Family History Of Pancreatic Ductal Adenocarcinoma Research Articles

Abstract CT022: Mutant KRAS peptide-based vaccine in patients at high risk of developing pancreatic cancer: Preliminary analysis from a phase I study

Abstract Background: The development of pancreatic ductal adenocarcinoma (PDAC) from the first driver event takes >10 years, providing a unique window of opportunity for early interception. As a frequent alteration identified in both PDAC and pancreatic premalignancy, mutant KRAS (mKRAS) has emerged as a potential target for immune-based interception strategies in individuals at high risk of developing pancreatic cancer. Methods: This is a single-arm, open-label, second-in-human phase I study of a pooled synthetic long peptide (SLP) vaccine with poly-ICLC adjuvant targeting up to six mKRAS subtypes (G12D, G12R, G12V, G12A, G12C, G13D) in patients with hereditary predisposition to developing PDAC (NCT05013216). Key inclusion: radiographic evidence of a pancreatic abnormality and eligibility under at least one of three high-risk groups based on family history of PDAC and/or germline mutation status. Vaccination schema: mKRAS vaccine given on weeks 1, 3, 5, and 13. Peripheral blood collected at baseline and weeks 5, 13, and 17 for analysis of immunogenicity by IFN-gamma ELISpot. Co-primary endpoints: safety and mKRAS-specific T cell response. Results: At the time of data cutoff (November 15, 2023), 15 out of 20 planned patients were vaccinated on study and evaluable for immunogenicity. All 15 patients achieved a mKRAS-specific T cell response, defined by the maximal fold change in the pooled average IFN-gamma-producing mKRAS-specific T cell density within 17 weeks post-vaccination (median: 12.3, range: 3.1-167). Differential immunogenicity elicited by individual mKRAS epitopes was noted in this cohort. Specifically, the mKRAS G12V peptide induced the highest fold change increase in antigen-specific T cell expansion (median: 32.6, range: 2.9-243) while the mKRAS G12D peptide was the least immunogenic (median: 7.6, range: 0.4-104). Regarding safety, all adverse events were grade 1 or grade 2 in severity per NCI CTCAE v5.0. The most frequent vaccine-related adverse events were injection site reactions (93.8%), fatigue (62.5%), chills (43.8%), and headache (37.5%). No safety signals were observed. Conclusions: For the first time, we demonstrate mKRAS-specific T cell responses induced by vaccination in a cohort of high-risk individuals with inherited predisposition to PDAC. These findings directly serve as proof-of-concept to advance vaccine strategies focused on intercepting the development of pancreatic cancer in high-risk populations. Support: Stand Up To Cancer, Lustgarten Foundation, and NIH/NCI. Citation Format: Saurav D. Haldar, Amanda Huff, Elizabeth Abou Diwan, Anna Ferguson, Carol Judkins, Jiayun Lu, Hao Wang, Hassan Sinan, Christopher Thoburn, Katherine M. Bever, Mark Yarchoan, Amy M. Thomas, Julie M. Nauroth, Daniel A. Laheru, Michael G. Goggins, Elizabeth M. Jaffee, Nilofer S. Azad, Neeha Zaidi. Mutant KRAS peptide-based vaccine in patients at high risk of developing pancreatic cancer: Preliminary analysis from a phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT022.

