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A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial., Competing Interests: Declaration of competing interest AM is a consultant for Tezcat Biotechnologies and is a co-inventor on a patent that has been licensed from Johns Hopkins University by Thrive Earlier Detection (an Exact Sciences company). RB received research funding from Immunovia and Freenome and serves as on the advisory board for Immunovia. The authors declare no other reported potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations., Methods: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed., Results: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344)., Conclusions: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Importance: 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., Objective: To compare the survival of patients with surveillance-detected PDAC with US national data., Design, Setting, and Participants: 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., Exposures: Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment., Main Outcomes and Measures: 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., Results: 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%])., Conclusions and Relevance: These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

Background: The International Cancer of the Pancreas Screening Consortium recommended annual imaging for individuals at increased risk for developing a pancreatic ductal adenocarcinoma (PDAC) who did not have concerning pancreatic findings or a cyst <3 cm without worrisome features. We aimed to determine if 3-cm cyst size accurately predicted advanced precursor lesions in high-risk individuals undergoing surveillance., Methods: Imaging for high-risk individuals (HRIs) undergoing PDAC surveillance from 2007 to 2021 was reviewed and pancreatic abnormalities were recorded including dominant cyst size and number of cysts. Subjects were excluded if they had the following: (1) no follow-up imaging after baseline, (2) solid lesion at baseline, or (3) development of solid lesion without having cyst on prior imaging., Results: Five of the 77 HRIs found to have a cystic lesion on surveillance developed a PDAC: 3 with cystic lesion >1 cm as compared with only 2 of 67 HRIs with cystic lesions <1 cm (P < 0.05). None of these cysts developed worrisome findings and 4/5 PDACs did not arise from visualized cystic precursor lesion., Conclusions: Patients with a cyst ≥1 cm were at increased risk for developing PDAC compared with patients with cyst <1 cm. Pancreatic ductal adenocarcinoma usually did not arise from a recognized cystic lesion., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Since its inception two years ago, the international, multicenter Pancreatic Cancer Early Detection (PRECEDE) Consortium has enrolled high-risk individuals (HRI) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Herein we aim to evaluate enrollment disparities in PRECEDE. Data on HRIs enrolled between May 2020 and March 2022 were collected, with HRIs defined as participants enrolled in PRECEDE meeting guideline-based criteria for PDAC surveillance. Of 1,273 HRIs enrolled, 1,113 were eligible for inclusion, with 47.2% meeting familial pancreatic cancer criteria without a known pathogenic variant (PV) and the remainder having a pathogenic variant in a PDAC-risk gene (CDKN2A, STK11, PRSS1, BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). Study participants were predominantly from the United States (82.7%), the most common age range at enrollment was 60-69 years (37.4%), and a non-PDAC cancer was present in 32.4%. There were racial/ethnic- and sex-based disparities among enrolled subjects, as the majority of participants were female (65.9%) and self-reported white (87.7%), with only 2.9% having Hispanic ethnicity. While more than 97% of participants consented to utilize imaging data and biosamples for research, there was no difference in rate of consent based on race/ethnicity, sex, or age, thereby demonstrating uniform participation in research activities among all subgroups after enrollment. Ensuring that diversity of HRIs in PDAC surveillance programs mirrors the communities served by participating centers is important. Substantial racial/ethnic- and sex-based disparities persist among recently enrolled HRIs undergoing PDAC surveillance, and therefore reducing these disparities will be a major focus of the PRECEDE Consortium moving forward., Prevention Relevance: Pancreatic cancer surveillance is critical to decreasing pancreatic cancer mortality; therefore, it is important that pancreatic cancer surveillance studies enroll diverse patients. We demonstrate that substantial racial/ethnic- and sex-based disparities exist amongst enrollment in the international PRECEDE consortium, highlighting the dire need for future efforts to reduce these disparities. See related Spotlight, p. 305., (©2023 American Association for Cancer Research.)

