Screening for pancreatic ductal adenocarcinoma alters the course of disease among high-risk individuals (HRIs) and is recommended by multiple societies including the International Cancer of the Pancreas Screening Consortium, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy. However, there are limited analyses on the screening rates and barriers to adherence among HRIs. This study aims to describe real-world longitudinal screening adherence of a HRI surveillance cohort and identify potential barriers to adherence.

Patients followed by Stanford's Benign Pancreas Clinic were identified as HRIs if they met screening criteria per the latest abovementioned screening guidelines, and were included in our study if they underwent at least 1 screening exam. Data on HRIs were obtained retrospectively from our hospital's electronic health record system. Patient and screening characteristics were analyzed by adherence rates.

262 HRIs undergoing recommended screening were identified. The mean follow-up time per patient was 4.9 years and the mean successful annual screening rate within the entire cohort was 67%. HRIs in the lowest quartile of adherence were more likely to have more EUS rather than MRI surveillance exams compared to those who were completely adherent (p = 0.01). HRIs who were completely adherent were also an older cohort compared to those with non-complete adherence (p = 0.02) or in the lowest quartile of adherence (p = 0.01).

It is difficult to achieve high adherence rates for annual pancreatic cancer screening of HRIs as recommended by the latest guidelines. Age and screening modality may be factors that contribute to adherence difficulty.

Early detection of pancreatic cancer (PC) remains challenging largely due to the low population incidence and few known risk factors. However, screening in at-risk populations and detection of early cancer has the potential to significantly alter survival. In this study, we aim to develop a predictive model to identify patients at risk for developing new-onset PC at two and a half to three year time frame. We used the Electronic Health Records (EHR) of a large medical system from 2000 to 2021 (N = 537,410). The EHR data analyzed in this work consists of patients' demographic information, diagnosis records, and lab values, which are used to identify patients who were diagnosed with pancreatic cancer and the risk factors used in the machine learning algorithm for prediction. We identified 73 risk factors of pancreatic cancer with the Phenome-wide Association Study (PheWAS) on a matched case-control cohort. Based on them, we built a large-scale machine learning algorithm based on EHR. A temporally stratified validation based on patients not included in any stage of the training of the model was performed. This model showed an AUROC at 0.742 [0.727, 0.757] which was similar in both the general population and in a subset of the population who has had prior cross-sectional imaging. The rate of diagnosis of pancreatic cancer in those in the top 1 percentile of the risk score was 6 folds higher than the general population. Our model leverages data extracted from a 6-month window of time in the electronic health record to identify patients at nearly sixfold higher than baseline risk of developing pancreatic cancer 2.5-3 years from evaluation. This approach offers an opportunity to define an enriched population entirely based on static data, where current screening may be recommended.

In the current study, we assessed whether repeated measurements of a panel of protein biomarkers with relevance to pancreatic ductal adenocarcinoma (PDAC) improves lead time performance for earlier detection over a single timepoint measurement. Specifically, CA125, CEA, LRG1, REG3A, THBS2, TIMP1, TNRFSF1A as well as CA19-9 were assayed in serially collected pre-diagnostic plasma from 242 PDAC cases and 242 age- and sex-matched non-case control participants in the PLCO cohort. We compared performance estimates of a parametric empirical Bayes (PEB) algorithm, which incorporates participant biomarker history, to that of a single-threshold (ST) method. We demonstrated improvements in AUC estimates (2-13 %) for all biomarkers when considering the PEB approach compared to ST. For CA19-9, the PEBCA19-9 yielded an AUC of 0.88 when at least one repeat measurement was within 3 years of clinical diagnosis. At a specificity of 98.5 %, the PEBCA19-9 identified 15 of the 41 PDAC cases and signaled positive at an average lead-time of 1.09 years whereas the ST approach captured 11 of the 41 PDAC cases with an average positive signal at 0.48 years. Among CA19-9 low individuals, a PEB algorithm based on repeat measurements of TIMP1 yielded an additional 14 % sensitivity at 98.5 % specificity. An adaptive algorithm that considers repeated CA19-9 measurements improves sensitivity and lead-time detection of PDAC compared to a single-threshold method. Additional protein biomarkers may improve sensitivity for earlier detection of PDAC among cases with low CA19-9.