Abstract 6515: Pancreatic ductal adenocarcinoma (PDAC) early detection

Abstract Introduction Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and is one of the deadliest cancer in the U.S., with a 5-year survival rate of just 11%. It is expected that ~62,000 new cases will be diagnosed in the US in 2023 and >70% of those will be at the regional or distant state, when curative resection is no longer an option. It is imperative that tools enabling early disease detection (stages I and II) are developed to improve patient survival outcomes. Here, we report the results of a study on the utility of extracellular vesicles (EVs) for early PDAC detection. Methods Our case-control training set was comprised of 75 pathologically confirmed PDAC cases (Stage I = 31, Stage II = 44) and 640 controls (including 11 subjects with pancreatitis) for EV biomarker and algorithm selection via machine learning. EVs from plasma were isolated using a proprietary technology, then EV-bound proteins of interest were analyzed via an immunoassay. A second independently collected cohort of 20 confirmed PDAC cases (Stage I = 10, Stage II = 10) and 27 controls (including 9 patients newly diagnosed with diabetes) was used for validation. Results The machine learning analysis using EV-isolated proteins generated a signature that utilized 8 different biomarkers, with an AUC of 0.989 (95% CI: 0.980 - 0.998) in the training set and an AUC of 0.987 (CI: 0.964 - 1.000) in the validation set. For the validation set, the sensitivity was 95% (CI: 76.4% - 99.1%) and the specificity was 92.6% (CI: 76.6% - 97.9%), with 10 out of 10 stage I cases and 9 out of 10 stage II cases correctly classified. Conclusions The ability to alter the future outcomes of PDAC patients will be predicated on development of a new generation of early-detection biomarkers and technologies. The use of EV protein signatures, a new class of cell-free biomarker, permits detection at high sensitivity and specificity, as demonstrated for the independently collected validation cohort. Studies aimed to assess this test for high-risk patients (family history of PDAC, known germline mutations, precursor lesions, hereditary pancreatitis, new onset diabetes will continue towards the establishment of real-world evidence. Citation Format: Juan P. Hinestrosa, Harmeet Dhani, Gregor Schroeder, Jean M. Lewis, Heath I. Balcer, Razelle Kurzrock, Dove Keith, Rosalie Sears, Paul Billings. Pancreatic ductal adenocarcinoma (PDAC) early detection. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6515.

Pancreatic imaging findings from the PRECEDE study: A large high-risk heritable cohort for pancreatic cancer.

689 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer typically discovered at incurable stages. The PRECEDE Consortium was established to accelerate early detection by using a large-scale, collaborative, innovative model, predicated on standardized collection of demographic, clinical, and imaging data from high-risk individuals (HRI). Here we report the initial pancreas imaging findings in Cohort 1, representing HRI with familial pancreatic cancer (FPC) or pathogenic germline variants (PGV) in PDAC susceptibility genes with a 1st or 2nd degree relative with PDAC. Methods: The PRECEDE Consortium (NCT04970056) began enrollment in 5/2020. HRI enrolled prospectively at centers worldwide into one of 7 cohorts based on personal and/or family history of PDAC and PGV status. PRECEDE’s planned enrollment is 10,000 patients. Data sharing is required to join PRECEDE, facilitated by a standardized data collection system and central database (PRECEDELink). Imaging (MRI/MRCP and EUS) is performed using standardized image acquisition and reporting templates. Imaging and clinical sequencing data are stored and analyzed in the PRECEDE data cloud. Results: By 9/16/2022, 26 sites enrolled 3156 patients in 7 cohorts, with 1716 in Cohort 1. Cohort 1 was 60% female, 80% white; 48% met FPC criteria, and 52% were PGV carriers. Within Cohort 1, 658 FPC and 965 PGV (1353 total, 79%) underwent imaging (68% MRI; 32% EUS). Overall, 573/1353 (42%) had pancreas abnormalities: 320/573 (49%) FPC, and 253/573 (36%) PGV (OR [95% CI] 1.65 [1.32–2.06], P < 0.001). Cysts were the most common abnormality, present in 549/1353 (41%) and accounting for 310/320 (97%) FPC and 239/253 (94%) PGV HRI abnormalities. Of 549 HRI with cysts, 262 (48%) had 1 cyst, including 137/310 (44%) FPC and 125/239 (52%) PGV HRI (OR 1.43 [1.07–1.92], P = .012) The remaining 287/549 (52%) had ≥2 cysts, including 173/310 (56%) FPC and 114/239 (48%) PGV HRI (OR 1.98 [1.49–2.64], P < 0.001). Worrisome features occurred in 83/1353 (6.1%) including: 14 (1%) cyst > 2 cm, 7 (0.5%) cyst ≥3 cm, 35 (2.6%) main pancreatic duct (MPD) diameter ≥5 mm; 2 (0.15%) duct strictures; and 25 (1.8%) solid masses. Solid masses included 1 (0.07%) PDAC, 9 (0.7%) neuroendocrine tumors, and 15 (1.1%) benign lesions (e.g. lipoma, splenule). Conclusions: Pancreatic abnormalities are common in a cohort of 1353 HRI enrolled in PRECEDE; 6.1% of HRI had findings with worrisome features and clinical implications. Multiple cysts were significantly more common in FPC HRI (OR 1.98); worrisome findings did not differ between FPC and PGV groups. The longitudinal study of this growing HRI cohort with standardized imaging and matched comprehensive epidemiological, clinical, and laboratory data, along with germline testing, will provide critical information and understanding of PDAC risk, and augment existing clinical decision-making models governing surveillance and treatment.