Purpose: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM)., Methods: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index., Results: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments., Conclusions: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769)., Competing Interests: Conflict of Interest M.D.B. discloses research support from Viacyte and Dexcom, DSMB membership for Insulet, and advisory board for Ariel Precision Medicine. Y.C.K. reports research support from Dexcom and advisory Board for Novo Nordisk Inc. K.M. is currently employed by Eli Lilly and Company. His contribution to this work preceded, and was independent of, this employment. None of the other authors have potential conflicts., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)

Purpose: To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS studies., Methods: Individuals recommended for pancreas surveillance were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point was the stage distribution of pancreatic ductal adenocarcinoma (PDAC) detected (stage I v higher-stage). Overall survival was determined using the Kaplan-Meier method., Results: Of 1,461 high-risk individuals enrolled into CAPS5, 48.5% had a pathogenic variant in a PDAC-susceptibility gene. Ten patients were diagnosed with PDAC, one of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance. Of the remaining nine, seven (77.8%) had a stage I PDAC (by surgical pathology) detected during surveillance; one had stage II, and one had stage III disease. Seven of these nine patients with PDAC were alive after a median follow-up of 2.6 years. Eight additional patients underwent surgical resection for worrisome lesions; three had high-grade and five had low-grade dysplasia in their resected specimens. In the entire CAPS cohort (CAPS1-5 studies, 1,731 patients), 26 PDAC cases have been diagnosed, 19 within surveillance, 57.9% of whom had stage I and 5.2% had stage IV disease. By contrast, six of the seven PDACs (85.7%) detected outside surveillance were stage IV. Five-year survival to date of the patients with a screen-detected PDAC is 73.3%, and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance (hazard ratio [95% CI]; 0.13 [0.03 to 0.50], P = .003)., Conclusion: Most pancreatic cancers diagnosed within the CAPS high-risk cohort in the recent years have had stage I disease with long-term survival.

