Pancreatic Cancer Action Network Research Articles

Abstract A019: Black race and CA 19-9 nonproduction is associated with limited pathologic response to neoadjuvant chemotherapy in patients with localized pancreatic cancer

Abstract Introduction: Black patients with pancreatic ductal adenocarcinoma (PDAC) are less likely to have major pathologic response (MPR) following induction chemotherapy. Our previous study suggested a lower baseline CA 19-9 among Black patients. We aimed to determine if CA 19-9 nonproduction contributes to racial differences in neoadjuvant chemotherapy (NAC) response. We then investigated the biological mechanisms underlying reduced response in CAnonprod with multi-omic analysis. Methods: Black and White patients with PDAC receiving ≥ 2 cycles of NAC followed by pancreatectomy at 7 high-volume centers were reviewed. Patients were categorized as CAproducers (CAprod, CA 19-9 > 5 U/mL) or CAnonprod (CA 19-9 ≤ 5 U/mL). Uni- and multi-variable models evaluated differences in rates of CAnonprod by race, and the association of CAnonprod with MPR (CAP 0/1). The Pancreatic Cancer Action Network SPARK platform was queried for patients with CA 19-9 and genomic data. Fisher’s exact test was used to compare differentially mutated genes between CAnonprod and CAprod. Differential gene expression (DEG) analysis identified significantly differentially expressed genes using an absolute fold change of ≥ 2 and p-adj < 0.05 as a cutoff. quanTIseq computational pipeline was used for immune cell deconvolution analysis of the two groups. Results: Our cohort included 385 CAprod and 30 CAnonprod. CAnonprod had a significantly higher rate of Black patients (50% vs 13%, p<0.01). Compared with CAprod, CAnonprod received similar rates of FOLFIRINOX (60% vs. 57%, p=0.27) and duration of NAC (4 vs 5 cycles, p=0.83). Rate of MPR was higher among CAprod compared to CAnonprod (26% vs 8%, p=0.03). No CAnonprod patient had a complete pathologic response vs 28 (7%) of CAprod (p=0.12). CAnonprod was independently associated with decreased odds of MPR (OR 0.21, CI [0.04-0.99]). Black race was independently associated with increased odds of CAnonprod (OR 8.66, CI [3.81 – 19.7]). When CA 19-9 production status was matched by race, there was no difference between rate of MPR between White and Black CAnonprod; both experienced low rates of MPR (12% and 9%, respectively, (p=0.68)). CAnonprod had higher rates of SWI/SNF alterations (50% CAnonprod vs 33% CAprod, p< 0.01; P-adj=ns), and ARID1B was the most frequently mutated gene in CAnonprod (28% vs 11%, p< 0.01; P-adj=ns). DEG analysis showed the LIPF gene was significantly downregulated in CAnonprod compared to CAprod. There was no difference in immune cell distribution between CAprod and CAnonprod. Conclusion: CA 19-9 non-production is more prevalent in Black patients and potentially mediates the lower rates of MPR following NAC. CA 19-9 non-production is associated with higher rates of SWI/SNF alterations and a downregulation of the LIPF gene encoding gastric lipase, unveiling a potential biologic or metabolomic difference in response to chemotherapy between races. Citation Format: Mary P. Martos, Erin M. Dickey, Kawther Abdilleh, Syed A. Ahmad, Shishir K. Maithel, Chet W. Hammill, Hong Jin Kim, Daniel E. Abbott, David A. Kooby, Alexander A. Parikh, Peter J. Hosein, Nipun B. Merchant, Jashodeep Datta, Caitlin A. Hester. Black race and CA 19-9 nonproduction is associated with limited pathologic response to neoadjuvant chemotherapy in patients with localized pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A019.

Abstract 6475: Leveraging real-world pancreatic cancer datasets to drive drug discovery and patient health

Abstract Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current therapeutic options offer a dismal overall survival with the 5-year survival at just ~12%. Analysis of the clinical and molecular underpinnings of pancreatic cancer is critical to developing both early detection methodologies as well as novel therapeutic options. The aggressiveness and deadly nature of this disease warranted the development of a data repository and analysis system dedicated to pancreatic cancer data. The Pancreatic Cancer Action Network’s (PanCAN) SPARK platform is a cloud-based data and analytics platform, powered by Velsera, that integrates real-world patient health data from PanCAN research initiatives and accelerates research by making pancreatic cancer data easier to access and use. Encompassing clinical, imaging, and genomics data from over 600 patients with pancreatic cancer within PanCAN’s Know Your Tumor ® (KYT) precision medicine service, the SPARK platform connects with petabytes of publicly available cancer data via the Cancer Genomics Cloud (CGC), also powered by Velsera. The CGC is part of NCI’s Cancer Research Data Commons (CRDC), a cloud-based data science infrastructure that connects data with analytics tools to allow researchers to share, integrate, analyze, visualize, and drive scientific discovery. Here, we demonstrate the application of these datasets by providing a case study demonstrating how to combine and enrich data to accelerate pancreatic cancer research. Currently, the genomic and proteomic data available on CRDC amounts to 402 and 304 cases of pancreatic tumor samples, respectively. We will use the capabilities of the SPARK and CGC platforms, which provide ready-to-use tools for multi-omics analysis that require no coding knowledge. Using the KYT and CRDC open-access pancreatic cancer data, we aim to demonstrate how to perform integrated analysis of data from diverse scientific domains, and share with collaborators all in one space, streamlining and increasing the potential for new scientific discoveries. Further expansion of the PanCAN and CGC datasets will undoubtedly provide a more comprehensive understanding of pancreatic cancer tumor biology. SPARK and CGC’s cloud based computation infrastructure, along with numerous available cancer datasets and easy-to-use multi-omics data processing workflows and data analytic tools will be instrumental in this process. Citation Format: Kawther Abdilleh, Zelia Worman, Rowan Beck, Cera Fisher, Divya Sain, Jack DiGiovanna, Lynn Matrisian, Sudheer Doss, Brandi Davis-Dusenbery. Leveraging real-world pancreatic cancer datasets to drive drug discovery and patient health [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6475.

