ≥ 5 mm at baseline, and the presence of pathogenic germline variants have been described as being associated with neoplastic progression. METHODS: We performed a retrospective study of high-risk individuals (HRIs) who underwent pancreatic surveillance at a tertiary referral center between May 2013 and April 2020. HRIs were included if they 1) had a pathogenic (P) or likely pathogenic (LP) germline variant that has been associated with PDAC, with at least one first- or second-degree relative with PDAC, or 2) were from familial pancreatic cancer (FPC) kindreds, defined as patients without an identifiable germline mutation but with two or more relatives with PDAC, at least one of whom is a first degree relative of the HRI. Initial surveillance imaging results and clinical data were reviewed. Univariable analyses were performed using Fisher’s exact test and multivariable analyses using logistic regression. RESULTS: A total of 117 patients met inclusion criteria: 39 with P/LP germline variants and 78 from FPC kindreds. Seventy-eight (66.7%) study subjects were female and median age was 63.3 ± 12.4. No other differences were noted in demographics. Of the 39 P/LP germline variants, 12 (30.8%) were in BRCA1, BRCA2 20 (51.3%), ATM 2 (5.1%), PALB2 1 (2.6%), and MSH2 4 (10.3%). Worrisome radiologic features included solid masses (n = 2), multifocal cysts (n = 26), or main pancreatic duct dilation ≥ 5 mm (n = 3) at baseline imaging with endoscopic ultrasound or magnetic resonance cholangiopancreatography. On initial surveillance, 27 (34.6%) patients from FPC kindreds exhibited worrisome radiologic findings compared to 4 (10.3%) of those with germline variants (p = 0.007). Multivariate logistic regression demonstrated that FPC (aOR 4.08, 95% CI 1.22–13.68) and age (aOR 1.10, 95% CI 1.04–1.17) were predictors of worrisome radiologic findings on initial surveillance when adjusting for confounders. CONCLUSION: In our study, patients in the FPC cohort exhibited a higher prevalence of worrisome radiologic features compared to patients with germline mutations. Further evaluation is needed to determine whether FPC patients with worrisome features are at increased risk of neoplastic progression compared to patients with P/LP germline variants in a high-risk cohort.Table 1.: Logistic Regression Analysis of Factors Associated with Worrisome Radiologic Features

Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers.

A family history of pancreatic cancer (PC) is a risk factor of PC, and risk levels increase as affected families grow in number and/or develop PC at younger ages. Familial pancreatic cancer (FPC) is defined as a client having at least two PC cases in a first degree relatives. In the narrow sense, FPC does not include some inherited cancer syndromes that are known to increase the risks of PC, such as Peutz–Jeghers syndrome (PJS), hereditary pancreatitis (HP), hereditary breast ovarian cancer syndrome (HBOC), and so on. FPC accounts for 5%–10% of total PC diagnoses and is marked by several features in genetic, epidemiological, and clinicopathological findings that are similar to or distinct from conventional PC. Recent advances in genetic medicine have led to an increased ability to identify germline variants of cancer-associated genes. To date, high-risk individuals (HRIs) in many developed countries, including FPC kindreds and inherited cancer syndromes, are screened clinically to detect and treat early-stage PC. This article highlights the concept of FPC and the most recent data on its detection.

Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer.

Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

Risk independence for the identification of cystic lesions in Familial Pancreatic Cancer (FPC) kindreds

Risk independence for the identification of cystic lesions in Familial Pancreatic Cancer (FPC) kindreds

Familial pancreatic cancer: Concept, management and issues.

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, “anticipation” is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

The Early Detection of Pancreatic Cancer: Whom and How?

The 5-year survival rate of pancreatic cancer is extremely low till now, because resectable cases are less than 20% and 5-year survival rate after surgical resection is only 10-20%. Early detection and curative surgery are important to prolong the survival which was well proved by colon cancer screening test in general population. However, screening test for general population can not prove the survival benefit in pancreatic cancer. So, many studies were performed for the development of screening strategies in high-risk groups of pancreatic cancer. The following were current candidates for screening: first-degree relatives of patients with pancreatic cancer from a familial pancreatic cancer kindred with at least two affected firstdegree relatives; patients with Peutz-Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer mutation carriers with ≥ 1 affected firstdegree relative. The recommended screening tests are endoscopic ultrasonography and magnetic resonance cholangiopancreatography. Screening is recommended at age 50 or 10 year earlier than the onset age of pancreatic cancer among family. However, the screening interval is not established and there is great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended. Korean J Pancreatobiliary 2015;20(4):198-203

The EUROPAC secondary screening for pancreatic cancer in familial pancreatic cancer and hereditary pancreatitis kindreds

The EUROPAC secondary screening for pancreatic cancer in familial pancreatic cancer and hereditary pancreatitis kindreds

Incidence of Post-ERCP Pancreatitis From Direct Pancreatic Juice Collection in Hereditary Pancreatitis and Familial Pancreatic Cancer Before and After the Introduction of Prophylactic Pancreatic Stents and Rectal Diclofenac

Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP). A prospective study (1999-2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008. There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06-0.84) in favor of prophylaxis (0.035). Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening.