Objective: To evaluate the significance of UDD in IPMNs., Background: The uncinate process of the pancreas has an independent ductal drainage system. International consensus guidelines of IPMNs still consider it as a branch-duct, even though it is the main drainage system for the uncinate process., Methods: A retrospective review of all surgically treated IPMNs at our institution after 2008 was performed. Preoperative radiological studies were reviewed by an abdominal radiologist who was blinded to the pathological results. In addition to the Fukuoka criteria, presence of UDD was recorded. Using multivariate analysis, the pathological significance of UDD in predicting advanced neoplasia [high grade dysplasia or invasive carcinoma (HGD/ IC)] was determined., Results: Two hundred sixty patients were identified (mean age at diagnosis was 68 years and 49% were females): 122 (47%) had HGD/IC. UDD was noted in 59 (23%), of which 36 (61%) had HGD/IC (P < 0.003). On multivariate analysis, UDD was an independent predictor of HGD/IC (odds ratio = 2.99, P < 0.04). Subgroup analysis on patients with IPMNs confined to the dorsal portion of the gland (n = 161), also demonstrated UDD to be a significant predictor of HGD/IC in those remote lesions (odds ratio: 4.41, P = 0.039)., Conclusions: This is the largest study to evaluate the significance of UDD in IPMNs and shows it to be a high-risk feature. This association persisted for remote IPMNs limited to the dorsal pancreas, suggesting UDD may be associated with an aggressive phenotype even in remote IPMN lesions., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response., Methods: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis., Results: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8 th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007)., Conclusions: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9., Methods: Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification., Results: The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%., Discussion: These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%)., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Individuals with a genetic susceptibility to pancreatic ductal adenocarcinoma (PDAC) may benefit from surveillance to increase the likelihood of early detection. Currently, candidates for surveillance are identified based on genetic test results and family history of PDAC, and surveillance is accomplished through imaging of the pancreas (endoscopic ultrasound or MRI). Novel methods that incorporate personalized risk, biomarkers, and radiomics are being investigated in an attempt to improve identification of at-risk individuals and to increase detection of precursor and early-stage lesions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Data from the International Cancer of the Pancreas Screening Consortium studies have demonstrated that screening for pancreatic ductal adenocarcinoma can be effective and that surveillance improves survival in high-risk individuals. Endoscopic ultrasound (EUS) and cross-sectional imaging are both used, although there is some suggestion that EUS is superior. Demonstration of the cost-effectiveness of screening is important to implement screening in high-risk groups., Methods: Results from centers with EUS-predominant screening were pooled to evaluate efficacy of index EUS in screening. A decision analysis model simulated the outcome of high-risk patients who undergo screening and evaluated the parameters that would make screening cost-effective at a US $100,000 per quality-adjusted life-year willingness to pay., Results: One-time index EUS has a sensitivity of 71.25% and specificity of 99.82% to detection to detect high-risk lesions. Screening with index EUS was cost-effective, particularly at lifetime pancreatic cancer probabilities of greater than 10.8%, or at lower probabilities if life expectancy after resection of a lesion that was at least 16 years, and if missed, lesion rates on index EUS are 5% or less., Conclusions: Pancreatic cancer screening can be cost-effective through index EUS, particularly for those individuals at high-lifetime risk of cancer., Competing Interests: S.K. received travel support from the Boston Scientific Corporation and Olympus. B.W.K, is a consultant of Exact Sciences and received travel support from Janssen. M.L.K. is a consultant of Boston Scientific, Olympus, and Pentax. Equity MAB: Dark Canyon Laboratories, VIRGO. The other authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 μL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p [AUC = 0.77; 95% confidence interval (CI), 0.66-0.87], miR-130a-3p (AUC = 0.74; 95% CI, 0.63-0.84), and miR-222-3p (AUC = 0.70; 95% CI, 0.58-0.81) were identified as significantly differentially abundant in plasma from stage II PDAC versus controls. Although none of the miRNAs individually outperformed the currently used serologic biomarker for PDAC, carbohydrate antigen 19-9 (CA19-9), combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI, 0.81-0.95) for CA 19-9 alone to 0.92 (95% CI, 0.86-0.97), 0.94 (95% CI, 0.89-0.98), and 0.92 (95% CI, 0.87-0.97), respectively. Gene set enrichment analyses of transcripts correlated with high and low expression of the three miRNAs in The Cancer Genome Atlas PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings. PREVENTION RELEVANCE: Development of minimally invasive biomarker assays for detection of premalignant disease and early-stage pancreatic cancer is key to improving patient survival. This study describes a limited volume plasma miRNA biomarker assay that can detect early-stage resectable pancreatic cancer in clinical samples necessary for effective prevention and clinical intervention., (©2021 American Association for Cancer Research.)

Aims: National studies have demonstrated disparities in the treatment and survival of pancreatic cancer patients based on socioeconomic status (SES). This study aimed to identify specific differences in perioperative management and outcomes based on patient SES and to study the role of a multidisciplinary clinic (MDC) in mitigating any variations., Methods: The study analyzed patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma in a large hospital system. The patients were categorized into groups of high and low SES and whether they were managed by the authors' pancreatic cancer MDC or not. The study compared differences in disease characteristics, receipt of multimodality therapy, perioperative outcomes, and recurrence-free and overall survival., Results: Of the 162 low-SES patients and 119 high-SES patients, 54% were managed in the MDC. Outside the MDC, low-SES patients were less likely to receive neoadjuvant chemotherapy and had less minimally invasive surgery, a longer OR time, less enhanced recovery participation, and more major complications (p < 0.05). No SES disparities were observed among the MDC patients. Despite similar tumor characteristics, the low-SES patients had inferior median overall survival (21 vs 32 months; p = 0.005), but the MDC appeared to eliminate this disparity. Low SES correlated with inferior survival for the non-MDC patients (17 vs 32 months; p < 0.001), but not for the MDC patients (24 vs 25 months; p = 0.33). These findings persisted in the multivariable analysis., Conclusion: A pancreatic cancer MDC standardizes treatment decisions, eliminates disparities in surgical outcomes, and improves survival for low-SES patients.