Currently, those recommended to undergo pancreatic cancer (PC) surveillance include appropriately aged individuals at high risk of PC due to an identifiable genetic susceptibility or those without identifiable genetic susceptibility who nonetheless have a strong family history of PC. With increases in identification of individuals at high risk for PC and increased use of PC surveillance in clinical practice, there has been increasing debate about who should undergo surveillance as well as how surveillance should be performed including use of imaging and blood-based testing. Furthermore, there is increasing interest in the outcomes of PC surveillance in high-risk individuals with some studies demonstrating that surveillance leads to downstaging of PC and improvements in survival. In this review, we summarize the current state of PC surveillance in high-risk individuals, providing an overview of the risk factors associated with PC, selection of high-risk individuals for PC surveillance, and the current, but non-uniform, recommendations for performing PC surveillance. Additionally, we review approaches to apply various imaging and blood-based tests to surveillance and the outcomes of PC surveillance.

Pancreatic cancer is a highly lethal malignancy and is predicted to become the second leading cause of cancer-related deaths by 2030. Early detection significantly improves outcomes, but general population screening remains infeasible due to the low prevalence of the disease and lack of specific biomarkers. This review evaluates current recommendations for pancreatic cancer surveillance in high-risk individuals, synthesises evidence from recent studies and explores the sustainability of current imaging-based surveillance programmes. Challenges such as overdiagnosis, economic feasibility and disparities in access highlight the need for targeted, cost-effective strategies. Collaborative initiatives and consortia are needed to advance biomarker research and refine risk stratification. By integrating evidence-based recommendations with sustainable approaches, this review outlines pathways to improve early detection and reduce mortality from pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and stromal cells that sustains anabolic growth and suppresses tumor immunity. These conceptual advances have generated novel immunotherapy regimens, particularly cancer vaccines, which are now in clinical testing. We also highlight the advent of KRAS targeted therapy, a milestone advance that has transformed treatment paradigms and offers a platform for combined immunotherapy and targeted strategies. This review provides a perspective summarizing current scientific and therapeutic challenges as well as practice-changing opportunities for the PDAC field at this major inflection point.

Pancreatic ductal adenocarcinoma continues to have a poor prognosis, although recent advances in neoadjuvant treatments (NATs) have provided some hope. Imaging assessment of suspected tumours can be challenging and requires a specific approach, with pancreas protocol CT being the primary imaging modality for staging with other modalities used as problem-solving tools to facilitate appropriate management. Imaging assessment post NAT can be particularly difficult due to a current lack of robust radiological criteria to predict response and differentiate treatment induced fibrosis/inflammation from residual tumour. This review aims to provide an update of pancreatic ductal adenocarcinoma with particular focus on three points: tumour staging pre- and post-NAT including vascular assessment, structured reporting with introduction of the PAncreatic Cancer reporting Template-UK (PACT-UK) radiology template, and the potential future role of artificial intelligence in the diagnosis and staging of pancreatic cancer.

Several studies suggest that new-onset diabetes mellitus is an early manifestation of pancreatic ductal adenocarcinoma (PDAC). Therefore, the International Cancer of the Pancreas Screening Consortium recommends glucose and hemoglobin A1c (HbA1c) monitoring in high-risk individuals (HRIs) undergoing surveillance. However, evidence that such monitoring improves PDAC detection is lacking. Our aim was to investigate the association between serum glucose and HbA1c values and the development of PDAC in HRIs undergoing surveillance.

Participants were recruited from the familial pancreatic cancer surveillance cohort, which follows hereditary predisposed HRIs yearly by magnetic resonance imaging and/or endoscopic ultrasound and blood sampling. Those who underwent fasting glucose and/or HbA1c monitoring at least once were eligible candidates.

Four hundred four HRIs met the inclusion criteria. During a median follow-up of 41 months (range 14-120), 9 individuals developed PDAC and 4 (without PDAC) were diagnosed with new-onset diabetes mellitus. Glucose levels ranged from 3.4 to 10.7 mmol/L (mean 5.6 ± 0.7) and HbA1c levels from 25 to 68 mmol/mol (mean 37.7 ± 4.1). The mean values did not differ significantly between PDAC cases and controls. The percentage of individuals with at least one elevated value were comparable between PDAC cases and controls for glucose (33% and 27%, P = 0.707) and HbA1c (22% and 14%, P = 0.623). No consistent glucose or HbA1c trends over time suggested a correlation with PDAC development.