Abstract 3157: Loss of heterozygosity as a molecular ‘second hit’ In familial pancreatic cancer.

Abstract BACKGROUND/HYPOTHESIS: Familial Pancreatic Cancer (FPC) has an autosomal dominant, variable penetrant mode of inheritance with &amp;gt;80% of its genetic cause yet to be discovered. We hypothesize that a high density DNA microarray analysis of Formalin-Fixed Paraffin Embedded (FFPE) FPC tumors will yield novel regions of genomic loss harboring disease causing FPC gene(s). METHODS: 158 FFPE FPC tumor specimens with matched normal tissue were reviewed by a pancreatic pathologist and tumors with &amp;lt;70% cellularity underwent laser capture microdissection. The samples with &amp;gt;70% cellularity were microdissected directly from marked unstained slides. A total of 74 samples were DNA extracted, whole genome amplified and processed on the Affymetrix 660K Oncoscan Microarray. Copy number analysis was performed using Nexus Copy Number Variation Version 6.1 software employing the SNP-FASST2 segmentation and Allele Specific Copy Number Analysis of Tumors (ASCAT) algorithms. PRELIMINARY RESULTS: A pair-wise analysis of 55 FPC samples with matched normal tissue was performed. Recurrent regions of loss of heterozygosity (LOH) were known loci of importance in pancreatic tumorigenesis, including CDKN2A, p53 and SMAD4. Copy neutral/gain LOH was observed throughout the genome and may account for &amp;gt;35% of chromosomal loss. Recurrent novel genetic loci displaying LOH was observed on chromosomes: 3p(25%), 5q(18%), 6p(22%), 12q(18%) and Xq (42%). Examination of 2 FPC siblings elucidates shared loss regions spanning the 3p22.2-3p22.3 and 17p13.3 loci. Candidate tumor suppressor genes (TSGs) of interest include DCLK3, SERPINF1, SERPINF2 and SMYD4. CONCLUSION: We have described for the first time the presence of copy neutral/gain LOH in FPC highlighting previously unknown regions displaying genetic loss. Further confirmation with quantitative PCR, integrating with germline exome sequencing data, and validation of putative TSGs shared by members of high risk FPC kindreds will help uncover novel genes associated with this disease. Citation Format: Zaheer S. Kanji, Stefano Serra, Spring Holter, Ayelet Borgida, Robert Grant, Steven Gallinger. Loss of heterozygosity as a molecular ‘second hit’ In familial pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3157. doi:10.1158/1538-7445.AM2013-3157

International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer

BackgroundScreening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia.ObjectiveTo develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition...

Genetic Testing by Cancer Site

It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz-Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation.

Importance of Age of Onset in Pancreatic Cancer Kindreds

BackgroundYoung-onset cancer is a hallmark of many familial cancer syndromes, yet the implications of young-onset disease in predicting risk of pancreatic cancer among familial pancreatic cancer (FPC) kindred members remain unclear.MethodsTo understand the relationship between age at onset of pancreatic cancer and risk of pancreatic cancer in kindred members, we compared the observed incidence of pancreatic cancer in 9040 individuals from 1718 kindreds enrolled in the National Familial Pancreas Tumor Registry with that observed in the general US population (Surveillance, Epidemiology, and End Results). Standardized incidence ratios (SIRs) were calculated for data stratified by familial vs sporadic cancer kindred membership, number of affected relatives, youngest age of onset among relatives, and smoking status. Competing risk survival analyses were performed to examine the risk of pancreatic cancer and risk of death from other causes according to youngest age of onset of pancreatic cancer in the family and the number of affected relatives.ResultsRisk of pancreatic cancer was elevated in both FPC kindred members (SIR = 6.79, 95% confidence interval [CI] = 4.54 to 9.75, P < .001) and sporadic pancreatic cancer (SPC) kindred members (SIR = 2.41, 95% CI = 1.04 to 4.74, P = .04) compared with the general population. The presence of a young-onset patient (<50 years) in the family did not alter the risk for SPC kindred members (SIR = 2.74, 95% CI = 0.05 to 15.30, P = .59) compared with those without a young-onset case in the kindred (SIR = 2.36, 95% CI = 0.95 to 4.88, P = .06). However, risk was higher among members of FPC kindreds with a young-onset case in the kindred (SIR = 9.31, 95% CI = 3.42 to 20.28, P < .001) than those without a young-onset case in the kindred (SIR = 6.34, 95% CI = 4.02 to 9.51, P < .001). Competing risk survival analyses indicated that the lifetime risk of pancreatic cancer in FPC kindreds increased with decreasing age of onset in the kindred (hazard ratio = 1.55, 95% CI = 1.19 to 2.03 per year). However, youngest age of onset for pancreatic cancer in the kindred did not affect the risk among SPC kindred members.ConclusionsIndividuals with a family history of pancreatic cancer are at a statistically significantly increased risk of developing pancreatic cancer. Having a member of the family with a young-onset pancreatic cancer confers an added risk in FPC kindreds.