Racial, ethnic, and sex-based disparities among high-risk individuals undergoing pancreatic cancer surveillance.

687 Background: The international, multi-center Pancreatic Cancer Early Detection (PRECEDE) Consortium enrolls high-risk individuals (HRIs) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Enrollment began in 2020, and despite challenges related to the COVID-19 pandemic, the PRECEDE Consortium rapidly accrued a large cohort of HRIs. The purpose of this study is to describe the characteristics of this cohort and assess racial, ethnic, and sex-based disparities. Methods: The PRECEDE Consortium (NCT04970056) is a prospective, multicenter study focused on improving survival from PDAC through early detection. Data from all HRIs who met criteria for PDAC surveillance and enrolled between May 2020 - March 2022 were collected and included in the analysis. Results: During the study period, 1299 HRIs enrolled in PRECEDE at 32 centers. HRIs were excluded if enrollment data was incomplete or criteria for PDAC surveillance were not met. Of 1113 who were included, 47.2% met criteria for familial pancreatic cancer (FPC) and 45.4% had a family history of PDAC along with a PV in a PDAC-risk gene (BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). The remainder had familial atypical mole melanoma syndrome (5.7%), Peutz-Jeghers syndrome (1.6%), or hereditary pancreatitis (0.2%). More females than males enrolled (65.9% vs. 33.5%). The distribution of HRIs by race and ethnicity is depicted; the majority identified as white (87.7%). Study participants were primarily from the US (82.7%), the median age was 61 (27-85) and 18.5% had Ashkenazi Jewish ancestry. Nearly all HRIs consented to allow access to imaging data (99.6%), collection of germline DNA (97.7%), and biosample collection (99.5%). There were no race, ethnicity, or sex-based differences in rates of consent for collection of imaging, DNA, or biosamples. Conclusions: Enrollment of HRIs in prospective studies of PDAC surveillance is essential for advancing early detection research in PDAC. A distinct advantage of the PRECEDE Consortium for examining enrollment disparities is that recruitment began in 2020, providing a unique and current snapshot of the international PDAC surveillance landscape. Despite the recent attention on addressing disparities in healthcare delivery, significant racial, ethnic, and sex-based disparities persisted in the cohort of HRIs enrolled in the PRECEDE Consortium. Ensuring that the diversity of participants in the PRECEDE Consortium mirrors the communities served by participating centers is crucial. Further examining and addressing the reasons for these disparities is a major focus of the PRECEDE Consortium moving forward. [Table: see text]

Standardization of MRI Screening and Reporting in Individuals With Elevated Risk of Pancreatic Ductal Adenocarcinoma: Consensus Statement of the PRECEDE Consortium.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a dismal survival rate. Screening the general population for early detection of PDAC is not recommended, but because early detection improves survival, high-risk individuals, defined as those meeting criteria based on a family history of PDAC and/or the presence of known pathogenic germline variant genes with PDAC risk, are recommended to undergo screening with MRI and/or endoscopic ultrasound at regular intervals. The Pancreatic Cancer Early Detection (PRECEDE) Consortium was formed in 2018 and is composed of gastroenterologists, geneticists, pancreatic surgeons, radiologists, statisticians, and researchers from 40 sites in North America, Europe, and Asia. The overarching goal of the PRECEDE Consortium is to facilitate earlier diagnosis of PDAC for high-risk individuals to increase survival of the disease. A standardized MRI protocol and reporting template are needed to enhance the quality of screening examinations, improve consistency of clinical management, and facilitate multiinstitutional research. We present a consensus statement to standardize MRI screening and reporting for individuals with elevated risk of pancreatic cancer.