In this HRI surveillance cohort, measuring glucose and HbA1c values did not contribute to PDAC detection. Larger and longer-term studies are needed to determine the final role of glucose and HbA1c monitoring in PDAC surveillance.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, accounting for over 90% of pancreatic cancers, and is characterized by limited treatment options and poor survival rates. Systems biology provides in-depth insights into the molecular mechanisms of PDAC. In this context, novel algorithms and comprehensive strategies are essential for advancing the identification of critical network nodes and therapeutic targets within disease-related protein-protein interaction networks. This study employed a comprehensive computational strategy using the metaheuristic algorithm Trader to enhance the identification of potential therapeutic targets. Analysis of the expression data from the PDAC dataset (GSE132956) involved co-expression analysis and clustering of differentially expressed genes to identify key disease-associated modules. The STRING database was used to construct a network of differentially expressed genes, and the Trader algorithm pinpointed the top 30 DEGs whose removal caused the most significant network disconnections. Enriched gene ontology terms included "Signaling by Rho GTPases," "Signaling by receptor tyrosine kinases," and "immune system." Additionally, nine hub genes-FYN, MAPK3, CDK2, SNRPG, GNAQ, PAK1, LPCAT4, MAP1LC3B, and FBN1-were identified as central to PDAC pathogenesis. This integrated approach, combining co-expression analysis with protein-protein interaction network analysis using a metaheuristic algorithm, provides valuable insights into PDAC mechanisms and highlights several hub genes as potential therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) continues to remain one of the leading causes of cancer-related death. Unlike other malignancies where universal screening is recommended, the same cannot be said for PDAC. The purpose of this study is to review which patients are at high risk of developing PDAC and therefore candidates for screening, methods/frequency of screening, and risk for these groups of patients.

Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven.

To compare the survival of patients with surveillance-detected PDAC with US national data.

This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023.

Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment.

Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted.

A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]).

These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

The goal of surveillance programs for individuals at risk (IAR) from familial pancreatic cancer (FPC) families or families with other inherited tumor syndromes predisposing to the development of pancreatic adenocarcinoma (PDAC), such as hereditary pancreatitis or Peutz-Jeghers syndrome, is the dectection and consecutive curative resection of early PDAC or even better its high-grade precursor lesions. Although the indication for surgery is quite established, the extent of surgery is not well defined due to the lack of evidence-based data. In addition, multiple factors have to be taken into account to determine an optimal personalized surgical strategy. This holds especially true since pancreatic surgery is associated with a relatively high morbidity and might impair the quality of life significantly. In this article the surgical aspects in the setting of hereditary PDAC are discussed.

In the early years of my GI fellowship, a healthy 40-year-old man came to my clinic and announced that he was going to die of pancreatic cancer. His brothers, father and uncles had all died of the disease; he felt his fate was inescapable. I asked whether his family members had seen doctors or had any tests. His answer was yes to both. Even so, doctors could not diagnose the pancreatic cancer at early stages. CT scans were always negative. I thought to myself, in order to help this patient-CT scans may not be reliable for early detection. Perhaps other methods of imaging the pancreas might be of more benefit. This patient opened a door that led to a 30-year journey of trying to detect pancreatic cancer at earlier stages when it is curable.

Infiltrating ductal adenocarcinoma of the pancreas, referred to here as "pancreatic cancer," is one of the deadliest of all of the solid malignancies. The five-year survival rate in the United States for individuals diagnosed today with pancreatic cancer is a dismal 12%. Many invasive cancers, including pancreatic cancer, however, arise from histologically and genetically well-characterized precursor lesions, and these precancers are curable. Precursor lesions therefore are an attractive target for early detection and treatment. This is particularly true for individuals with an increased risk of developing invasive cancer, such as individuals with a strong family history of pancreatic cancer, and individuals with a germline variant known to increase the risk of developing pancreatic cancer. There is therefore a need to understand the precursor lesions that can give rise to invasive pancreatic cancer in these individuals.