Pancreatic Cancer Action Network's SPARK: A Cloud-Based Patient Health Data and Analytics Platform for Pancreatic Cancer.

Pancreatic cancer currently holds the position of third deadliest cancer in the United States and the 5-year survival rate is among the lowest for major cancers at just 12%. Thus, continued research efforts to better understand the clinical and molecular underpinnings of pancreatic cancer are critical to developing both early detection methodologies as well as improved therapeutic options. This study introduces Pancreatic Cancer Action Network's (PanCAN's) SPARK, a cloud-based data and analytics platform that integrates patient health data from the PanCAN's research initiatives and aims to accelerate pancreatic cancer research by making real-world patient health data and analysis tools easier to access and use. The SPARK platform integrates clinical, molecular, multiomic, imaging, and patient-reported data generated from PanCAN's research initiatives. The platform is built on a cloud-based infrastructure powered by Velsera. Cohort exploration and browser capabilities are built using Velsera ARIA, a specialized product for leveraging clinicogenomic data to build cohorts, query variant information, and drive downstream association analyses. Data science and analytic capabilities are also built into the platform allowing researchers to perform simple to complex analysis. Version 1 of the SPARK platform was released to pilot users, who represented diverse end users, including molecular biologists, clinicians, and bioinformaticians. Included in the pilot release of SPARK are deidentified clinical (including treatment and outcomes data), molecular, multiomic, and whole-slide pathology images for over 600 patients enrolled in PanCAN's Know Your Tumor molecular profiling service. The pilot release of the SPARK platform introduces qualified researchers to PanCAN real-world patient health data and analytical resources in a centralized location.

Association of race and CA 19-9 nonproduction with limited pathologic response to neoadjuvant chemotherapy in patients with localized pancreatic cancer.

609 Background: Black patients with pancreatic ductal adenocarcinoma (PDAC) are less likely to have major pathologic response (MPR) following induction chemotherapy compared to non-Black patients. Rare reports have suggested that Black patients are more likely to be CA 19-9 non-producers. We aimed to determine if disproportionate rates of CA 19-9 nonproduction underlie racial differences in neoadjuvant chemotherapy response in patients with localized PDAC. We also explored differences in somatic mutations between CA 19-9 producers (CAprod) and non-producers (CAnonprod). Methods: Black and White patients with localized PDAC receiving ≥ 2 cycles of neoadjuvant chemotherapy followed by pancreatectomy (2010-2019) at 7 high-volume centers were reviewed. Patients were categorized as CAprod (CA 19-9 > 5 U/mL) or CAnonprod (CA 19-9 ≤ 5 U/mL). Uni- and multi-variable models evaluated differences in rates of CAnonprod by race, and the association of CAnonprod with MPR (CAP 0/1). The Pancreatic Cancer Action Network (PanCAN)’s SPARK health data platform which contains clinical and multi-omic data from the PanCAN Know Your Tumor program was queried to identify patients with CA 19-9 and genomic data. Fisher’s exact test was used to compare differentially mutated genes between CAprod and CAnonprod patients. Results: Our cohort included 385 (93.3%) CAprod and 30 (6.7%) CAnonprod. CAnonprod patients were more likely to be Black than CAprod (50.0% vs 12.5%, p<0.01). There were no other differences in demographic or clinical features between CAnonprod and CAprod. Most patients received FOLFIRINOX vs Gemcitabine based chemotherapy (60.3% CAprod vs. 56.7% CAnonprod, p=0.27) with a median number of 4.0 vs 5.0 cycles (p=0.83), respectively. Rate of MPR was significantly higher in patients with CAprod compared with CAnonprod patients (26.3% vs 7.7%, p=0.03). No CAnonprod patient had a complete pathologic response vs 28 (7.3%) of CAprod (p=0.12). CAnonprod was independently associated with decreased odds of MPR (OR 0.21, CI [0.04-0.99]). Black race was independently associated with increased odds of CAnonprod (OR 8.66, CI [3.81 – 19.7]). When stratified by production of CA 19-9, there was no significant difference between rate of MPR between Black and White patients. In the PanCAN KYT analysis, CAnonproduc had higher rates of SWI/SNF alterations (50.0% of CAnonprod vs 30.1% of CAprod, P<0.01;P-adj=ns; ARID1B was the most frequently mutated SWI/SNF gene in CAnonprod (31.0% vs 9.0% CApos, p<0.01; P-adj=ns). Conclusions: CAnonprod were more likely to be Black and have significantly worse rates of MPR following neoadjuvant chemotherapy in patients with localized PDAC. Moreover, CAnonprod was associated with higher rates of SWI/SNF alterations, noting a potential biologic basis for racial differences in chemotherapy response to curative-intent treatment for PDAC.

A phase II telemedicine study of pemigatinib in adult patients with unresectable or metastatic pancreas cancer with FGFR2 gene fusions or other FGFR genetic alterations.

