High Risk For Pancreatic Ductal Adenocarcinoma Research Articles

Blood type as a risk factor for pancreatic ductal adenocarcinoma.

10559 Background: Non-O blood type has been associated with increased risk of pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer death in the United States (US), in largely white populations. We aimed to explore PDAC risk across blood types in the racially diverse Veteran’s Health Administration (VA), the largest integrated healthcare system in the US. Methods: We included all individuals in the VA from 2002 - 2022 with at least one inpatient or outpatient encounter and a non-missing race. We defined the index date as 1.5 years after the initial VA encounter and excluded individuals with prior PDAC. We defined the exposure by non-O (A, B, AB) or type O blood type. We defined PDAC based on a previously validated algorithm of ≥2 sources (cancer registry, hospitalizations, or outpatient oncology encounters) with 95% positive predictive value. Using time to PDAC as the outcome in a multivariable Cox regression, we evaluated the association between blood type and PDAC risk, adjusting for age, sex, BMI, smoking, alcohol use, Hepatitis C (HCV) and diabetes. We censored at time of death, 1.5 years after the last VA encounter, or the end of the study period. We performed a subgroup analysis to evaluate the association of blood type by race. Results: Of the 2.5 million individuals with an available blood type, 1.35 million (52.6%) had a non-O blood type (Table) and over a quarter of our cohort (28.2%, 725,878) were over baseline age 50. Median time to PDAC diagnosis was 8.6 years. There were 877 PDAC cases (0.03%), with 530 (60.4%) of those having a non-O blood type. Compared to those with type O blood, risk of PDAC for individuals with non-O blood type was higher overall [adjusted HR = 1.37 (95% CI 1.20-1.57)], and higher among Whites (n=1,689,092, HR 1.52, 95% CI 1.27-1.82) than Black patients (n=525,666, HR 1.15, 95% CI 0.90-1.48), though this was limited by smaller sample size. Conclusions: Non-O blood type was associated with higher risk of PDAC in a diverse population. Given the potential differences between races, we will further explore the impact of neighborhood-level socioeconomic data on PDAC risk. [Table: see text]

Development of a multi-analyte blood test for the early detection of pancreatic ductal adenocarcinoma (PDAC) and performance compared to CA19-9.

e16360 Background: Early detection of PDAC can improve survival but is hampered by the lack of recognizable symptoms in early disease. Imaging has been the mainstay for surveillance of high-risk individuals but has proven to be cumbersome and may lack sensitivity to detect small tumors. CA19-9 is the only available blood biomarker for PDAC, but it is neither sensitive nor specific enough for it to be recommended for high-risk surveillance. A sensitive and specific blood biomarker for PDAC could positively impact this situation. Methods: Serum samples from patients across multiple centers with stage I and II PDAC (n = 75) and matched controls at high risk for PDAC (genetic and familial) (n = 83) were assessed for more than 2,900 protein analytes using O-link multiplex technology and conventional immunoassays for selected protein candidates. Machine learning was used to combine the biomarker candidates to create 4-plex signatures discriminating PDAC and controls. Results: ROC (receiver operating characteristic) curve analysis of these revealed signatures with performance superior to CA19-9 and a previously commercially available assay, IMMRay PanCan-d (AUC of 0.97 and 0.94 vs. 0.87 for CA19-9 and 0.88 for IMMRay). A subset of these candidate biomarkers has now been transitioned to standardized ELISA assays which are being used to construct a final signature for clinical validation in an independent set of PDAC and high-risk control samples. Conclusions: A novel multi-analyte blood test utilizing newly-discovered PDAC biomarkers has the potential to improve early detection of PDAC in high-risk individuals.

The Population-level Prevalence of Exocrine Pancreas Insufficiency and the Subsequent Risk of Pancreatic Cancer.