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive cancers. It has a poor 5-year survival rate of 12%, partly because most cases are diagnosed at advanced stages, precluding curative surgical resection. Early-stage PDA has significantly better prognoses due to increased potential for curative interventions, making early detection of PDA critically important to improved patient outcomes. We examine current and evolving early detection concepts, screening strategies, diagnostic yields among high-risk individuals, controversies, and limitations of standard-of-care imaging.

Surveillance for pancreatic ductal adenocarcinoma (PDAC) is recommended for high-risk individuals with genetic variants in PDAC-associated genes and/or family history. Surveillance uptake and adherence may depend on the perception of PDAC risk and cancer worry. We aimed to determine PDAC risk perception in at-risk individuals and assess factors associated with PDAC surveillance uptake.

At-risk individuals identified from a prospective academic registry were sent a survey electronically. PDAC risk perception, cancer worry and surveillance uptake were surveyed. Factors associated with increased risk perception and surveillance were assessed. Five-year PDAC risk was calculated using the PancPRO risk assessment model, and correlation with subjective risk assessment was assessed.

The overall survey response rate was 34% (279/816). The median perceived PDAC risk was twofold (IQR 1-4) above respondents' estimates of general population risk. Factors significantly associated with higher perceived PDAC risk included non-Hispanic white race, post-graduate education level, PDAC-affected first-degree relative, genetic variants and lack of personal cancer history. Cancer worry had a very weak correlation across PDAC risk estimates (r=0.16). No correlation between perceived PDAC risk and 5-year calculated PDAC risk was found. Older age, having a first-degree relative with PDAC, meeting with a medical provider about PDAC cancer risk and awareness of surveillance modalities were significant predictors of undergoing PDAC surveillance.

Individuals at risk for PDAC do not report risk perception that correlates with calculated risk. This presents an opportunity for counselling of at-risk patients to individualise management and improve surveillance uptake for eligible individuals.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate. PDAC surveillance is recommended in high-risk individuals (HRIs) with strong PDAC family history or a pathogenic germline variant (PGV) in a PDAC susceptibility gene. We aimed to explore a potential correlation between genetic status, extent of family history, pancreatic findings, and surveillance implications in heterogeneous PDAC HRIs.

A total of 239 HRIs from 202 families were tested genetically and underwent prospective pancreatic surveillance for 6 years.

The cohort was divided into 3 groups: familial pancreatic cancer (FPC; 70 individuals, 54 families), familial non-FPC (81 individuals, 73 families), and hereditary pancreatic cancer (PC) (88 individuals, 75 families). PGVs were detected in 37.6% of all families, including 11.1% of FPC families and 9.6% of familial non-FPC families. The hereditary PC group had earlier onset of PDAC compared with the other 2 groups. BRCA2 PGV carriers showed earlier onset of PDAC and pancreatic cysts. Of the 239 HRIs, PDAC was detected in 11 individuals (4.6%), with 73% diagnosed at an early stage; 4 (1.67%) had pancreatic neuroendocrine tumor; 6 (2.5%) had main-duct intraductal papillary neoplasm (IPMN); and 41 (17.15%) had side-branch IPMN. Seventeen individuals were referred to surgery, and 12 were alive at the end of the study.

The percentage of PDAC was similar in the 3 groups studied. The hereditary PC group, and particularly BRCA2 PGV carriers, had an earlier age of PDAC onset. PGVs were detected in a significant percentage of HRIs with PC. Surveillance seems effective for detection of early-stage PDAC and precursor lesions.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a very poor prognosis, with near-identical incidence and mortality. According to the World Health Organization Globocan Database, the estimated number of new cases worldwide will rise by 70% between 2020 and 2040. There are no effective screening methods available so far, even for high-risk individuals. The prognosis of PDAC, even at its early stages, is still mostly unsatisfactory. Impaired glucose metabolism is present in about 3/4 of PDAC cases.

Available literature on pancreatic cancer and diabetes mellitus was reviewed using a PubMed database. Data from a national oncology registry (on PDAC) and information from a registry of healthcare providers (on diabetes mellitus and a number of abdominal ultrasound investigations) were obtained.