Purpose: A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We hypothesized that a glycan biomarker for PDACs called sialylated tumor-related antigen (sTRA) could be used for this purpose., Experimental Design: We tested for differences between PDACs classified by glycan expression in multiple systems: sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects., Results: The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the nonexpressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy., Conclusions: This research demonstrates that a glycan biomarker could have value to detect chemotherapy-resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC., (©2020 American Association for Cancer Research.)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene SMAD4 (or its signaling partner TGFBR2 ). Reexpression of SMAD4 abrogated the collective invasion phenotype in SMAD4 -mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4 -mutant PDAC organoids required exogenous TGFβ, suggesting that invasion in SMAD4 -mutant organoids is mediated through noncanonical TGFβ signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFβ-stimulated invasion in SMAD4 -mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on SMAD4 status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in SMAD4 -mutant and SMAD4 wild-type tumors are different in both morphology and molecular mechanism., (©2020 American Association for Cancer Research.)

Background & Aims: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes., Methods: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls)., Results: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions., Conclusions: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes., Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter., Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality., Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC at the time of surgery. Survival was better in high-risk individuals who had either low- or high-risk neoplastic precursor lesions compared with that in patients who developed PDAC., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background & Aims: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations., Methods: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci., Results: KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs., Conclusions: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA (sialylated tumor-related antigen) is a biomarker for PDAC that improves upon CA19-9., Experimental Design: We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case-control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set., Results: The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and 2 versions of the sTRA assay, and another optimized for sensitivity, which included 2 sTRA assays. Both panels achieved statistical improvement ( P < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement ( P < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared with 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker., Conclusions: sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer., (©2019 American Association for Cancer Research.)

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types., Competing Interests: Conflict of interest statement: C.M.S. and M.T.Y.-S. are founders and coowners of B9, Inc. and have no conflicts of interest with respect to the new technology described in this article. N.P., K.W.K., and B.V. are founders of Personal Genome Diagnostics, Inc. and PapGene, Inc. K.W.K. and B.V. are members of the Scientific Advisory Board of Sysmex-Inostics and Morphotek. B.V. is also a member of the Scientific Advisory Board of Exelixis GP. These companies and others have licensed technologies from Johns Hopkins, including those related to early diagnostics. N.P., K.W.K., and B.V. are the inventors of some of these technologies and receive equity or royalties from their licenses. The terms of these arrangements are being managed by the university in accordance with its conflict of interest policies. N.P., K.W.K., and B.V. have no conflicts of interest with respect to the new technology described in this article, as defined by the Johns Hopkins University policy on conflict of interest.

Objectives: Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets., Methods: The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321)., Results: Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4-26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls., Conclusions: MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

Molecular indicators to specify the risk posed by a pancreatic cyst would benefit patients. Previously we showed that most cancer-precursor cysts, termed mucinous cysts, produce abnormal glycoforms of the proteins MUC5AC and endorepellin. Here we sought to validate the glycoforms as a biomarker of mucinous cysts and to specify the oligosaccharide linkages that characterize MUC5AC. We hypothesized that mucinous cysts secrete MUC5AC displaying terminal N-acetylglucosamine (GlcNAc) in either alpha or beta linkage. We used antibody-lectin sandwich assays to detect glycoforms of MUC5AC and endorepellin in cyst fluid samples from three independent cohorts of 49, 32, and 66 patients, and we used monoclonal antibodies to test for terminal, alpha-linked GlcNAc and the enzyme that produces it. A biomarker panel comprising the previously-identified glycoforms of MUC5AC and endorepellin gave 96%, 96%, and 87% accuracy for identifying mucinous cysts in the three cohorts with an average sensitivity of 92% and an average specificity of 94%. Glycan analysis showed that MUC5AC produced by a subset of mucinous cysts displays terminal alpha-GlcNAc, a motif expressed in stomach glands. The alpha-linked glycoform of MUC5AC was unique to intraductal papillary mucinous neoplasms (IPMN), whereas terminal beta-linked GlcNAc was increased in both IPMNs and mucinous cystic neoplasms (MCN). The enzyme that synthesizes alpha-GlcNAc, A4GNT, was expressed in the epithelia of mucinous cysts that expressed alpha-GlcNAc, especially in regions with high-grade dysplasia. Thus IPMNs secrete a gastric glycoform of MUC5AC that displays terminal alpha-GlcNAc, and the combined alpha-GlcNAc and beta-GlcNAc glycoforms form an accurate biomarker of mucinous cysts., Competing Interests: The authors have declared that no competing interests exist.

Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.

Background and Aims: The American Gastroenterological Association (AGA) recently reported evidence-based guidelines for the management of asymptomatic neoplastic pancreatic cysts. These guidelines advocate a higher threshold for surgical resection than prior guidelines and imaging surveillance for a considerable number of patients with pancreatic cysts. The aims of this study were to assess the accuracy of the AGA guidelines in detecting advanced neoplasia and present an alternative approach to pancreatic cysts., Methods: The study population consisted of 225 patients who underwent EUS-guided FNA for pancreatic cysts between January 2014 and May 2015. For each patient, clinical findings, EUS features, cytopathology results, carcinoembryonic antigen analysis, and molecular testing of pancreatic cyst fluid were reviewed. Molecular testing included the assessment of hotspot mutations and deletions for KRAS, GNAS, VHL, TP53, PIK3CA, and PTEN., Results: Diagnostic pathology results were available for 41 patients (18%), with 13 (6%) harboring advanced neoplasia. Among these cases, the AGA guidelines identified advanced neoplasia with 62% sensitivity, 79% specificity, 57% positive predictive value, and 82% negative predictive value. Moreover, the AGA guidelines missed 45% of intraductal papillary mucinous neoplasms with adenocarcinoma or high-grade dysplasia. For cases without confirmatory pathology, 27 of 184 patients (15%) with serous cystadenomas (SCAs) based on EUS findings and/or VHL alterations would continue magnetic resonance imaging (MRI) surveillance. In comparison, a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detected advanced neoplasias with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value., Conclusions: The AGA guidelines were inaccurate in detecting pancreatic cysts with advanced neoplasia. Furthermore, because the AGA guidelines manage all neoplastic cysts similarly, patients with SCAs will continue to undergo unnecessary MRI surveillance. The results of an alternative approach with integrative molecular testing are encouraging but require further validation., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Genetic testing of germline DNA is used in patients suspected of being at risk of pancreatic ductal adenocarcinoma (PDAC) to better define the individual's risk and to determine the mechanism of risk. A high genetic risk increases the pretest probability that a biomarker of early cancer is a true positive and warrants further investigation. The highest PDAC risk is generally associated with a hereditary predisposition. However, the majority of PDAC results from complex, progressive gene-environment interactions that currently fall outside the traditional risk models. Over many years, the combination of inflammation, exposure to DNA-damaging toxins, and failed DNA repair promote the accumulation of somatic mutations in pancreatic cells; PDAC risk is further increased by already present oncogenic germline mutations. Predictive models and new technologies are needed to classify patients into more accurate and mechanistic PDAC risk categories that can be linked to improved surveillance and preventative strategies., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The sialyl-Lewis A (sLeA) glycan forms the basis of the CA19-9 assay and is the current best biomarker for pancreatic cancer, but because it is not elevated in ∼25% of pancreatic cancers, it is not useful for early diagnosis. We hypothesized that sLeA-low tumors secrete glycans that are related to sLeA but not detectable by CA19-9 antibodies. We used a method called motif profiling to predict that a structural isomer of sLeA called sialyl-Lewis X (sLeX) is elevated in the plasma of some sLeA-low cancers. We corroborated this prediction in a set of 48 plasma samples and in a blinded set of 200 samples. An antibody sandwich assay formed by the capture and detection of sLeX was elevated in 13 of 69 cancers that were not elevated in sLeA, and a novel hybrid assay of sLeA capture and sLeX detected 24 of 69 sLeA-low cancers. A two-marker panel based on combined sLeA and sLeX detection differentiated 109 pancreatic cancers from 91 benign pancreatic diseases with 79% accuracy (74% sensitivity and 78% specificity), significantly better than sLeA alone, which yielded 68% accuracy (65% sensitivity and 71% specificity). Furthermore, sLeX staining was evident in tumors that do not elevate plasma sLeA, including those with poorly differentiated ductal adenocarcinoma. Thus, glycan-based biomarkers could characterize distinct subgroups of patients. In addition, the combined use of sLeA and sLeX, or related glycans, could lead to a biomarker panel that is useful in the clinical diagnosis of pancreatic cancer. Précis: This paper shows that a structural isomer of the current best biomarker for pancreatic cancer, CA19-9, is elevated in the plasma of patients who are low in CA19-9, potentially enabling more comprehensive detection and classification of pancreatic cancers., Competing Interests: Conflicts of Interest: None declared., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer through the CCK-B receptor (CCK-BR). A splice variant of the CCK-BR that results from a single nucleotide polymorphism (SNP) has been identified. Because the splice variant receptor has an extended third intracellular loop, an area involved in cell signaling and growth, we hypothesized that this genetic variant could contribute to the poor prognosis and short survival of this malignancy., Methods: DNA from 931 patients with pancreatic cancer was evaluated for the SNP (C > A; rs1800843) in the CCK-BR gene. For statistical analysis, the Fisher exact test was used to compare the genotype and allele frequency between the cancer cohort and normal controls and the dependence of genotype on factors, such as stage of disease and age, was analyzed using Cox proportional hazards models., Results: Compared to the normal cohort, the frequency of the A-allele in pancreatic cancer subjects was increased (P = 0.01123; odds ratio, 2.283). Even after adjustment for stage of disease, survival of subjects with the minor allele was significantly shorter than those with the wild-genotype (hazard ratio, 1.83; P = 3.11 × 10(-11))., Conclusions: The CCK-BR SNP predicts survival and should be studied as a candidate genetic biomarker for those at risk of pancreatic cancer.