TPS717 Background: Advanced pancreas cancer has a poor prognosis with few effective targeted therapies. Given this current state, novel therapies for pancreas cancer are an unmet need. Genomic alterations in FGFR, including fusions and point mutations are known driver mutations in cancer. FGFR kinase inhibitors have been FDA approved in cholangiocarcinoma and urothelial carcinoma, however, have not been well studied in other cancers. Our team previously identified and treated four patients with advanced pancreas cancer and FGFR2 fusions with FGFR kinase inhibitors resulting in durable responses and prolonged survival. Additionally, through a review of Foundation Medicine’s clinical genomic database, consisting of 30,229 pancreas cancer tumors, we determined that FGFR1-3 fusions have a prevalence of approximately 1% in pancreas cancer, most commonly in FGFR2 (0.8%). Our observations provide preliminary evidence that FGFR targeted therapy results in excellent clinical outcomes. We hypothesize that FGFR altered pancreas cancer treated with a FGFR kinase inhibitor will result in durable responses. We developed a phase 2, telemedicine trial of pemigatinib, an FDA approved FGFR kinase inhibitor, in FGFR altered pancreas cancer. Since the COVID-19 pandemic, telemedicine is used in routine oncology care and clinical trials and is associated with cost savings for patients. The growing adoption of this technology provides an opportunity to enhance the study of ultra-rare cancers. Methods: The trial consists of unresectable or metastatic pancreas cancer of any histology in two cohorts: 1) Primary cohort of FGFR2 fusions (n=30) and 2) exploratory cohort of other known activating mutations in FGFR (n=10). Patients are identified from across the United States through Foundation Medicine, Caris Life Sciences, and the Pancreatic Cancer Action Network. Eligible patients will be treated with oral pemigatinib through telemedicine by investigators at The Ohio State University in collaboration with local oncologists for supportive care. This trial uses single-stage phase 2 design with sample size calculations based on an expected overall response rate of ≥ 33% and <10% as unfavorable response, at one‐sided Type I error of 0.05, 90% power and up to 13% attrition rate. Results: The primary objective is overall response rate. Secondary objectives are overall survival, progression free survival, and duration of response. Exploratory objectives are analysis of correlation of circulating tumor DNA with response to treatment and development of resistance. Conclusions: FGFR kinase inhibitorshave the potential to be an effective targeted therapy in pancreas cancer. Additionally, telemedicine is a novel tool that can aid in the study of ultra-rare cancers and reduce barriers to patient participation in clinical trials.

Abstract C002: Interleukin-1 receptor accessory protein (IL1RAP) overexpression is associated with worse prognosis in PDAC and is targetable by nadunolimab

Abstract Introduction: The pancreatic tumor microenvironment (TME) is a major driver of tumor progression, chemoresistance and immune suppression, and the IL-1 axis has been implicated in tumor-promoting signaling networks. The IL1RAP-IL1R1 receptor complex is required for both IL-1α and IL-1β signaling and is expressed on tumor and stromal/immune cells. Nadunolimab is a fully humanized, ADCC-enhanced IgG1 antibody that targets IL1RAP and disrupts both IL-1α/IL-1β signaling. In the phase 1/2a trial CANFOUR (NCT03267316) in which 73 PDAC patients with previously untreated, locally advanced or metastatic PDAC received nadunolimab with gemcitabine/nab-paclitaxel (GN), encouraging preliminary data show median iPFS of 7.2 mo, median OS of 12.9 mo and 1-year survival of 58%. The present analyses investigated the correlation between IL1RAP expression and disease severity as well as therapeutic efficacy of nadunolimab/GN. Methods: Evaluable screening biopsies from 46 CANFOUR PDAC patients were stained for IL1RAP by immunohistochemistry. mRNA data was obtained from the GTEx, TCGA and Pancreatic Cancer Action Network’s Know Your Tumor (KYT) databases and correlated to patient data (TCGA, KYT) and mutational data (KYT). Results: IL1RAP expression was detected on tumor cells, fibroblasts, and infiltrating immune cells in tumor biopsies. Notably, all tumor cells expressed IL1RAP and stratification of evaluable samples into high or low tumor cell expression of IL1RAP revealed significantly prolonged median OS on nadunolimab/GN in IL1RAP high compared to IL1RAP low patients (14.2 vs 10.6 mo, p=0.017). This was also reflected in longer iPFS (8.0 vs 5.8 mo), 1-year survival (69 vs 40%) and iORR (52 vs 32%). Although varying in intensity, IL1RAP expression on stromal cells did not correlate significantly with treatment efficacy. In interrogating bulk RNA seq data from the GTEx, TCGA and KYT databases, IL1RAP was overexpressed in pancreatic cancer compared to normal tissue, with higher expression in advanced stage disease. Moreover, as KRAS mutations promote tumor inflammation and KRASG12D has been implicated in activating the IL-1 axis, we observed that KRASG12D tumors had a higher expression of IL1RAP and IL-1α, but not IL-1β, compared to KRAS-wildtype tumors. In both early and late-stage PDAC, high levels of IL1RAP strongly correlated with poor survival (both p<0.0001). Patients responding to GN tended to have lower IL1RAP levels than patients with progressive or stable disease, in stark contrast to the results with nadunolimab/GN. To understand the effects of nadunolimab/GN in the TME, spatial transcriptomics in screening and on-treatment biopsies are being analyzed with Nanostring GeoMx. Conclusion: IL1RAP is upregulated in pancreatic cancer, its expression correlates with oncogenic KRAS driver mutations and is strongly associated with poor survival. The IL1RAP-targeting antibody nadunolimab has shown promising target-dependent efficacy in combination with 1st line chemotherapy, indicating that IL1RAP is a both highly relevant and targetable protein in PDAC. Citation Format: Eric Van Cutsem, Kawther Abdilleh, Jashodeep Datta, Manuel Hidalgo, Camilla Rydberg Millrud, Petter Skoog, Annika Sanfridson, Dominique Tersago, David Liberg. Interleukin-1 receptor accessory protein (IL1RAP) overexpression is associated with worse prognosis in PDAC and is targetable by nadunolimab [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C002.