A MATHEMATICAL MODEL TO STRATIFY CANCER RISK IN FAMILIAL PANCREATIC CANCER KINDREDS

Aim: To create a mathematical model to stratify the risk of cancer in individuals from familial pancreatic cancer (FPC) kindreds. Background: The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer is screening individuals from FPC kindreds. Improved risk stratification will increase positive predictive value of screening. Methods: 1251 individuals from 85 families with ≥3 pancreatic cancers (total affected 297) were divided into training and test sets. Their histories were used to create and validate a hazard model based on the probability that an individual: 1) belongs to a high risk family; 2) is a gene carrier; 3) will develop cancer in a fixed period. Evaluation was by Harrell's C index (modified ROC) and Hosmer-Lemeshow statistics. Results: The model was accurate in terms of both discrimination [area under curve = 0.72 (CI 0.68-0.76), remaining >0.7 up to 69 years] and calibration [no significant difference between estimated and observed events e.g. at 60-64 years p = 0.935, (ideal p = 1.0), goodness of fit: χ2 = 0.83]. This was maintained to age 79 years. Discussion: This model gives an individual probability of developing cancer within a set period. Once fully integrated with its user interface, registered clinicians will be able to access it online to aid them in clinical consultations. Conclusion: This interface is a tool with applications in patient counselling and selection for secondary screening in high risk individuals.

Allele-specific expression in the germline of patients with familial pancreatic cancer: An unbiased approach to cancer gene discovery

Physiologic allele-specific expression (ASE) in germline tissues occurs during random X-chromosome inactivation1 and in genomic imprinting2, wherein the two alleles of a gene in a heterozygous individual are not expressed equally. Recent studies have confirmed the existence of ASE in apparently non-imprinted autosomal genes3-14; however, the extent of ASE in the human genome is unknown. We explored ASE in lymphoblastoid cell lines of 145 individuals using an oligonucleotide array based assay. ASE of autosomal genes was found to be a very common phenomenon in ~20% of heterozygotes at 78% of SNPs at 84% of the genes examined. Comparison of 100 affected individuals from familial pancreatic cancer kindreds and 45 controls revealed three types of changes in the germline: (a) loss of ASE, (b) gain of ASE, and, (c) rare instances of “extreme” (near monoallelic) ASE. The latter changes identified heterozygous deleterious mutations in a subset of these genes. Consequently, an ASE assay efficiently identifies candidate disease genes with altered germline expression properties as compared to controls, and provides insights into mechanisms that confer an inherited disease risk for pancreatic cancer.

Interobserver agreement for EUS findings in familial pancreatic-cancer kindreds

Interobserver agreement for EUS findings in familial pancreatic-cancer kindreds

A Clinical and Economic Evaluation of Endoscopic Ultrasound for Patients at Risk for Familial Pancreatic Adenocarcinoma

Background and Aims: Approximately 10% of pancreatic adenocarcinoma is familial. Approximately 50% of Ist-degree relatives (FDRs) have endoscopic ultrasound (EUS) findings of chronic pancreatitis. We modeled the natural history of these patients to compare 4 management strategies. Methods: We performed a systematic review, and created a Markov model for 45-year-old male FDRs, with findings of chronic pancreatitis on screening EUS. We compared 4 strategies: doing nothing, prophylactic total pancreatectomy (PTP), annual surveillance by EUS, and annual surveillance with EUS and fine needle aspiration (EUS/FNA). Outcomes incorporated mortality, quality of life, procedural complications, and costs. Results: In the Do Nothing strategy, the lifetime risk of cancer was 20%. Doing nothing provided the greatest remaining years of life, the lowest cost, and the greatest remaining quality-adjusted life years (QALYs). PTP provided the fewest remaining years of life, and the fewest remaining QALYs. Screening with EUS provided nearly identical results to PTP, and screening with EUS/FNA provided intermediate results between PTP and doing nothing. PTP provided the longest life expectancy if the lifetime risk of pancreatic cancer was at least 46%, and provided the most QALYs if the risk was at least 68%. Conclusions: FDRs from familial pancreatic cancer kindreds, who have EUS findings of chronic pancreatitis, have increased risk for cancer, but their precise risk is unknown. Without the ability to further quantify that risk, the most effective strategy is to do nothing.