To study the prevalence of exocrine pancreas insufficiency (EPI) at a population level and the subsequent risk of pancreatic ductal adenocarcinoma (PDAC). Using TriNetX (a database of over 79 million US residents), we included patients ≥18 years with EPI (identified via ICD-10 codes) and continuous follow-up from 2016-2022. Patients with prior pancreas resection and PDAC before an EPI diagnosis were excluded. The primary outcome was EPI prevalence. Secondary outcomes included imaging utilization, PDAC risk and, pancreas enzyme replacement therapy (PERT) utilization. We performed 1:1 propensity score matching of patients with EPI vs. patients without an EPI diagnosis. Adjusted odds ratio (aOR) and hazard ratios (aHR) with 95% confidence intervals were reported. The population prevalence of EPI was 0.8% (n = 24,080) with a mean age of 55.6 years at diagnosis. After propensity score matching, PDAC risk among patients with EPI was twice as high compared to patients without EPI (AHR 1.97, 95% confidence interval [CI] 1.66-2.36). This risk persisted even after excluding patients with a history of acute or chronic pancreatitis (aOR: 4.25, 95% CI 2.99-6.04). Only 58% (n = 13, 390) of patients with EPI received PERT with a mean treatment duration of 921 days. No difference was observed in PDAC risk between patients with EPI treated with PERT vs. those that did not receive PERT (AHR 1.10, 95% CI 0.95-1.26, p = 0.17). Despite a low prevalence, patients with EPI may have a higher risk of PDAC and many of these patients with EPI were not on PERT. PERT did not appear to impact incident PDAC risk after an EPI diagnosis.

Potential of artificial intelligence in the risk stratification for and early detection of pancreatic cancer.

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.

Predicting pancreatic ductal adenocarcinoma using artificial intelligence analysis of pre-diagnostic computed tomography images.

Early stage diagnosis of Pancreatic Ductal Adenocarcinoma (PDAC) is challenging due to the lack of specific diagnostic biomarkers. However, stratifying individuals at high risk of PDAC, followed by monitoring their health conditions on regular basis, has the potential to allow diagnosis at early stages. To stratify high risk individuals for PDAC by identifying predictive features in pre-diagnostic abdominal Computed Tomography (CT) scans. A set of CT features, potentially predictive of PDAC, was identified in the analysis of 4000 raw radiomic parameters extracted from pancreases in pre-diagnostic scans. The naïve Bayes classifier was then developed for automatic classification of CT scans of the pancreas with high risk for PDAC. A set of 108 retrospective CT scans (36 scans from each healthy control, pre-diagnostic, and diagnostic group) from 72 subjects was used for the study. Model development was performed on 66 multiphase CT scans, whereas external validation was performed on 42 venous-phase CT scans. The system achieved an average classification accuracy of 86% on the external dataset. Radiomic analysis of abdominal CT scans can unveil, quantify, and interpret micro-level changes in the pre-diagnostic pancreas and can efficiently assist in the stratification of high risk individuals for PDAC.

Leukocyte Telomere Length and Its Interaction with Germline Variation in Telomere-Related Genes in Relation to Pancreatic Adenocarcinoma Risk.

Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We therefore investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate SNPs previously reported to be associated with variation in LTL. A case-control study of 1,460 PDAC cases and 1,459 frequency-matched controls was performed using biospecimens and data from the Mayo Clinic Biospecimen Resource for Pancreas Research. Quantitative PCR was used to measure LTL and categorized into tertiles based on sex-specific control distribution. Eleven telomere-related SNPs also were genotyped. Logistic regression was used to calculate ORs and 95% confidence intervals (CI). Shorter peripheral blood LTL was associated with a higher risk of PDAC (ORT1vsT3 = 1.26, 95% CI = 1.03-1.54, P trend = 0.02; ORcontinuous = 1.14, 95% CI = 1.02-1.28), but the association was restricted to cases with treatment-naïve blood samples (ORT1vsT3 = 1.51, 95% CI = 1.16-1.96, P trend = 0.002; ORcontinuous = 1.25, 95% CI = 1.08-1.45) and not cases whose blood samples were collected after initiation of cancer therapy (ORT1vsT3 = 1.10, 95% CI = 0.87-1.39, P trend = 0.42; ORcontinuous = 1.08, 95% CI = 0.94-1.23). Three SNPs (TERC-rs10936599, ACYP2-rs11125529, and TERC-rs1317082) were each associated with interindividual variation in LTL among controls, but there was no evidence of effect modification by these SNPs. Treatment-naïve short LTL is associated with a higher risk of PDAC, and the association does not differ by germline variation in the candidate telomere-related SNPs examined. Peripheral blood LTL might serve as a molecular marker for risk modeling to identify persons at high risk of PDAC.

Abstract A67: Microbial polyamines and early detection of pancreatic cancer

Abstract The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated to the abysmal survival rate in patients. In addition to several potential detection tools under active investigation, we present the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. A combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota in a spontaneous genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC) showed a progressive Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were found to be significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation, validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentration. Therefore, at the early stages of tumorigenesis, the gut microbial composition changes in a way to promote inflammation and release metabolites that foster host tumorigenesis, thereby fulfilling the “vicious cycle hypothesis” of the role of the microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which will result in improved outcomes. Citation Format: Roberto Mendez, Kousik Kesh, Nivedita Arora, Leá Di Martino, Florencia McAllister, Nipun Merchant, Sulagna Banerjee, Santanu Banerjee. Microbial polyamines and early detection of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A67.

Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer.

The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated with the abysmal survival rates in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. We used a combination of 16s rRNA pyrosequencing and whole-genome sequencing of gut fecal microbiota in a genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUMAnN2 pipeline. Serum polyamine levels were measured from murine and patient samples using chromogenic assay. Our results showed a Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentrations. Therefore, at the early stages of tumorigenesis, there is a strong correlation between microbial changes and release of metabolites that foster host tumorigenesis, thereby fulfilling the 'vicious cycle hypothesis' of the role of microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which may result in improved outcomes.

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

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

140P - Oral cavity immune response in pancreatic ductal adenocarcinoma (PDAC)

Background: We studied the humoral immune response in patients with pancreatic ductal adenocarcinoma (PDAC) using mouthwashes from the oral cavity. We found lower immune response against recall antigens, fusobacterium nucleatum and tumor associated antigens before immunotherapy treatment. We also found better prognosis when the antibodies against tested antigens got higher. Finally, we found significant differences in the humoral immune response in the oral cavity against serum. Methods: Antigens from fusobacterium nucleatum, recall and tumor associated antigens were tested by IgG + IgM + IgA ELISA in both oral cavity and serum of PDAC patients n = 50. We provided 5 ml of saline solution to all the patients and controls to rinse the oral cavity hardly for 5 minutes and deposit the content in 15 ml tube. Sera were obtained. All was done after the approval of the local IRB committee. Results: All the evaluated antigens were lower in the oral cavity of PDAC patients compared with controls (p = 0.001). Serum responses for all antigens were significantly different than oral cavity (p = 0.03). At the end of the immunotherapy treatment consisting in a combination of immunomodulation, multi peptide antigen specific active immunotherapy and immunogenic chemotherapy with doxorubicin and oxaliplatin the levels of antibodies were increased significantly. For example, FAP (p = 0.0001), EGFR (p = 0.005), Fascin-1 (p = 0001), VCP (P = 001). Also, the immunotherapy combination significantly increased antibody immune response against fusobaterium lysate (p = 0001). Conclusions: PDAC is a challenge disease especially in late stages. PDAC patients had low antibody titters against several antigens in comparison with controls and before treatment the oral cavity. Serum antibodies were lower than oral cavity even after treatment. Oral cavity antibodies may be a useful early biomarker in patients in high risk of PDAC. This data also suggest that antibodies get low when the cancer or premalignant lesions of PDAC are present. Legal entity responsible for the study: Centro de Investigacion de Cancer en Sonora (CICS). Funding: CICS USA. Disclosure: All authors have declared no conflicts of interest.

Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance

Screening of individuals who have a high risk of pancreatic ductal adenocarcinoma (PDAC), because of genetic factors, frequently leads to identification of pancreatic lesions. We investigated the incidence of PDAC and risk factors for neoplastic progression in individuals at high risk for PDAC enrolled in a long-term screening study. We analyzed data from 354 individuals at high risk for PDAC (based on genetic factors of family history), enrolled in Cancer of the Pancreas Screening cohort studies at tertiary care academic centers from 1998 through 2014 (median follow-up time, 5.6 years). All subjects were evaluated at study entry (baseline) by endoscopic ultrasonography and underwent surveillance with endoscopic ultrasonography, magnetic resonance imaging, and/or computed tomography. The primary endpoint was the cumulative incidence of PDAC, pancreatic intraepithelial neoplasia grade 3, or intraductal papillary mucinous neoplasm with high-grade dysplasia (HGD) after baseline. We performed multivariate Cox regression and Kaplan-Meier analyses. During the follow-up period, pancreatic lesions with worrisome features (solid mass, multiple cysts, cyst size > 3 cm, thickened/enhancing walls, mural nodule, dilated main pancreatic duct > 5 mm, or abrupt change in duct caliber) or rapid cyst growth (>4 mm/year) were detected in 68 patients (19%). Overall, 24 of 354 patients (7%) had neoplastic progression (14 PDACs and 10 HGDs) over a 16-year period; the rate of progression was 1.6%/year, and 93% had detectable lesions with worrisome features before diagnosis of the PDAC or HGD. Nine of the 10 PDACs detected during routine surveillance were resectable; a significantly higher proportion of patients with resectable PDACs survived 3years (85%) compared with the 4 subjects with symptomatic, unresectable PDACs (25%), which developed outside surveillance (log rank P < .0001). Neoplastic progression occurred at a median age of 67 years; the median time from baseline screening until PDAC diagnosis was 4.8 years (interquartile range, 1.6-6.9 years). In a long-term (16-year) follow-up study of individuals at high-risk for PDAC, we found most PDACs detected during surveillance (9/10) to be resectable, and 85% of these patients survived for 3 years. Weidentified radiologic features associated with neoplastic progression.

Pancreatic Cancer Diagnostics and Treatment--Current State.

Pancreatic ductal adenocarcinoma (PDAC) represents permanent and ever rising issue worldwide. Five-year survival does not exceed 3 to 6%, i.e. the worst result among solid tumours. The article evaluates the current state of PDAC diagnostics and treatment specifying also development and trends. Percentage of non-resectable tumours due to locally advanced or metastatic condition varies 60-80%, mostly over 80%. Survival with non-resectable PDAC is 4 to 8 months (median 3.5). In contrast R0 resection shows the survival 18-27 months. Laboratory and imaging screening methods are not indicated on large scale. Risk factors are smoking, alcohol abuse, chronic pancreatitis, diabetes mellitus. Genetic background in most PDAC has not been detected yet. Some genes connected with high risk of PDAC (e.g. BRCA2, PALB2) have been identified as significant and highly penetrative, but link between PDAC and these genes can be seen only in 10-20%. This article surveys perspective oncogenes, tumour suppressor genes, microRNA. Albeit CT is still favoured over other imaging methods, involvement of NMR rises. Surgery prefers the "vessel first" approach, which proves to be justified especially in R0 resection. According to EBM immunotherapy same as radiotherapy are not significant in PDAC treatment. Chemotherapy shows limited importance in conversion treatment of locally advanced or borderline tumours or in case of metastatic spread. Unified procedures cannot be defined due to inhomogenous arrays. Surgical resection is the only chance for curative treatment of PDAC and depends mainly on timely indication for surgery and quality of multidisciplinary team in a high-volume centre.

Abstract 1141: MAb-PAM4 can differentiate between pancreatic ductal adenocarcinoma and chronic pancreatitis.

Abstract Background: Due to the asymptomatic nature of pancreatic ductal adenocarcinoma (PDAC) in its early stages of growth, and its relatively low incidence, screening methods have not received high attention. However, with recent studies providing the ability to identify specific patient groups at high risk for PDAC, a rationale exists for longitudinal surveillance as a means to improve early detection specifically in these high-risk settings. Individuals with a family history of PDAC, those patients with long-standing chronic pancreatitis (CP), patients with new-onset diabetes who meet certain other conditions, or those with FAMMM syndrome, etc., could be evaluated on a long-term basis for the detection of early malignant changes by use of a MAb-PAM4-based immunoassay procedure. Methods: We have developed and validated (in over 600 patient specimens) an enzyme immunoassay (EIA) based upon use of MAb-PAM4 for quantitation of antigen in the serum of patients diagnosed with pancreatic ductal adenocarcinoma. In addition, the antibody has been used for immunohistochemical evaluation of malignant, benign, and normal pancreatic tissues. Results: 71% of patients with confirmed early-stage disease and 91% with advanced disease were positive by EIA for circulating PAM4-antigen. Overall specificity was 81% with respect to benign pancreatic disease. Of 126 patients diagnosed with benign conditions of the pancreas, 24 (19%) were positive for the PAM4-antigen, with the majority of these cases being diagnosed with chronic pancreatitis [18 of 80 positive (23%)], all of whom had surgical resection performed for severity and/or duration of disease activity. ROC curve analyses of PAM4 assays revealed a statistically significant difference between the PDAC and CP groups (P&amp;lt;0.0001), with an area under the curve of 0.84 ± 0.02 (95% CI: 0.79-0.89). The positive likelihood ratio for differentiating PDAC from benign conditions of the pancreas was 4.00, which was significant (P&amp;lt;0.001). It is very important to emphasize that the “true” specificity of this assay is likely underestimated. Immunohistochemistry data have shown the PAM4-biomarker is absent from normal pancreas and benign, non-neoplastic lesions of the pancreas. In over 50 surgical specimens of CP, the PAM4-biomarker was identified only within PanIN lesions that are associated with long-term CP, and not by the inflamed tissue. Conclusions: Our results suggest that PAM4-positive CP patients (and likely other PAM4-positive patients diagnosed with benign conditions of the pancreas) may very likely have pancreatic neoplasia (invasive and/or precursor lesions), and therefore should be followed closely. Indeed, such studies might reveal new cutoff values or kinetic changes that would support early surgical intervention. (Supported in part by NIH grant CA096924.) Citation Format: David V. Gold, Chanjuan Shi, Guy Newsome, David M. Goldenberg. MAb-PAM4 can differentiate between pancreatic ductal adenocarcinoma and chronic pancreatitis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1141. doi:10.1158/1538-7445.AM2013-1141

PAM4 enzyme immunoassay alone and in combination with CA 19‐9 for the detection of pancreatic adenocarcinoma

The monoclonal antibody PAM4 has high specificity for pancreatic ductal adenocarcinoma (PDAC), as well as its precursor lesions, but has not been found to be reactive with normal and benign pancreatic tissues. The objective of the current study was to evaluate a PAM4-based serum enzyme immunoassay alone and in combination with the carbohydrate antigen (CA) 19-9 assay for the detection of PDAC, with particular attention to early stage disease. Sera from patients with confirmed PDAC (N = 298), other cancers (N = 99), benign disease of the pancreas (N = 120), and healthy adults (N = 79) were evaluated by a specific enzyme immunoassay for the concentration of PAM4 and CA 19-9 antigen levels by blinded analyses. All tests for statistical significance were 2-sided. The overall sensitivity for PAM4 detection of PDAC was 76%, with 64% of patients with stage I disease also identified. The detection rate was considerably higher (85%) for patients with advanced disease. The assay demonstrated high specificity compared with benign pancreatic disease (85%), with a positive likelihood ratio of 4.93. CA 19-9 provided an overall sensitivity of 77%, and was positive in 58% of patients with stage I disease; however, the specificity was significantly lower for CA 19-9 (68%), with a positive likelihood ratio of 2.85 (P = .026 compared with PAM4). It is important to note that a combined PAM4 and CA 19-9 biomarker serum assay demonstrated an improved sensitivity (84%) for the overall detection of PDAC without a significant loss of specificity (82%) compared with either arm alone. The PAM4 enzyme immunoassay identified approximately two-thirds of patients with stage I PDAC with high discriminatory power with respect to benign, nonneoplastic pancreatic disease. These results provide a rationale for testing patient groups considered to be at high risk for PDAC with a combined PAM4 and CA 19-9 biomarker serum assay for the detection of early stage PDAC.