Background & Aims: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in combination with cytopathology is the optimal method for diagnosis and staging of pancreatic ductal adenocarcinoma (PDAC) and other pancreatic lesions. Its clinical utility, however, can be limited by high rates of indeterminate or false-negative results. We aimed to develop and validate a microRNA (miRNA)-based test to improve preoperative detection of PDAC., Methods: Levels of miRNAs were analyzed in a centralized clinical laboratory by relative quantitative polymerase chain reaction in 95 formalin-fixed paraffin-embedded specimens and 228 samples collected by EUS-FNA during routine evaluations of patients with solid pancreatic masses at 4 institutions in the United States, 1 in Canada, and 1 in Poland., Results: We developed a 5-miRNA expression classifier, consisting of MIR24, MIR130B, MIR135B, MIR148A, and MIR196, that could identify PDAC in well-characterized, formalin-fixed, paraffin-embedded specimens. Detection of PDAC in EUS-FNA samples increased from 78.8% by cytology analysis alone (95% confidence interval, 72.2%-84.5%) to 90.8% when combined with miRNA analysis (95% confidence interval, 85.6%-94.5%). The miRNA classifier correctly identified 22 additional true PDAC cases among 39 samples initially classified as benign, indeterminate, or nondiagnostic by cytology. Cytology and miRNA test results each were associated significantly with PDAC (P < .001), with positive predictive values greater than 99% (95% confidence interval, 96%-100%)., Conclusions: We developed and validated a 5-miRNA classifier that can accurately predict which preoperative pancreatic EUS-FNA specimens contain PDAC. This test might aid in the diagnosis of pancreatic cancer by reducing the number of FNAs without a definitive adenocarcinoma diagnosis, thereby reducing the number of repeat EUS-FNA procedures., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