Abstract A008: PanCAN SPARK: A cloud-based health data integration platform for pancreatic cancer data

Abstract The Pancreatic Cancer Action Network (PanCAN) is leading large-scale research initiatives that will help transform the way pancreatic cancer is detected and treated including the Know Your Tumor precision medicine service, the Precision Promise adaptive clinical trial platform, the Early Detection Initiative, and the Patient Registry. Combined, these initiatives will generate a wide range of patient health data including molecular, multi-omic, clinical, patient-reported, treatment, outcomes, and imaging data. Here we introduce SPARK, a cloud-based data and analytics platform powered by Seven Bridges. SPARK integrates patient health data from PanCAN’s research initiatives and serves to accelerate research by making pancreatic cancer data easier to access and use. The platform supports the full spectrum of clinical data analysis with PanCAN patient health data as well as bioinformatics and analytical tools designed to leverage clinico-genomic data in a centralized location. SPARK fills an unmet need in pancreatic cancer research by providing researchers rapid and secure access to a wide range of pancreatic cancer patient health data on a platform backed by a robust cloud-based analytical infrastructure. The pilot release of the PanCAN SPARK platform brings qualified researchers closer to identifying novel treatments and ultimately improving patient outcomes. Citation Format: Kawther Abdilleh, Omar Khalid, Dennis Ladnier, Wenshuai Wan, Sara Seepo, Garrett Rupp, Valentin Corelj, Zelia F. Worman, Bruce Press, Jack DiGiovanna, Satty Chandrashekhar, Eric Collisson, Karen Cui, Anirban Maitra, Paul A. Rejto, Kevin White, Lynn Matrisian, Sudheer Doss. PanCAN SPARK: A cloud-based health data integration platform for pancreatic cancer data [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A008.

Abstract C071: Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma

Abstract Background: Keratin 17 (K17) is a negative prognostic biomarker, overexpressed in the biologically most aggressive forms of pancreatic ductal adenocarcinoma (PDAC). In other anatomic sites and disease processes, K17 expression also correlates with immune cell infiltrates and could block T-cell infiltration. Thus, we hypothesized that K17 expression correlates with the inflammatory microenvironment in PDAC. In this study, we aimed to determine the relationship between the stromal immune cell infiltrates and K17 expression, using multiplexed immunohistochemistry (mIHC) and our suite of deep learning tools to quantitatively evaluate the expression of four biomarkers of T-cells and macrophages in PDAC. Methods: mIHC was performed on representative sections of 201 primary PDACs from Stony Brook University Hospital, Thomas Jefferson University Hospital, Cedars Sinai Medical Center, and from a national cohort (KYT, Pancreatic Cancer Action Network, and Perthera). Antibodies for CD4 (helper T-cells), CD8 (cytotoxic T-cells), CD16 (pan-macrophage), CD163 (M2 macrophages), pancytokeratin, and K17 were provided by Roche Diagnostics Corporation through a sponsored research agreement. mIHC was performed on a Discovery Ultra Autostainer (Roche), using horseradish peroxidase (HRP) and alkaline phosphatase (AP)-based protocols with multiple chromogens (Red: CD4, Purple: CD8, Yellow: CD16, Green: CD163, Teal: pancytokeratin, and Brown: K17) to enable multispectral imaging of diverse immune cell populations within the cancer microenvironment. A deep learning analysis workflow was used to detect and classify stromal inflammatory cells, in whole slide images (WSIs), generated using an Olympus VS120 digital microscope (Olympus, Tokyo, Japan). Pixel-wise predictions from a color auto-encoder (ColorAE) union UNET anchor UNET model were combined to create multi-class masks that were further analyzed to perform detection and classification. Results: The analysis of the inflammatory microenvironment focused on defining immune cell infiltrates located within 25 microns of the closest K17-positive versus K17-negative tumor cell in each representative section. Across the sum of K17-positive and negative zones/section, CD4 cell counts ranged from 0-10,617 (mean 2,709), CD8 cell counts ranged from 63-28,596 (mean 6,745), CD16 cell counts ranged from 4-7,797 (mean 3,024), and CD163 cell counts ranged from 35-34,696 (mean 14,968). CD4 T-helper cells, CD8 cytotoxic T cells, and CD16 macrophages were more numerous (respectively, p=0.0012; p=<0.0001; p=<0.0001) in K17-negative tumor zones compared to K17-positive zones. By contrast, the number of CD163 (M2) tumor-promoting macrophages was greater in K17 positive zones (p=0.0019). Conclusion: K17 expression by tumor cells impacts the chronic inflammatory microenvironment, shielding tumor cells from immune cell mediated cytotoxic responses, while recruiting tumor-promoting M2 macrophages, indicating that K17 impacts the immune response as a fundamental hallmark of aggression in PDAC. Citation Format: Lyanne Oblein, Michael Horowitz, Mahmudul Hasan, Sruthi Babu, Mariana Torrente-Goncalves, Lucia Roa, Jaymie Oentoro, Jason Harper, Xin Yao Zheng, Wei Jiang, Andrew Hendifar, Natalie Moshayedi, Brent Larson, Veronica Placencio-Hickok, Edik Blais, Emmanuel Petricoin, Joel Saltz, Natalia D. Marchenko, Luisa F. Escobar-Hoyos, Kenneth Shroyer. Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C071.