The PRECEDE consortium: A longitudinal international cohort study of individuals with genetic risk or familial pancreatic cancer.

e16239 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with lack of effective early detection strategies. There is an incomplete understanding of who is at risk for PDAC development and the contribution of heritability to that risk. Further, efforts at biomarker development for detection of early stage disease have been hampered by small sample sizes, lack of coordination, and inadequate access to high quality clinical data and biospecimens in relevant clinical populations. The PRECEDE Consortium was established to serve as a collaborative international network of PDAC clinical and research centers to accelerate early detection advances by standardizing collection of clinical data and biospecimens from patients at increased risk for PDAC. The consortium goal is to increase the overall survival rate for PDAC to 50% in 10 years by enabling transformative biomarker-driven discoveries in early detection of high-risk premalignant lesions and early stage cancers. Methods: The PRECEDE Consortium (NCT04970056; precedestudy.org) launched in 2019 and began enrollment in May, 2020. Data and biospecimen sharing are required for centers to join the consortium, which is facilitated through use of standardized data and biospecimen collection, and a centralized database (PRECEDELink) managed by a data coordinating center (Arbor Research). Imaging and clinical sequencing data will be stored and analyzed via a PRECEDE solution in the Amazon Web Services cloud. Participants age 18-90 are enrolled into one of seven cohorts based on personal and/or family history of PDAC and carrier status of pathogenic germline variants (PGV) in cancer predisposition genes (CPG). Three-generation pedigrees are collected at enrolment from participants, and standardized clinical germline testing is offered. Blood sample collection for DNA, plasma, and serum is completed at enrollment, and repeated annually for individuals meeting guidelines for annual surveillance. Results: To date, 24 clinical sites have enrolled 2187 participants, with a target of 10,000 participants enrolled from100 sites over the next 5 years. Among enrolled patients, 55% meet criteria for annual surveillance by MRI or endoscopic ultrasound. Demographics of the cohort to date: 56% female; 73% white; 35% CPG PGV carriers; 32% meet criteria for familial pancreatic cancer. Conclusions: The PRECEDE Consortium study is a large international, longitudinal, prospective cohort study designed to accelerate the pace and scale of early diagnosis. Planned projects will address modifiers of risk, penetrance of disease, creating comprehensive risk models for clinical decision-making, and development and validation of biomarker assays. The PRECEDE Consortium provides a unique, innovative platform to bring together key stakeholders (academia, patients, public and private sector) to effect progress.

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals

BackgroundSurveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. MethodsIndividuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. Results165 individuals (“FPC-cohort” N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected.Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. ConclusionSerum N-glycan monitoring may support early detection in a pancreas surveillance program.

Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study.

Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.

EUS-based Pancreatic Cancer Surveillance in BRCA1/BRCA2/PALB2/ATM Carriers Without a Family History of Pancreatic Cancer

Carriers of a pathogenic/likely pathogenic (P/LP) BRCA1/BRCA2/ATM/PALB2 variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)-based PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS at a tertiary care center. Of 194 P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS, 64 (33%) had no family history of PDAC and had at least 1 EUS for PDAC surveillance. These individuals underwent 143 total EUSs, were predominantly female (72%), and BRCA2 carriers (73%), with the majority having a personal history of cancer other than PDAC (67%). The median age at time of first EUS was 62 years [interquartile range (IQR), 53-67 years] and a median of 2 EUSs (IQR 1-3) were performed per patient, with a median of 3 years (IQR 2-4.5 years) between the first and last EUS for those with more than 1 EUS. Pancreatic abnormalities were detected in 44%, including cysts in 27%, and incidental luminal abnormalities in 41%. Eight percent developed a new pancreatic mass or cyst during surveillance, 2 individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC; however, the effectiveness of PDAC surveillance in this population requires further study. PREVENTION RELEVANCE: BRCA1/BRCA2/ATM/PALB2 carriers have increased pancreatic ductal adenocarcinoma (PDAC) risk, yet are typically not eligible for PDAC surveillance in the absence of PDAC family history. Herein we describe outcomes of PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC, showing that PDAC surveillance can be considered in this high-risk group.