With improvements in abdominal imaging, detection of incidental pancreatic cysts are becoming increasingly common. Analysis of pancreatic cyst fluid from fine-needle aspiration is particularly important in identifying intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), which have significant implications in clinical intervention and follow-up. Previous controlled studies have shown that KRAS mutations in cyst fluid are highly specific for mucinous differentiation in pancreatic cysts; however, this has not been examined in the clinical setting. Over a 6-year study period, 618 pancreatic cyst fluids obtained by fine-needle aspiration at the time of endoscopic ultrasound were tested for KRAS mutations as part of routine evaluation for a cystic neoplasm. Of the 618 specimens, 603 (98%) from 546 patients were satisfactory for molecular analysis. Patients ranged in age from 17 to 90 years (mean, 63.9 years) and were predominantly female (68%). Pancreatic cysts were relatively evenly distributed throughout the pancreas and ranged in size from 0.6 to 11.0 cm (mean, 2.3 cm). Mutations in KRAS were detected in 232 of 603 (38%) aspirates. Although sufficient for molecular analysis, 320 of 603 (53%) specimens were either less than optimal (38%) or unsatisfactory (15%) for cytopathologic diagnosis. Surgical follow-up information was available for 142 (26%) patients and consisted of 53 KRAS-mutated and 89 KRAS-wild-type cysts. Overall, KRAS mutations had a specificity of 100%, but a sensitivity of 54% for mucinous differentiation. When stratified by cyst type, KRAS had a sensitivity of 67% and 14% for IPMNs and MCNs, respectively. In summary, KRAS mutations were highly specific for mucinous differentiation, but were inadequate in identifying MCNs. Future molecular studies and the combination of other fluid markers are required to improve the detection and classification of pancreatic mucinous neoplasms by endoscopic ultrasound fine-needle aspiration.

Biomarkers are most frequently proteins that are measured in the blood. Their development largely relies on antibody creation to test the protein candidate performance in blood samples of diseased versus nondiseased patients. The creation of such antibody assays has been a bottleneck in biomarker progress due to the cost, extensive time, and effort required to complete the task. Targeted proteomics is an emerging technology that is playing an increasingly important role to facilitate disease biomarker development. In this study, we applied a SRM-based targeted proteomics platform to directly detect candidate biomarker proteins in plasma to evaluate their clinical utility for pancreatic cancer detection. The characterization of these protein candidates used a clinically well-characterized cohort that included plasma samples from patients with pancreatic cancer, chronic pancreatitis, and healthy age-matched controls. Three of the five candidate proteins, including gelsolin, lumican, and tissue inhibitor of metalloproteinase 1, demonstrated an AUC value greater than 0.75 in distinguishing pancreatic cancer from the controls. In addition, we provide an analysis of the reproducibility, accuracy, and robustness of the SRM-based proteomics platform. This information addresses important technical issues that could aid in the adoption of the targeted proteomics platform for practical clinical utility.

Purpose: Serum-biomarker based screening for pancreatic cancer could greatly improve survival in appropriately targeted high-risk populations., Experimental Design: Eighty-three circulating proteins were analyzed in sera of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC, n = 333), benign pancreatic conditions (n = 144), and healthy control individuals (n = 227). Samples from each group were split randomly into training and blinded validation sets prior to analysis. A Metropolis algorithm with Monte Carlo simulation (MMC) was used to identify discriminatory biomarker panels in the training set. Identified panels were evaluated in the validation set and in patients diagnosed with colon (n = 33), lung (n = 62), and breast (n = 108) cancers., Results: Several robust profiles of protein alterations were present in sera of PDAC patients compared to the Healthy and Benign groups. In the training set (n = 160 PDAC, 74 Benign, 107 Healthy), the panel of CA 19-9, ICAM-1, and OPG discriminated PDAC patients from Healthy controls with a sensitivity/specificity (SN/SP) of 88/90%, while the panel of CA 19-9, CEA, and TIMP-1 discriminated PDAC patients from Benign subjects with an SN/SP of 76/90%. In an independent validation set (n = 173 PDAC, 70 Benign, 120 Healthy), the panel of CA 19-9, ICAM-1 and OPG demonstrated an SN/SP of 78/94% while the panel of CA19-9, CEA, and TIMP-1 demonstrated an SN/SP of 71/89%. The CA19-9, ICAM-1, OPG panel is selective for PDAC and does not recognize breast (SP = 100%), lung (SP = 97%), or colon (SP = 97%) cancer., Conclusions: The PDAC-specific biomarker panels identified in this investigation warrant additional clinical validation to determine their role in screening targeted high-risk populations., (©2010 AACR.)