Abstract A020: Patients with pancreatic cancer reporting prediagnosis pain have greater pain intensity scores, symptom burden, and ER visits: need for improved, ongoing management in pancreatic pain and associated symptoms

Abstract Objective: This study assessed the pancreatic cancer (PC) patient-reported burdens of PC pain from 2016-2020 in an online patient-reported outcomes (PRO) survey supported by the Pancreatic Cancer Action Network (PanCAN). Assessments of PC symptoms, PC pain intensity, physical and mental functioning, associated symptom management and resource utilization were analyzed between PC patients reporting prediagnosis PC pain vs those who did not. Methods: Through years 2016 - 2020, PC patient volunteers filled out an online PRO survey composed of independent surveys and standalone items in this cross-sectional study. PC patient responses to Patient Information, PC Experience, General Health Assessment and Pain Management surveys were collected to assess PC pain and related factors in activities and associated symptoms. Comparisons between PC patient group responses to two survey items were assessed: 1) presence or absence of prediagnosis PC pain; 2) pain intensity, scored by an 11-point numeric rating scale (NRS). Patient groups: NRS=0-3 (none to mild pain) and NRS=5-8 (moderate to severe pain). Descriptive statistics were used for numbers and frequencies and all bivariate analyses were performed using Chi-square or Fisher’s Exact tests. Results: Survey responses to 108 items ranging from 5-100% participation were collected and analyzed from 1978 PC patient volunteers. Significant differences were noted in postdiagnosis average pain intensities based on presence or absence of prediagnosis pain: NRS 2.64+2.54 vs NRS 1.56+2.01, respectively, p=0.0039. The presence of PC pain (abdominal and/or back pain) was the most frequent prediagnosis symptom reported (62%, N=1222) followed by digestive problems (55.32%, p=0.0001), weight loss and/or loss of appetite (54.88%, p=0.0001) and fatigue (46.54%, p=0001). Significantly greater impairment of those with prediagnostic pain was noted in 45% of 20 health assessment statements, including pain interference>physical functioning >anxiety >depression >fatigue, and increased resource utilization for PC pain management was noted (ER visits N=42 vs N=8 respectively, p=0.018 and/or hospitalizations, N=30 vs N=4, respectively, p=NS). Patient responses to pain ranged from NRS 0-8 (N=155), and group NRS 5-8 scores reported had significantly greater impairment in 85% of 20 health assessment statements. No improvements in average pain intensity scores were noted between yrs 2018-2020 vs yrs prior to 2018. Conclusions: PC pain is the most frequent prediagnostic PC symptom and is associated with an increase in postdiagnosis average pain intensity, greater impairment in physical function, and an increase in ER visits compared to those who do not report prediagnostic pain. The results suggest that PC pain is not adequately managed early in the course of the disease. There is a need to better assess symptoms, QOL, and therapeutic interventional outcomes to determine the contribution of improvements in tumor reduction and survival with patient symptom reduction and better physical and mental functioning. Citation Format: Terry A. McNearney, Biai D.E. Digbeu, Dennis Ladnier, Kawther Abdilleh, Sudheer Doss, Lynn M. Matrisian, Jacques G. Baillargeon. Patients with pancreatic cancer reporting prediagnosis pain have greater pain intensity scores, symptom burden, and ER visits: need for improved, ongoing management in pancreatic pain and associated symptoms [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A020.

Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC).

TPS4188 Background: The success rate of drug development in PDAC is disappointingly low.PrP is a transformative, adaptive platform clinical trial designed to continuously evaluate many novel therapeutic options while increasing the probability that patients (pts) are randomized to effective experimental therapies. It cultivates enhanced cooperation among groups representing pts advocacy, pharmaceutical companies, academia, and the FDA. This patient-centric study aims to become the largest Phase 3 registrational study in PDAC and represents a fundamental shift in drug development for PDAC in the United States (US). Methods: PrP (NCT04229004) is a platform clinical trial sponsored by the Pancreatic Cancer Action Network (PanCAN), developed based on the FDA 2020 guidance document regarding "complex innovative designs" in registration trials https://www.fda.gov/media/130897/download . It utilizes adaptive randomization and other Bayesian statistical innovations provided by Berry Consultants LLC, including the “time machine” which uses all previously randomized controls for each arm, suitably adjusted for line of therapy and the time period of the arm. Focused on 1st and 2nd line treatment of mPDAC, PrP uses an adaptive platform design with randomization to one of 2 control arms (gemcitabine + nab-paclitaxel (GA) or mFOLFIRINOX, 30% of pts) or experimental therapy (70% of pts). Candidate experimental arms are reviewed by an Arm Selection Committee based on validity of the treatment target and strength of the pre-clinical and clinical data. The primary endpoint is overall survival (OS). Pts undergo pre- and on-treatment biopsies with state-of-the-art genomic, transcriptomic, and immune analysis, along with a serial collection of blood-based research samples. Pts are managed using novel supportive care techniques; PrP contains 3 sub-protocols evaluating quality of life, sarcopenia, and actigraphy. PrP launched in 2020 and has enrolled > 130 pts; 30 US sites have been selected with 17 currently active. Current experimental arms include: (i) GA + Pamrevlumab, an anti-CTGF Ab, (ii) Racemetyrosine monotherapy, a cancer metabolism-based therapy (for follow-up of patients) and (iii) an immuno-oncology arm in activation. Other arms are in the planning stages. Compared to traditional designs, PrP offers several advantages: multiple investigational treatments evaluated in parallel over time; ̃175 pts per experimental arm required to initiate a regulatory registration; and continuous learning from every patient, resulting in significant savings of time and resources. PrP has created an entirely new learning environment for accelerating drug development in PDAC. Clinical trial information: NCT04229004.