An unusual presentation of very early onset metastatic pancreatic adenocarcinoma in a young man: case report

Pancreatic ductal adenocarcinoma (PDAC) is rare below 45 years of age and usually presents with constitutional symptoms, pain and jaundice. A 25 year old man, non-smoker, non-alcoholic presented to us with a lump in central upper abdomen of 1 month duration. Abdominal examination revealed a hard epigastric mass of size 7×10 cm. There were no other associated symptoms and no history of any similar illnesses in the family members. All laboratory parameters were within normal limits. Computed tomography showed a heterogeneous mass of size 7×13×15 cm arising from the head and neck of pancreas abutting the anterior abdominal wall with multiple abdominal and pelvic peritoneal deposits. Ultrasound guided core needle biopsy suggested PDAC. Hence, a diagnosis of very early onset metastatic PDAC was rendered and the patient was referred for palliative chemotherapy. PDAC below 45 years of age is known as very early onset PDAC. It is usually associated with family history of PDAC and known risk factors. This case was unique because of absence of the characteristic clinical features and known risk factors, early onset of occurrence and negative family history, which led to a diagnostic dilemma.

Longitudinal Changes of Serum N-Glycan Levels for Earlier Detection of Pancreatic Cancer in High-Risk Individuals

Background: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. Alternatively, individuals with lesions progressing to malignancy can be recognized by molecular biomarkers. We aimed to identify changes in serum protein glycosylation levels over time to earlier detect PDAC in high-risk individuals undergoing surveillance. Methods: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs and we included those of which at least two consecutive serum samples were available. Mass spectrometry analysis was performed to determine total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis (PDAC cases versus controls) and relative abundances were calculated for each glycosylation feature. Findings: 165 individuals (“FPC-cohort” N=119; Leiden cohort N=46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (estimated >10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected.Ten individuals (6%) developed PDAC during 35 months of follow-up. Upon comparison of these patients with all other individuals, several glycosylation characteristics were increased, namely fucosylation, tri- and tetra-antennary structures, and specific sialic linkage types. Other glycosylation characteristics decreased, such as complex-type diantennary and bisected glycans. The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. Interpretation: This study explores the applicability of serum N-glycan longitudinal monitoring for early detection in a pancreas surveillance program. Funding: The current study was supported by ZonNW project number 531002011 and Genootschap Bollenstreek – Bollenstreekfonds, Lisse-Hillegom, The Netherlands. Declaration of Interest: F.P. Vleggaar: Boston Scientific (Consultant) H.F., M.J Bruno: Boston Scientific (Consultant, support for industry and investigator-initiated studies), Cook Medical (Consultant, support for industry and investigator-initiated studies), Pentax Medical (Consultant, support for investigator-initiated studies), Mylan (Support for investigator-initiated studies), ChiRoStim (Support for investigator-initiated studies), all other authors have nothing to declare. Ethical Approval: The institutional ethical review boards of participating centers (2007_024, Amsterdam University Medical Center; MEC-2021-448 EMC; MEC P00.107 LUMC) have approved the study

Risk of Developing Pancreatic Cancer in Patients with Chronic Pancreatitis.