New-onset diabetes mellitus in subjects older than 60 years should be an incentive for a prompt and detailed investigation to exclude PDAC. Type 2 diabetes mellitus, diabetes mellitus associated with chronic non-malignant diseases of the exocrine pancreas, and PDAC-associated type 3c diabetes mellitus are the most frequent types. Proper differentiation of particular types of new-onset diabetes mellitus is a starting point for a population-based program. An algorithm for subsequent steps of the workup was proposed.

The structured, well-differentiated, and elaborately designed approach to the elderly with a new onset of diabetes mellitus could improve the current situation in diagnostics and subsequent poor outcomes of therapy of PDAC.

Evidence supporting the effectiveness of pancreatic cancer (PC) screening is scant. Most clinical studies concern small populations with short follow-up durations. Mathematical models are useful to estimate long-term effects of PC screening using short-term indicators. This systematic review aims to evaluate the impact of PC screening on life expectancy (LE) in model-based studies. Therefore, we searched four databases (Embase, Medline, Web-of-science, Cochrane) until 30 May 2022 to identify model-based studies evaluating the impact of PC screening on LE in different risk populations. Two authors independently screened identified papers, extracted data and assessed the methodological quality of studies. A descriptive analysis was performed and the impact of screening strategies on LE of different risk groups was reported. Our search resulted in 419 studies, of which eight met the eligibility criteria (mathematical model, PC screening, LE). Reported relative risks (RR) for PC varied from 1 to 70. In higher risk individuals (RR > 5), annual screening (by imaging with 56% sensitivity for HGD/early stage PC) predicted to increase LE of screened individuals by 20 to 260 days. In the general population, one-time PC screening was estimated to decrease LE (2-110 days), depending on the test characteristics and treatment mortality risk. In conclusion, although the models use different and sometimes outdated or unrealistic assumptions, it seems that PC screening in high-risk populations improves LE, and that this gain increases with a higher PC risk. Updated model studies, with data from large clinical trials are necessary to predict the long-term effect of PC screening more accurately.

Pancreatic ductal adenocarcinoma (PDAC) is the third most lethal cancer in the United States, with a 5-year life expectancy of 11%. Most symptoms manifest at an advanced stage of the disease when surgery is no longer appropriate. The dire prognosis of PDAC warrants new strategies to improve the outcomes of patients, and early detection has garnered significant attention. However, early detection of PDAC is most often incidental, emphasizing the importance of developing new early detection screening strategies. Due to the low incidence of the disease in the general population, much of the focus for screening has turned to individuals at high risk of PDAC. This enriches the screening population and balances the risks associated with pancreas interventions. The cancers that are found in these high-risk individuals by MRI and/or EUS screening show favorable 73% 5-year overall survival. Even with the emphasis on screening in enriched high-risk populations, only a minority of incident cancers are detected this way. One strategy to improve early detection outcomes is to integrate artificial intelligence (AI) into biomarker discovery and risk models. This expert review summarizes recent publications that have developed AI algorithms for the applications of risk stratification of PDAC using radiomics and electronic health records. Furthermore, this review illustrates the current uses of radiomics and biomarkers in AI for early detection of PDAC. Finally, various challenges and potential solutions are highlighted regarding the use of AI in medicine for early detection purposes.

Herein, we report the frequency and distribution of germline pathogenic variants (PVs) among females with breast cancer (BC) and at least one other non-BC who underwent multi-gene panel testing (MGPT). Among females with PVs diagnosed first with BC or ovarian cancer (OC), we sought to enumerate the frequency of subsequent PV-associated cancers.

Females with BC and cancer of ≥ 1 other site (multiple primary cancers, MPC) who underwent MGPT through Ambry Genetics from March 2012 to December 2016 were included if they had testing of at least 21 genes of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53). Phenotypic data were abstracted from test requisition forms and clinical notes.

Of 6,617 evaluable patients, most were White (70.8%) and median age at first cancer, second cancer, and MGPT was 49 (interquartile range [IQR]: 18), 59 (IQR: 16), and 63 (IQR: 16) years, respectively. PVs were found among 14.1% (932/6617) of the overall cohort and in 16.4% (440/2687) of females who were diagnosed first with BC. Among those, 55.2% (243/440) had an actionable PV associated with a subsequent cancer diagnosis including 150 OCs. Of the 2443 females with breast and ovarian cancer, few (n = 97, 9.5%) were diagnosed first with OC, limiting our analysis.