Pancreatic cancer is a highly lethal malignancy with a dismal 5-year survival of less than 5%. The scarcity of early biomarkers has considerably hindered our ability to launch preventive measures for this malignancy in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL), a 24-kDa glycoprotein, was reported to be upregulated nearly 27-fold in pancreatic cancer cells compared to normal ductal cells in a microarray analysis. Given the need for biomarkers in the early diagnosis of pancreatic cancer, we investigated the expression of NGAL in tissues with the objective of examining if NGAL immunostaining could be used to identify foci of pancreatic intraepithelial neoplasia, premalignant lesions preceding invasive cancer. To examine a possible correlation between NGAL expression and the degree of differentiation, we also analysed NGAL levels in pancreatic cancer cell lines with varying grades of differentiation. Although NGAL expression was strongly upregulated in pancreatic cancer, and moderately in pancreatitis, only a weak expression could be detected in the healthy pancreas. The average composite score for adenocarcinoma (4.26+/-2.44) was significantly higher than that for the normal pancreas (1.0) or pancreatitis (1.0) (P<0.0001). Further, although both well- and moderately differentiated pancreatic cancer were positive for NGAL, poorly differentiated adenocarcinoma was uniformly negative. Importantly, NGAL expression was detected as early as the PanIN-1 stage, suggesting that it could be a marker of the earliest premalignant changes in the pancreas. Further, we examined NGAL levels in serum samples. Serum NGAL levels were above the cutoff for healthy individuals in 94% of pancreatic cancer and 62.5% each of acute and chronic pancreatitis samples. However, the difference between NGAL levels in pancreatitis and pancreatic cancer was not significant. A ROC curve analysis revealed that ELISA for NGAL is fairly accurate in distinguishing pancreatic cancer from non-cancer cases (area under curve=0.75). In conclusion, NGAL is highly expressed in early dysplastic lesions in the pancreas, suggesting a possible role as an early diagnostic marker for pancreatic cancer. Further, serum NGAL measurement could be investigated as a possible biomarker in pancreatitis and pancreatic adenocarcinoma.

Pancreatic cancer (PC) is the most fatal of all gastrointestinal cancers, wherein its mortality compares strikingly with its incidence. Unfortunately, 80-90% of PCs are diagnosed in the nonresectable stage. While the lifetime risk of PC in developed countries is approximately 1-3%, it is the fifth most common cause of cancer deaths among both males and females in Western countries. It occurs in excess in Jews. Approximately 5-10% of PC shows familial clustering. Examination of such familial clusters must take into consideration cancers of diverse anatomic sites, such as malignant melanoma in the familial atypical multiple melanoma (FAMMM) syndrome due to the CDKN2A (p16) germline mutation, and combinations of colorectal and endometrial carcinoma, ovarian carcinoma, and several other cancers in hereditary nonpolyposis colorectal cancer (HNPCC), which are due to mismatch repair germline mutations, the most common of which are MSH2 and MLH1 . Other hereditary disorders predisposing to PC include Peutz-Jeghers syndrome, due to the STK11 mutation, familial pancreatitis due to the cationic trypsinogen gene, site-specific familial pancreatic cancer which may be due to the 4q32-34 mutation, hereditary breast-ovarian cancer (HBOC) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1 , familial adenomatous polyposis due to the ATP gene, and ataxia telangiectasia due to the ATM germline mutation. This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC. Unfortunately, there are no PC screening programs with acceptable sensitivity and specificity. However, the gold standard for screening at this time is endoscopic ultrasound. Clearly, there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity. Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews. Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the disease's pathogenesis, as well as screening and control, may take place.