Background: Patients with chronic pancreatitis (CP) have an increased risk of developing pancreatic ductal adenocarcinoma (PDAC). We present data on PDAC in one of the most extensive European single-centre cohort studies of patients with CP. Methods: Retrospective analysis of prospectively collected data of patients with CP was performed. Aetiology of CP was determined according to the M-ANNHEIM classification system and only patients with definite CP > 18 years at data analysis were included. The final dataset included 581 patients with definite CP diagnosed between 2003 and 2018. Results: At CP diagnosis, there were 371 (63.9%) males and 210 (36.1%) females (median age 57 years, range 2–86). During 3423 person-years of observation, six pancreatic cancers were diagnosed (0.2% year). The mean time between diagnosis of CP and the occurrence of PDAC was 5.0 years (range 2.7–8.6). None of the cancer patients had a family history of PDAC. Diabetes mellitus (DM) was present in five of six (83.3%) patients with PDAC: in three patients before and in two after CP diagnosis. Clinical/laboratory signs of pancreatic exocrine insufficiency (PEI) were present in five of six (83.3%) patients with PDAC: in two at diagnosis of CP and in three after diagnosis. The mean survival time was 4 months after the diagnosis of PDAC (range 0.5–13). PDAC occurred significantly more often (p < 0.001) in two groups of patients without previous acute pancreatitis (AP): 2 of 20 patients (10%) with low body mass index (BMI) and PEI and in 3 of 10 (30%) patients with high BMI and DM at diagnosis of CP. Conclusions: Patients with CP have a high risk of developing PDAC, although risk is low in absolute terms. Our data suggest the possibility of defining subgroups of patients with a particularly elevated risk of PDAC. Such a possibility would open a path to personalised decision making on initiation of PDAC surveillance of patients with no previous episode of AP, (i) with low BMI and PEI, or (ii) elevated BMI and DM.

The impact of lung and bone metastases on prognosis in advanced PDAC.

494 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal disease inherently resistant to cytotoxic treatment. Despite the prevalence of liver and peritoneal metastases, subsets of patients also develop lung and bone metastases highlighting phenotypic heterogeneity. We reviewed the prognostic implications of metastatic sites on survival. Methods: This retrospective cohort study included all patients with PDAC who received surgical or oncological treatment at the University Health Network from September 2012 until December 2016. Clinical and pathological variables were obtained from patient electronic records. Radiological images and pathology reports were reviewed to ascertain sites of metastatic disease. The Kaplan-Meier method for survival and multivariable cox regression analysis identified prognostic factors. Results: 1153 patients were reviewed and 985 were included. 55% were male and the median age at diagnosis was 67 years. 287 (29%) completed curative surgery and 698 (71%) had locally advanced or metastatic disease; the median survival was 22 months and 9 months respectively. Lung and bone metastases were present in 18% (N = 180) and 6% (N = 58) of patients. In multivariable analysis increasing age and stage at diagnosis correlated with inferior survival (p &lt; 0.0001) and the presence of any lung (HR 0.77; 95% CI 0.63-0.94, p = 0.01) or bone metastases (HR 0.74; 95% CI 0.54-1.0, p = 0.05) resulted in improved outcomes. Liver and peritoneal disease were not prognostic. Sex and family history of PDAC did not associate with survival. There was no association between site of metastases and sex however patients with bone metastases were significantly younger at first diagnosis (median age 63yrs, p &lt; 0.01). Conclusions: Patients with advanced PDAC and metastases to lung or bone may represent distinct biological subtypes of PDAC. Molecular profiling of available tissue is ongoing.

Multigene hereditary cancer panel testing for patients with pancreatic cancer.