Adoptive transfer of Trac-targeted T cell receptor engineered T cells with defective Tgfbr2 signaling promotes pancreatic cancer eradication

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterized by a suppressive tumor microenvironment (TME) with elevated Tgfb. Adoptive transfer of T cell receptor (TCR) engineered T cells specific to mesothelin (Msln) effectively targets autochthonous PDA, but the TME promotes engineered T cell dysfunction and limits efficacy. To test our hypothesis that Tgfb is a key mediator of engineered T cell dysfunction in PDA, we first created a Msln-specific TCR Trac knock-in mouse model to generate a uniform source of Msln406-414:H-2Db-specific T cells. Using CRISPR/Cas9, we next knocked out Tgfbr2 in Msln-specific T cells. Both Tgfbr2WT and Tgfbr2KO engineered T cells preferentially accumulate in orthotopic KPC tumors, comprising over 70% of the total CD8+ intratumoral T cells. In combination with vaccination, engineered T cells cause a 10-fold reduction in tumor weight at day 12 post tumor implantation. Loss of Tgfbr2 in effector T cells increases Klrg1, IFNg, TNFa and decreases exhaustion markers PD1, Lag3 and Tox in engineered T cells. Further supporting our data, Tgfbr2 cKO mice receiving orthotopic KPC2a PDA implantation had reduced tumor growth compared to Tgfbr2 WT littermates. Analysis of the endogenous tumor-specific T cells using a tetramer support the role of Tgfb in promoting T cell exhaustion and tumor growth in PDA. Ongoing 2-photon studies on the extent Tgfβ impacts engineered T cell migration, interactions with dendritic cells and stromal modifications will be discussed. Overall, disruption of Tgfβ is a key mediator of both engineered and endogenous tumor-antigen-specific T cell fate by promoting potent Klrg1+ T cells at the expense of Tox+ exhausted T cells and leading to durable tumor control in PDA. Supported by grants from NIH (R01 CA249393, R01 CA255039, T32 AI 007313), Dennis W. Watson Fellowship, American Association for Cancer Research (AACR) Pancreatic Cancer Action Network Career Development Award (17-20-25-STRO), an AACR Pancreatic Cancer Action Network Catalyst Award (19-35-STRO), an American Cancer Society Institutional Research Grant (124166-IRG-58-001-55-IRG65)

Distinct myeloid antigen presenting cells dictate differential fates of tumor-specific CD8 T cells in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) contains numerous protumor myeloid cells at the expense of antitumor dendritic cells (cDC1s). We identify that tumor antigenicity is a major determinant of myeloid composition and functionality. Neoantigen-tumors contained pro-tumor macrophages and a paucity of cDC1s whereas neoantigen+ tumors accumulate cDC1s via Xcr1 signaling and macrophages exhibit a diminished role. Effective immunotherapies increased splenic cDC1s, which were required for endogenous T cell expansion following α-PD-L1 and transferred effector and memory T cells. Batf3−/− mice, which lack cDC1s, failed to spontaneously generate tumor-specific CD8 T cells and were resistant to T cell therapy and α-PD-L1. In contrast, agonistic α-CD40 exhibited partial benefit in Batf3−/− mice and expanded atypical tumor-specific CD8 T cells. Monocyte depletion abrogated atypical tumor-specific CD8 T cell priming yet enhanced α-CD40-mediated antitumor activity in Batf3−/− mice. In contrast, α-Gr1 abrogated the therapeutic benefit of CD40 agonist in Batf3−/− mice. In sum, our study supports that CD40 agonist promotes a cDC1-dependent antitumor immunity and a monocyte-dependent protumor arm of immune system. These results further underscore an essential antigen presenting role for cDC1s in the expansion and differentiation of naïve, effector, and memory T cells into Klrg1+ potent cytotoxic effector T cells capable of targeting pancreatic cancer. M.R. is supported by National Institutes of Health (NIH) T32 AI 007313 E.J.S. is supported by NIH T35 AI118620 I.M.S. is supported by NIH R01 CA249393, R01 CA255039, Department of Defense #PA200286, an American Association for Cancer Research (AACR) Pancreatic Cancer Action Network Career Development Award (17-20-25-STRO), an AACR Pancreatic Cancer Action Network Catalyst Award (19-35-STRO), American Cancer Society Institutional Research Grant (124166-IRG-58-001-55-IRG65).

Potential Cost-Effectiveness of Risk-Based Pancreatic Cancer Screening in Patients With New-Onset Diabetes.

There are no established methods for pancreatic cancer (PAC) screening, but the NCI and the Pancreatic Cancer Action Network (PanCAN) are investigating risk-based screening strategies in patients with new-onset diabetes (NOD), a group with elevated PAC risk. Preliminary estimates of the cost-effectiveness of these strategies can provide insights about potential value and inform supplemental data collection. Using data from the Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) risk model validation study, we assessed the potential value of CT screening for PAC in those determined to be at elevated risk, as is being done in a planned PanCAN Early Detection Initiative trial. We created an integrated decision tree and Markov state-transition model to assess the cost-effectiveness of PAC screening in patients aged ≥50 years with NOD using CT imaging versus no screening. PAC prevalence, sensitivity, and specificity were derived from the END-PAC validation study. PAC stage distribution in the no-screening strategy and PAC survival were derived from the SEER program. Background mortality for patients with diabetes, screening and cancer care expenditure, and health state utilities were derived from the literature. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were tracked over a lifetime horizon and discounted at 3% per year. Results are presented in 2020 US dollars, and we took a limited US healthcare perspective. In the base case, screening resulted in 0.0055 more LYs, 0.0045 more QALYs, and $293 in additional expenditures for a cost per QALY gained of $65,076. In probabilistic analyses, screening resulted in a cost per QALY gained of <$50,000 and <$100,000 in 34% and 99% of simulations, respectively. In the threshold analysis, >25% of screen-detected PAC cases needed to be resectable for the cost per QALY gained with screening to be <$100,000. We found that risk-based PAC screening in patients with NOD is likely to be cost-effective in the United States if even a modest fraction (>25%) of screen-detected patients with PAC are resectable. Future studies should reassess the value of this intervention once clinical trial data become available.

Abstract PO-050: Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC)

Abstract Background: Drug development in PDAC has been disappointing with an extremely low trial success rate despite considerable effort. PrP is a transformative, adaptive clinical trial platform that attempts to correct this by continuously and rapidly evaluating novel therapeutic options while maximizing the probability of patient (pt) randomization to an experimental treatment and nurturing enhanced cooperation among groups representing pt advocacy, pharmaceuticals, translational/clinical academia, and the FDA. This patient-centric study represents a fundamental shift in drug development for PDAC in the United States and aims to become the largest Phase 2/3 registrational study ever launched in this disease. Methods: PrP (NCT04229004) is a clinical trial platform sponsored by the Pancreatic Cancer Action Network (PanCAN) and funded solely through non-government sources. The protocol was finalized based on the FDA 2020 guidance document regarding "complex innovative designs" in registration trials https://www.fda.gov/media/130897/download. It utilizes adaptive randomization along with several trial design and Bayesian statistical innovations provided by Berry Consultants LLC. All pts undergo pre-and on-treatment biopsies with state-of-the-art genomic, transcriptomic, and immune analysis, along with collection of blood samples for research purposes throughout the study. Pts are managed using novel standardized supportive care techniques, and PrP contains 3 sub-protocols involving quality of life, sarcopenia and actigraphy. PrP was launched in 2020, and currently includes 20 US sites. Focused on both 1st and 2nd line treatment of metastatic PDAC, PrP uses an adaptive platform design with 30% of pts randomized between one of the 2 standard of care control arms (gemcitabine + nab-paclitaxel and mFOLFIRINOX) and 70% to experimental arms, currently either SM-88, a cancer metabolism-based agent (Tyme Inc); or Pamrevlumab, an antibody inhibiting the activity of the connective tissue growth factor (Fibrogen Inc.) The study is ongoing with &amp;gt;100 pts enrolled to date. The Data and Safety Monitoring Committee regularly reviews the data and continues to recommend that the trial proceeds as planned. New study arms will be added after review by an Arm Selection Committee that assesses the validity of the treatment target and the adequacy of the preexisting pre-clinical and clinical data. An additional experimental arm is anticipated in 2021. Conclusion: Compared to traditional trial designs, PrP offers several advantages: multiple investigational treatments can be evaluated in parallel over time; only ~ 175 pts per experimental arm required to initiate a regulatory registration; and increased learning from every patient during the trial, altogether resulting in both time saving and a 30-50% cost saving. In effect, PrP has created an entirely new “learning community” and can substantially accelerate drug development for PDAC. Citation Format: Vincent J. Picozzi, Anne-Marie Duliege, Anirban Maitra, Manuel Hidalgo, Andrew Eugene Hendifar, Gregory L. Beatty, Sudheer Doss Doss, Regina Deck, Lynn M. Matrisian, Julie Fleshman, Diane M. Simeone. Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-050.

Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling.

Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies. Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology. These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis. We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Leveraging patient-reported outcomes (PROs) in patients with pancreatic cancer: The Pancreatic Cancer Action Network (PanCAN) online patient registry experience.

BackgroundThe Pancreatic Cancer Action Network (PanCAN) Patient Registry is an online, pancreatic cancer‐specific, global registry enabling patients to self‐report sociodemographics, disease/management characteristics, and patient‐reported outcomes (PROs). We sought to describe the creation, user experience, and research potential of the PanCAN Registry.MethodsWe obtained data to describe (1) the creation of the Registry (questionnaire development, marketing efforts, and regulatory considerations); (2) the user experience (user characteristics and interactions with the registry following inception); and (3) the research potential of the registry (comparing PROs and treatment patterns by age [±65 years] and treatment site [community or academic] for users with de novo metastatic disease).ResultsThe Registry was conceived as part of PanCAN’s strategic plan for a personalized therapy initiative. PanCAN staff and disease expert consultants developed questionnaires hosted on an electronic PRO platform. Users had the option to include their data in research efforts, and the Registry platform received institutional review board approval. From 7/2015 to 12/2020, 2187 patients visited the registry and 1697 (77.6%) completed at least one survey (median age = 64 years [range: 24–90], 47.9% women, 88.7% White, 34.0% metastatic disease). Among patients with metastatic disease (N = 567), 46.0% were ≥65 years old and 67.5% received treatment at community sites. Patients ≥65 years reported feeling less hopeful about the treatment plan (12.4% vs. 24.3%, p = 0.003), and patients treated at community sites reported more frequent treatment breaks of >2 weeks (58.2% vs. 28.1%, p < 0.001).ConclusionsOur findings demonstrate the feasibility, usability, and research potential of an online PRO registry for patients with cancer. This description of the PanCAN Registry should inform future registry‐building efforts to facilitate standardized PRO reporting and provide a valuable research database. Clinical trial registration number: Not applicable.

Through the Patient Lens: How to be a Cancer Patient

Through the Patient Lens: How to be a Cancer Patient

Trends in pancreatic cancer clinical trials in the United States

Trends in clinical trials for pancreatic cancer between 2011-2020 were tracked in the Pancreatic Cancer Action Network database originally designed to assist in identifying open trials for eligible patients. More than 125 trials specific for pancreatic cancer or including no more than one additional cancer type have been open each year, the majority for patients with a diagnosis of pancreatic adenocarcinoma (PAC). The trends indicate an active and progressive pancreatic cancer research community and include an increasing number of trials for previously treated patients, the emergence of trials for post-adjuvant or maintenance therapy, an increasing number of research-intensive phase 0 trials, increasing seamless phase I/II and II/III trials to improve efficiency, and an increasing number of phase III trials despite historical failures. Trials were analyzed by treatment type and included trials to optimize standard chemotherapy or radiation therapy, trials targeting tumor pathways, the stroma, or the immune system, biomarker-specified trials, and a miscellaneous category of trials testing tumor metabolism, complementary medicine approaches, or alternate energy sources. There was a dramatic increase in immunotherapy trials over this time. Several biomarker-specified trials were initiated, and FDA approval was obtained for biomarker-specified targeted agents, many in a tissue-agnostic setting, indicating an increase in a precision medicine approach to pancreatic cancer treatment. An increasing number of trials tested non-standard approaches, many which progressed to phase III. The trends suggest an encouraging trajectory of pancreatic cancer clinical research.

Leveraging patient-reported outcomes (PROs) in patients with pancreatic cancer: The Pancreatic Cancer Action Network (PanCAN) online patient registry experience.

154 Background: By allowing patients (pts) to self-report key issues related to their quality of life and symptoms, PROs have important clinical and research implications. The PanCAN Registry, which began collecting data in July 2015, is a pancreatic cancer-specific global online registry enabling pts to report sociodemographics, disease/management characteristics, and PROs via online surveys. We sought to describe pt experiences with the PanCAN Registry. Methods: We assessed individual characteristics and interactions with the registry (visits, survey completions, and longitudinal use) from 7/2015-10/2019 for pts who provided permission to use their data. The registry allows pts to complete surveys about their experience (e.g. basics of pancreatic cancer, general information), symptoms (e.g. fatigue, pain), diagnostics (e.g. labs, scans), and drug therapy (e.g. type, frequency). We validated PROs using the PanCAN Know Your Tumor database. For a subset of pts (those with de novo metastatic disease), we compared PROs, treatment patterns, and side effects by age (+/- 65 years) and treatment site (community or academic). Results: Of 2,836 pts who visited the registry, 2,076 (73%) completed at least one survey (median age = 64 [range: 18-97], 48% women, 92% white, 32% metastatic disease). Pts most commonly completed the basics (73%), general information (39%), and drug therapy (37%) surveys. Overall, 10% answered surveys longitudinally. We observed 95% concordance between PROs and the PanCAN Know Your Tumor database. Among the 667 pts with de novo metastatic disease, 34% were older (age 65+) and 50% were treated at academic sites. Younger pts were more hopeful about the treatment plan (strongly agree: 24% v 12%, p &lt; .01) and reported less constipation (moderate/severe: 33% v 48%, p &lt; .01) compared with older pts. Pts treated at academic sites reported less frequent treatment breaks of &gt; 2 weeks (28% v 58%, p = 0.01) and more frequent severe cytopenias (27% v 12%, p = 0.01) compared with those treated at community sites. Conclusions: With &gt; 2,800 pts visiting the PanCAN registry and &gt; 70% completing a survey, these findings demonstrate the feasibility, robustness, and research potential of an online PRO registry. We observed important differences by age and treatment site regarding pts’ outlook, symptoms, treatment patterns, and side effects. With increasing focus on PROs, registries like this can facilitate standardized PRO reporting and monitoring, while also providing a valuable research database.

The potential cost-effectiveness of a risk-based pancreatic cancer screening strategy in new-onset diabetes.

7017 Background: There are no established methods for pancreatic cancer (PC) screening, but the National Cancer Institute and the Pancreatic Cancer Action Network (PanCAN) are investigating risk-based screening strategies in new-onset diabetes (NOD)—a group with elevated PC risk. Preliminary estimates of the cost-effectiveness of these strategies can provide insights about potential value and inform supplemental data collection. Using data from the Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) risk model validation study, we assessed the potential value of CT screening for PC in those determined to be at elevated PC risk, as is being done in a planned PanCAN Early Detection Initiative (EDI) trial. Methods: We created an integrated decision tree and Markov state-transition model to assess the cost-effectiveness of screening those age ≥50 and with NOD for PC using CT imaging vs. no screening. PC prevalence, sensitivity, and specificity were derived from the ENDPAC validation study. PC stage distribution in the no screening strategy and PC survival were derived from SEER. Background mortality for diabetics, screening and cancer care expenditure, and health state utilities were derived from the literature. The base case assumed 40% of screen-detected PC cases were resectable, and a threshold analysis explored the fraction required for screening to be &lt;$100,000 per QALY gained. Life years (LYs), quality-adjusted life years (QALYs), and costs were tracked over a lifetime horizon and discounted at 3% per year. Results are presented in 2019 USD, and we took a U.S. payer perspective. Results: In the base case, screening resulted in 0.0055 more LYs, 0.0045 more QALYs, and $305 in additional expenditure for a cost per QALY gained of $68,059 (Table). Among PC cases, screening resulted in 0.67 more LYs, 0.55 more QALYs, and $22,691 in additional expenditure. In probabilistic analyses, screening resulted in a cost per QALY gained of &lt;$50,000 and &lt;$100,000 in 34% and 99% of simulations, respectively. In the threshold analysis, &gt;25% of screen-detected cases needed to be resectable for the cost per QALY gained with screening to be &lt;$100,000. Conclusions: We found that risk-based pancreatic cancer screening in NOD is likely to be cost-effective in the U.S. if even a modest fraction (&gt;25%) of screen-detected cases are resectable. Future studies should reassess the value of this intervention once PanCAN EDI data become available. [Table: see text]