Females with MPC, including BC, have a high frequency of germline PVs (14.1%). These data delineate the opportunities for intercepting subsequent cancers associated with genetic risk among females diagnosed first with BC.

Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment- and survival-related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high-risk individuals (HRI) could: (1) improve compliance with guideline-based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival.

Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC-associated genes at minimum.

Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC-related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non-MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification.

Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at-risk relatives in one clinic.

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.

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.

Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer-related mortality. The fact that the vast majority of patients with PDAC are diagnosed at an advanced stage highlights the need of early diagnosis. As hereditary factors are associated with approximately 5% of all PDAC cases, a screening programme to these high-risk individuals (HRI) has been proposed. The aim of screening methods is to identify selected group of patients with morphological abnormalities at an early stage, in order to be treated promptly. In this study, we evaluate the surgical outcomes and the appropriateness of pancreatic resection in HRIs who were selected for screening.

A systematic literature search of the PubMed, Embase, and Cochrane databases was performed. The clinicopathological features were recorded and evaluated.

Six studies were selected for data collection. A total number of 77 patients were identified. Twenty-one patients had a germline mutation, with CDKN2A being the most prominent one (15.6%). Distal pancreatectomy was the most common surgical procedure (42.8%), followed by pancreaticoduodenectomy (33.8%). The mean disease-free survival was 23.6 months and tumour recurrence occurred in 9 patients (11.7%). Disease-specific mortality was 17.8%, while overall mortality was 19.5%. The most frequently reported postoperative diagnosis was PDAC (28 cases, 38.9%), followed by IPMN (23 cases, 31.9%), whereas high-grade PanIN lesions were found in 13 patients (18.1%).

High-risk individuals for pancreatic cancer, who are eventually operated may have a relatively uneventful postoperative course, however the oncological outcomes are comparable to the general population.

Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer.

Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated.

Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P = .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%.

Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease.

Pancreatic cancer surveillance in high-risk individuals may lead to detection of pancreatic ductal adenocarcinoma (PDAC) at an earlier stage and with improved survival. This study evaluated the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants (PVs) in CDKN2A.

Prospectively collected data were analyzed from individuals participating in pancreatic cancer surveillance. Surveillance consisted of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound.

Three hundred forty-seven germline PV carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years. A total of 36 cases of PDAC were diagnosed in 31 (8.9%) patients at a median age of 60.4 (interquartile range 51.3-64.1) years. The cumulative incidence of primary PDAC was 20.7% by age 70 years. Five carriers (5 of 31; 16.1%) were diagnosed with a second primary PDAC. Thirty (83.3%) of 36 PDACs were considered resectable at the time of imaging. Twelve cases (12 of 36; 33.3%) presented with stage I disease. The median survival after diagnosis of primary PDAC was 26.8 months, and the 5-year survival rate was 32.4% (95% CI, 19.1 to 54.8). Individuals with primary PDAC who underwent resection (22 of 31; 71.0%) had an overall 5-year survival rate of 44.1% (95% CI, 27.2 to 71.3). Nine (2.6%; 9 of 347) individuals underwent surgery for a suspected malignant lesion, which proved to not be PDAC, and this included five lesions with low-grade dysplasia.

This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in CDKN2A. This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.

Individuals at increased risk of developing pancreatic cancer, including those with a significant family history of the disease and those with pancreatic cancer susceptibility gene variants, can benefit from pancreas surveillance. Most pancreatic cancers diagnosed during surveillance are early-stage and such patients can achieve long-term survival. Determining who should undergo pancreas surveillance is still a work-in-progress, but the main tools clinicians use to estimate an individual's risk of pancreatic cancer are patient's age, the extent of their family history of pancreatic cancer, and whether or not they have a pancreatic cancer susceptibility gene mutation.

Patient-derived organoids (PDO) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping).

PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized controlled clinical trial.

Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathologic response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment-naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, carbohydrate-antigen 19-9 (CA-19-9), and favorable RECIST imaging response.

PDOs established from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC. See related commentary by Zhang et al., p. 3176.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer, due to both its late stage at diagnosis and its resistance to chemotherapy. However, recent advances in our understanding of the biology of PDAC have revealed new opportunities for early detection and targeted therapy of PDAC. In this review, we discuss the pathogenesis of PDAC, including molecular alterations in tumor cells, cellular alterations in the tumor microenvironment, and population-level risk factors. We review the current status of surveillance and early detection of PDAC, including populations at high risk and screening approaches. We outline the diagnostic approach to PDAC and highlight key treatment considerations, including how therapeutic approaches change with disease stage and targetable subtypes of PDAC. Recent years have seen significant improvements in our approaches to detect and treat PDAC, but large-scale, coordinated efforts will be needed to maximize the clinical impact for patients and improve overall survival.

PALB2 (BRCA2 partner and localizer) is a BRCA2-interacting protein that is required for BRCA2 genome caretaker tasks and interacts with BRCA1. Women with PALB2 mutation have a 40% to 60% higher risk of breast cancer, almost equivalent to women who have BRCA mutations. PALB2 mutation may also increase the risk of pancreatic cancer. New guidelines for PALB2 mutation in breast cancer advise pancreatic cancer screening, which includes M.R.I.s of the pancreas as well as endoscopic ultrasonography, for women who have a family history of pancreatic cancer. Using the Cancer Genome Atlas (TCGA) and The Human Protein Atlas we examined genes that co-express with PALB2 in breast and pancreatic cancer.

We used cBioPortal for Cancer Genomics to analyze data in TCGA. cBioPortal provides visualization, analysis and download of large-scale cancer genomics data sets. We used the UCSC Xena Browser to additionally analyze gene expression in TCGA.

Six genes, EARS2, ARL6IP1, DNAJA3, KNOP1, RPUSD1, and TMEM186, significantly coexpressed with PALB2 in both breast and pancreatic cancer. Glutamyl-tRNA synthetase 2 (EARS2) was the only gene coexpressing with PALB2 in the breast and pancreatic cancer subjects that was significantly related to pancreatic cancer survival. Elevated PALB2 and EARS2 gene expression are both significantly associated with the PAM50 Luminal B subtype and high risk of recurrence, suggesting why these women may need active intervention, such as prophylactic mastectomy.

EARS2 expression might be a risk factor for pancreatic cancer in breast cancer patients with PALB2 mutations. By assessing EARS2 expression in breast tumors, the clinician might obtain a second piece of information that, with family history of pancreatic cancer, could inform the decision to perform pancreatic cancer screening.

The aim of this study was to assess the feasibility of cross-sectional imaging for detection of pancreatic cancer (PDAC) in patients with new-onset hyperglycemia and diabetes (NOD).

We conducted a prospective pilot study from November 2018 to March 2020 within an integrated health system. Patients aged 50-85 years with newly elevated glycemic parameters without a history of diabetes were invited to complete a 3-phase contrast-enhanced computed tomography pancreas protocol scan while participating in the Prospective Study to Establish a NOD Cohort. Abnormal pancreatic findings, incidental extrapancreatic findings, and subsequent clinical evaluation were identified. Variability in clinical reporting between medical centers based on descriptors of pancreatic duct and parenchyma was assessed.

A total of 130 of 147 participants (88.4%) consented to imaging; 93 scans were completed (before COVID-19 stay-at-home order). The median age was 62.4 years (interquartile range 56.3-68.8), 37.6% women; Hispanic (39.8%), White (29.0%), Black (14.0%), and Asian (13.3%). One (1.1%) case of PDAC (stage IV) was diagnosed, 12 of 93 participants (12.9%) had additional pancreatic findings: 5 fatty infiltration, 3 cysts, 2 atrophy, 1 divisum, and 1 calcification. There were 57 extrapancreatic findings among 52 of 93 (56%) unique patients; 12 of 57 (21.1%) prompted clinical evaluation with 2 additional malignancies diagnosed (nonsmall cell lung and renal oncocytoma). Reports from 1 participating medical center more frequently provided description of pancreatic parenchyma and ducts (92.9% vs 18.4%), P < 0.0001.

High proportion of incidental findings and variability in clinical reports are challenges to be addressed for a successful NOD-based early detection strategy for PDAC.