244 Background: Pancreatic ductal adenocarcinoma (PC) is associated with multiple hereditary cancer syndromes. Genes implicated in hereditary PC include ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2 and PMS2. The advent of multi-gene hereditary cancer panel testing streamlines diagnoses and medical management for clinicians and patients. Our objective was to assess the yield of pathogenic/likely pathogenic variants (PV/LPV) in individuals with PC undergoing panel testing as an initial test at GeneDx. Methods: We retrospectively reviewed panel test results of 605 individuals reporting a personal history of PC. Panel testing evaluated up to 32 genes associated with hereditary cancer. Individuals reporting neuroendocrine pathology or previous BRCA1/BRCA2 testing were excluded. Results: In this cohort, 61 PV/LPV were detected in 57 individuals in the following genes: ATM (17), BRCA2 (14), BRCA1 (5), CDKN2A (5), PALB2 (5), CHEK2 (4), MLH1 (2), MUTYH (2), PMS2 (2), BARD1 (1), FANCC (1), MSH2 (1), RAD51D (1) and TP53 (1), corresponding to a positive yield of 9.4% (57/605). Fifty-one of 61 PV/LPV were detected in genes associated with PC (84%) while 10 PV/LPV (16%) were identified in other genes including BARD1, CHEK2, FANCC, MUTYH, and RAD51D. The diagnostic yield among those reporting a family history of PC (33/294, 11.2%) was not statistically different from those without a reported family history (24/311, 7.7%). However, PV/LPV in ATM were detected more often in individuals reporting a family history of PC compared to those without a family history (4.1% vs. 1.6%, p=0.018). Conclusions: In total, 9.4% of patients with PC tested positive for PV/LPV in 14 different genes by panel testing. Although the majority of PV/LPV were identified in known PC genes, 16% of positive findings occurred in genes not typically associated with PC. ATM was most commonly implicated and more frequently reported in patients reporting family histories of PC. Assessing whether these genes are indeed causally related to PC and/or are possibly associated with other cancer types requires further investigation. Based on our results we conclude multi-gene panel testing may be considered as a first option for patients with PC regardless of their family history.

Prevalence and Progression of Pancreatic Cystic Precursor Lesions Differ Between Groups at High Risk of Developing Pancreatic Cancer.

The aim of this study was to compare the prevalence of cystic pancreatic lesions and their natural behavior in 2 distinct high-risk groups for developing pancreatic ductal adenocarcinoma (PDAC): (1) carriers of a mutation that predisposes to PDAC and (2) individuals without a known gene mutation but with a family history of PDAC (familial pancreatic cancer [FPC]). Pancreatic surveillance by annual magnetic resonance imaging and endoscopic ultrasound was performed in individuals with an estimated lifetime risk of developing PDAC of 10% or greater. Progression of a lesion was defined as growth 4 mm or greater or the development of worrisome features. We included 186 individuals: 98 mutation carriers and 88 FPC individuals (mean follow-up, 51 months). Individuals with FPC were significantly more likely than mutation carriers to have a pancreatic cyst 10 mm or greater (16% vs 5%, P = 0.045). Pancreatic cysts detected in mutation carriers, however, were significantly more likely to progress than those in FPC individuals (16% vs 2%, P = 0.050). This study provides evidence that the prevalence and growth characteristics of pancreatic cysts differ between distinct high-risk groups: individuals with FPC have a higher prevalence of pancreatic cysts 10 mm or greater, whereas cysts in mutation carriers are more likely to progress. These observations may help to develop more optimally tailored surveillance strategies in specific high-risk populations.

Self-Reported Questionnaire Detects Family History of Cancer in a Pancreatic Cancer Screening Program.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death; approximately 5-10% of PDAC is hereditary. Self-administered health history questionnaires (HHQs) may provide a low-cost method to detail family history (FH) of malignancy. Pancreas Center patients were asked to enroll in a registry; 149 with PDAC completed a HHQ which included FH data. Patients with FH of PDAC, or concern for inherited PDAC syndrome, were separately evaluated in a Prevention Program and additionally met with a genetic counselor (GC) to assess PDAC risk (n = 61). FH obtained through GC and HHQ were compared using Wilcoxon signed-rank sum and generalized linear mixed models with Poisson distribution. Agreement between GC and HHQ risk-assessment was assessed using kappa (κ) statistic. In the Prevention Program, HHQ was as precise in detecting FH of cancer as the GC (all p > 0.05). GC and HHQ demonstrated substantial agreement in risk-stratification of the Prevention Program cohort (κ = 0.73, 95% CI 0.59-0.87.) The sensitivity of the HHQ to detect a patient at elevated risk (i.e., moderate- or high-risk) of PDAC, compared to GC, was 82.9% (95% CI 67.3-92.3%) with a specificity of 95% (95% CI 73.1-99.7%). However, seven patients who were classified as average-risk by the HHQ were found to be at an elevated-risk of PDAC by the GC. In the PDAC cohort, 30/149 (20.1%) reported at least one first-degree relative (FDR) with PDAC. The limited sensitivity of the HHQ to detect patients at elevated risk of PDAC in the Prevention Program cohort suggests that a GC adds value in risk-assessment in this population. The HHQ may offer an opportunity to identify high-risk patients in a PDAC population.

Factors associated with cancer worries in individuals participating in annual pancreatic cancer surveillance

It is important to adequately and timely identify individuals with cancer worries amongst participants in a pancreatic ductal adenocarcinoma (PDAC) surveillance program, because they could benefit from psychosocial support to decrease distress. Therefore, the aim of this study was to assess both psychosocial and clinical factors associated with cancer worries. High-risk individuals participating in PDAC-surveillance were invited to annually complete a cancer worry scale (CWS) questionnaire which was sent after counseling by the clinical geneticist (T0), after intake for participation in PDAC-surveillance (T1), and then annually after every MRI and endoscopic ultrasonography (EUS) (T2 and further). Analyses were performed to identify factors associated with cancer worries in the second year of surveillance (T3). We found a significant intra-individual decrease in cancer worries (β = −0.84, P < 0.001), nevertheless, 33 % of individuals had a CWS-score ≥14 at T3. We found one factor significantly associated with cancer worries at T3: having a family member affected by PDAC <50 years of age (β = 0.22, P = 0.03). The detection of a cystic lesion, a shortened surveillance interval, or undergoing pancreatic surgery did not lead to more cancer worries (P = 0.163, P = 0.33, and P = 0.53, respectively). In conclusion, this study identified ‘a family history of PDAC <50 years of age’ as the only predictor of cancer worries experienced after 2 years of surveillance in individuals at high risk of developing PDAC. This knowledge could help clinicians to timely identify individuals ‘at risk’ for high levels of cancer worries who would likely benefit from psychosocial support.

Familial Pancreatic Cancer: To Screen or not to Screen?

Familial Pancreatic Cancer: To Screen or not to Screen?

Identification of genetic risk for pancreatic adenocarcinoma

Recent consortium guidelines support research-based screening for those at high risk of pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)). Genetic testing plays an important role in the establishment of high-risk PDAC research clinics by delineating those individuals who would benefit from screening protocols. We retrospectively examined patients referred for PDAC-related genetic testing from January 2009 to June 2014. Patients were referred for a personal and/or family history of PDAC or a questioned diagnosis of hereditary pancreatitis (HP). Of the 75 referred patients, 36 underwent testing, of which 11 (31%) were mutation-positive. In total, 36% of patients with chronic pancreatitis carried a mutation, 11% of patients with a family history of PDAC carried a mutation, and 20% of patients with a personal history of PDAC carried a mutation. The most common barrier to testing was lack of insurance coverage. Genetic testing yields a suitable number of mutation-positive individuals who may benefit from increased screening. Subjects with possible HP yielded the highest positive rate. Individuals with idiopathic pancreatitis, onset of pancreatitis before the age of 30 years, and those with a family history of PDAC should be considered for testing. Sub-optimal insurance coverage remains a major deterrent to obtaining testing.

BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts.

Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. Patients in a high-risk PDAC prevention and genetics program or those with a personal history of PDAC who were referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. A total of 37 patients without PDAC underwent BRCA1/2 testing at the study institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six patients carried Ashkenazi Jewish founder mutations (3 with BRCA1 and 3 with BRCA2), and 1 patient was found to have a BRCA2 mutation on comprehensive testing. Thirty-two patients with PDAC underwent BRCA1/2 genetic testing. Five patients had Ashkenazi Jewish founder mutations (2 with BRCA1 and 3 with BRCA2), and 2 patients were found to have BRCA2 mutations on comprehensive testing. The diagnostic yield was 7 of 32 patients (21.9%). BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation-positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer.