Incidence Of Pancreatic Ductal Adenocarcinoma Research Articles

Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and is associated with a poor prognosis. The majority of these cancers are detected at a late stage, contributing to the bad prognosis. This underscores the need for novel, enhanced early detection strategies to improve the outcomes. While population-based screening is not recommended due to the relatively low incidence of PDAC, surveillance is recommended for individuals at high risk for PDAC due to their increased incidence of the disease. However, the outcomes of pancreatic cancer surveillance in high-risk individuals are not sorted out yet. In this review, we will address the identification of individuals at high risk for PDAC, discuss the objectives and targets of surveillance, outline how surveillance programs are organized, summarize the outcomes of high-risk individuals undergoing pancreatic cancer surveillance, and conclude with a future perspective on pancreatic cancer surveillance and novel developments.

Abstract 2896: Elucidating the role of transglutaminase 2 (TGM2) in pancreatic ductal adenocarcinoma pathogenesis and its therapeutic implications

Abstract Pancreatic cancer remains one of the deadliest malignancies, with limited therapeutic options and a poor prognosis due to delayed symptom presentation and disease detection. Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 8%, predominantly attributed to oncogenic KRAS mutations and loss-of-function mutations in TP53, SMAD4, and P16. Our lab is interested in studying Transglutaminase 2 (TGM2), a multifunctional enzyme involved in protein cross-linking and cellular signaling, because it is highly correlated with cancer cell survival, malignancy, metastasis, and treatment resistance. Clinically, overexpression of TGM2 is associated with poorer survival in patients with Pancreatic Ductal Adenocarcinoma so it is imperative to understand the mechanism of its action in disease progression. To elucidate the role of TGM2 in PDAC, we studied the targeted deletion of TGM2 in the context of a mouse model of PDAC and saw a significant reduction in PDAC incidence and precursor lesion formation, suggesting that TGM2 has a role in the tumor microenvironment. Using single cell sequencing, we found TGM2 levels to be elevated in certain cell populations, specifically endothelial cells and cancer cells. We discovered high TGM2 levels in TIE2-GFP mouse vessels and subsequently found high TGM2 levels in patient tumor vasculature. Further studies aim to conditionally ablate TGM2 in endothelial cells to assess its mechanistic involvement in PDAC initiation and progression. Additionally, we are studying concurrent conditional TGM2 and SMAD4 deletions in mice to investigate pancreatic cancer precursor lesion formation and are further evaluating the protective mechanisms of a TGM2 deletion in a more aggressive mouse model of PDAC. Our preliminary findings substantiate TGM2 as a critical player in PDAC pathogenesis, opening avenues for targeted therapeutics to ultimately improve patient prognosis. Citation Format: Polina Wright, Azeddine Atfi. Elucidating the role of transglutaminase 2 (TGM2) in pancreatic ductal adenocarcinoma pathogenesis and its therapeutic implications [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 2896.

Abstract 1466: Tobacco carcinogen impacts redox pathway to facilitate pancreatic ductal adenocarcinoma (PDAC) initiation and progression

Abstract The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) is only 10%. PDAC is projected to soon become the second leading cause of cancer death. Tobacco is one of the main risk factors for PDAC. Incidence of PDAC increases 2-fold among tobacco users, and 20-35% of PDAC cases are attributed to smoking. However, the specific pathways activated by tobacco carcinogens remain elusive.This research project addresses the impact of carcinogens in pancreatic cancer etiology. We hypothesize that carcinogens in tobacco increase reactive oxygen species (ROS), which elevates the Nrf2 redox pathway to facilitate PDAC initiation and progression. Specifically, we focus on two major subclasses of carcinogens: the heavy metal cadmium (Cd) and the polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BaP). Using mouse pancreatic ductal organoid cultures, we found that acute carcinogen exposure increases Nrf2 activity, which is sustained after "intermediate" exposure (5 passages). Intriguingly, chronic exposure (10 passages) downregulates Nrf2 activity, which has been shown to be associated with acquired metastatic potential. Furthermore, we found an upregulation in NFkB and EGFR signaling after intermediate exposure, which are involved in microenvironment remodeling and increased proliferative potential. Overall, we demonstrate that acute carcinogen exposure elevates ROS levels and activates the Nrf2 pathway, whereas prolonged exposure upregulates NFkB and EGFR pathways. Furthermore, we have established a novel carcinogenesis model using 3D organoid culture to recapitulate each step in pancreatic tumorigenesis. Collectively, this project contributes to our understanding of tobacco-related PDAC pathogenesis. Citation Format: Xiaoxue Lin, McKenna Stamp, Alexandra Fowler, Chelsea Bottomley, Shira Okhovat, Kristina Peck, Dannielle Engle. Tobacco carcinogen impacts redox pathway to facilitate pancreatic ductal adenocarcinoma (PDAC) initiation and progression [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 1466.

The Disproportionate Rise in Pancreatic Cancer in Younger Women Is Due to a Rise in Adenocarcinoma and Not Neuroendocrine Tumors: A Nationwide Time-Trend Analysis Using 2001-2018 United States Cancer Statistics Databases.

In previous studies, a significant increase in the incidence of pancreatic cancer among younger women compared to men in the United States was noted. However, the specific histopathologic characteristics were not delineated. This population-based study aimed to assess whether this disproportionate rise in pancreatic cancer in younger women was contributed by pancreatic ductal adenocarcinoma (PDAC) or pancreatic neuroendocrine tumors (PanNET). The United States Cancer Statistics (USCS) database was used to identify patients with pancreatic cancer between 2001 and 2018. The results showed that, in younger adults, the incidence of PDAC has increased in women [average annual percentage change (AAPC) = 0.62%], while it has remained stable in men (AAPC = -0.09%). The PDAC incidence rate among women increased at a greater rate compared to men with a statistically significant difference in AAPC (p < 0.001), with neither identical nor parallel trends. In contrast, cases of PanNET did not demonstrate a statistically significant sex-specific AAPC difference. In conclusion, this study demonstrated that the dramatic increase in the incidence rate of PDAC explains the disproportionate rise in pancreatic cancer incidence in younger women. This prompts further prospective studies to investigate the underlying reasons for these sex-specific disparities in PDAC.

Trends in incidence and survival of early-stage pancreatic ductal adenocarcinoma in the United States.

633 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival with nearly 80% mortality within the first year after diagnosis. There have been modest incremental improvements in survival over the last decade, however the reason for this improvement is unclear. The aim of this study is to evaluate the trends of diagnosis and survival in the last two decades using large public national databases. Methods: Incidence rates of PDAC between 2001 and 2020 (age-adjusted to the 2000 US standard population) were evaluated in the United States Cancer Statistics (USCS) database, representing approximately 98% of the US population. The data was analyzed with SEER*Stat using Joinpoint regression. A survival analysis was subsequently conducted using the American College of Surgeons’ (ACS) National Cancer Database (NCDB), of PDAC cases diagnosed between 2004 and 2015.Survival outcomes were stratified by AJCC stage. Kaplan-Meier survival curves were generated, and log-rank tests were conducted to assess differences in survival between stages. Cox proportional hazards model was employed to estimate hazard ratios and adjust for potential confounders. The analysis was performed with IBM SPSS 24. Results: From 2001 to 2020, the age-adjusted incidence rate of early-stage PDAC increased from 1.1 to 2.8 (per 100,000 person-years), while locally advanced PDAC increased from 3.6 to 4.3, and from 6.4 to 7.7 for metastatic PDAC (all p&lt;0.01). The Annual Percent Change (APC) was 5.7 for Early-Stage PDAC (95% CI 5.1-6.4), 1.4 for locally advanced (95% CI 0.8-1.9), and 0.8 for Metastatic PDAC (95% CI 0.6-1.1). The incidence rate ratio (IRR) almost doubled for early-stage PDAC, increasing from 0.10 to 0.19. Conversely, for metastatic and locally advanced stages, the IRR decreased from 0.58 to 0.52 and 0.32 to 0.29, respectively. Survival analysis revealed 5-year overall survival rates of 74%, 69%, 57%, and 33% for stages 0, IA, IB, and IIA, respectively, with an overall improvement from 2004 to 2015. This increase was consistent among all age groups, genders, and races. Stages IA and IB demonstrated larger increases 45.9% and 56.6%, respectively (IA: 47% in 2004 to 75% in 2015; IB: 38% in 2004 to 68% in 2015). Conclusions: This study highlights a marked increase in the incidence of early-stage PDAC, surpassing the overall incidence increase, suggesting improving diagnostic capabilities over the last two decades. Furthermore, the substantial improvement in 5-year survival rates for stages IA and IB indicates progress in the management of early-stage PDAC. These findings emphasize the importance of continued efforts in early detection and treatment strategies for PDAC.

Abstract PR03: Addressing disparities in the Native American population in Oregon: The development of multi-disciplinary frameworks to study pancreatic ductal adenocarcinoma in Native American communities

Abstract In Oregon, the incidence of pancreatic ductal adenocarcinoma (PDAC) is 2-times higher among Native American (NA) communities compared to the rest of the population. At Oregon Health &amp; Science University, we have formed a multi-disciplinary team that includes clinicians, translational scientists, and population scientists. Additionally, we have initiated a process of establishing a collaboration with the Confederated Tribes of Warm Springs, one of Oregon’s largest Tribal community. By fostering the connections of NA healthcare providers within OHSU’s Knight Cancer Institute and Brenden-Colson Center for Pancreatic Care, and with the established Community Outreach, Research, and Engagement (CORE) team, we aim to build trust with the Confederated Tribes of Warm Springs to accomplish shared goals. To date, our team has made multiple visits to foster this connection. Recently, we conducted one-on-one interviews with Warm Springs community members to better understand the communities’ barriers to health information and health care. These interviews help focus our strategies to directly address barriers community members identify as most important to them. Interviews (&amp;lt;30 minutes long) were conducted and recorded with CORE trained personal at the Warm Springs Health fair and are now being evaluated. As part of our protocol, community members were reimbursed for their time and information with a twenty-dollar gift card from a local coffee shop. In addition to this interview, community members identified using an easel board outside our cancer center’s health booth to provide the most effective learning styles to help shape our future efforts in education and awareness. The data that was collected is also aiding in the development of culturally appropriate approaches and programs that are guided and shaped by NA communities through co-adapting and implementing our proven, Research in Oregon Communities’ Review System (ROCRS) for Tribes to receive, review, and co-design incoming research requests. Future projects look to complement this work by bringing two research studies (e.g., a diabetes early detection program and a NA genetic registry) through a collaborative research review, to determine feasibility, acceptability, and adoption, within the Warm Springs community. Citation Format: Jared Delaney, Grace McCarthy, Jackie Shannon, Rosalie Sears, Brett Sheppard, Jonathan Brody, Claymore Kills First. Addressing disparities in the Native American population in Oregon: The development of multi-disciplinary frameworks to study pancreatic ductal adenocarcinoma in Native American communities [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 PR03.

Recent Advances and Future Challenges in Pancreatic Cancer Care: Early Detection, Liquid Biopsies, Precision Medicine and Artificial Intelligence

The incidence of pancreatic ductal adenocarcinoma (PDAC) is rising. While surgical techniques and peri-operative care have improved, the overall survival for PDAC remains poor. Thus, novel and bold research initiatives are needed along the spectrum of clinical care, a few of which will be discussed in this article. Early detection is crucial, with specific high-risk groups possibly benefiting from targeted screening programs. Liquid biopsies (such as circulating exosomes, tumor DNA, or tumor cells) offer promise as multifunctional biomarkers for early detection, treatment guidance, and recurrence monitoring. Precision medicine is being explored via targeted therapies for actionable mutations, such as PARP inhibitors for BRCA mutations, and immunotherapy strategies. Artificial intelligence (AI) is emerging as a powerful tool in medical imaging, biomarker discovery, genetics research, and treatment planning, and it can aid in diagnosis, treatment selection, and patient monitoring. However, its associated challenges include ethics, data security, algorithm reliability, and validation. Collaborative efforts between medical professionals, researchers, and AI experts are vital for unlocking AI’s potential to enhance pancreatic cancer care. In conclusion, despite the challenges, advancements in liquid biopsies, precision medicine, and AI offer hope for enhancing the diagnosis, treatment, and management of pancreatic cancer.

HPB P06 The clinical and molecular landscape of early onset pancreatic cancer

Abstract Background The incidence of Pancreatic ductal adenocarcinoma (PC) is rising in the western world. There is a particularly concerning trend in the rapid increase in incidence of early onset PC (EOPC). The reason for this, and the implications of EOPC is not well understood. The aim of this study was to investigate the clinical outcomes of patients with EOPC and the molecular heterogeneity between EOPC and late onset disease. Methods Clinical, pathological and survival outcome data was obtained from 2 large independent prospective cohorts curated by the Australian Pancreatic Genome Initiative (APGI) and the West of Scotland pancreatic unit (Glasgow Royal Infirmary). Patients were categorised into 2 age groups, &amp;lt; 50 and &amp;gt;50 years at time of diagnosis. Clinicopathological and outcome data were compared between groups. Molecular data was obtained from the APGI’s contribution to the International Cancer Genome Consortium, this included transcriptomic, genomic and immunohistochemical data. Molecular subtypes, gene expression signatures, mutational signatures, and tumour microenvironment data was compared between groups. Results N=851 patients were identified and n=71 (8%) were &amp;lt; 50 years old. EOPC was associated with earlier recurrence (10.9 vs 14.2 months, P=0.011) and higher incidence of liver recurrence (50% vs 37%, P=0.031). There were no differences in validated clinicopathological variables. Despite an increased proportion of patients with EOPC receiving adjuvant chemotherapy (P=0.020), recurrence was earlier in those that completed &amp;gt; 3 cycles (12.6 vs 16.0 months, P=0.022). There is enrichment of the poor prognostic squamous (basal) subtype (42% vs 28%) in EOPC. There were no differences in the incidence of germline mutations to account for the early onset of disease. Conclusions EOPC appears to be increasing in incidence and is associated with earlier recurrence and more aggressive disease pattern. This appears to be associated with resistance to adjuvant chemotherapy and more aggressive, adverse molecular pathology. The onset of early disease cannot be explained by inherited genomic aberrations. Ongoing mutation signature, gene expression and microenvironmental data analysis will be presented upon acceptance of this abstract.

Risk of pancreatic cancer in people with new-onset diabetes: A Danish nationwide population-based cohort study

BackgroundNew onset diabetes (NOD) in people 50 years or older may indicate underlying pancreatic ductal adenocarcinoma (PDAC). The cumulative incidence of PDAC among people with NOD remains uncertain on a population-based level. MethodsThis was a nationwide population-based retrospective cohort study based on the Danish national health registries. We investigated the 3-year cumulative incidence of PDAC in people 50 years or older with NOD. We further characterised people with pancreatic cancer-related diabetes (PCRD) in relation to demographic and clinical characteristics, including trajectories of routine biochemical parameters, using people with type 2 diabetes (T2D) as a comparator group. ResultsDuring a 21-year observation period, we identified 353,970 people with NOD. Among them, 2105 people were subsequently diagnosed with pancreatic cancer within 3 years (0.59%, 95% CI [0.57–0.62%]). People with PCRD were older than people with T2D at diabetes diagnosis (median age 70.9 vs. 66.0 years (P < 0.001) and had a higher burden of comorbidities (P = 0.007) and more prescriptions of medications used to treat cardiovascular diseases (all P < 0.001). Distinct trajectories of HbA1c and plasma triglycerides were observed in PCRD vs. T2D, with group differences observed for up to three years prior to NOD diagnosis for HbA1c and up to two years for plasma triglyceride levels. ConclusionsThe 3-year cumulative incidence of PDAC is approximately 0.6% among people 50 years or older with NOD in a nationwide population-based setting. Compared to T2D, people with PCRD are characterised by distinct demographic and clinical profiles, including distinctive trajectories of plasma HbA1c and triglyceride levels.

Aspirin Use and Risk of Pancreatic Ductal Adenocarcinoma: A Large Case-Control Study.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5%. The incidence and mortality rates of PDAC are increasing, and the results of medical treatments remain unsatisfactory. Some conflicting evidence suggests that aspirin intake may reduce the risk of PDAC. This study aimed to evaluate the association between regular low-dose aspirin use (80-mg aspirin tablets, 5-7 tablets/week) and the risk of PDAC. This prospective, hospital-based, case-control study was performed on 470 PDAC patients (case group) and 526 sex and age-matched controls, in Tehran, Iran from 2011 to 2018. The participants were interviewed regarding the patterns of aspirin use. Data are expressed as mean±SD or frequency and percentage as appropriate. Differences in frequency between the case and control groups were evaluated based on the analysis of the contingency table (χ2 test and Fisher's exact test). Propensity score models were designed to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for PDAC with respect to aspirin use, adjusted for age, sex, smoking status, opium use, diabetes mellitus, place of residence, and family history of cancer in first-degree relatives. About 60% of PDAC patients were male in this study. Also, 25.2% of PDAC patients had a family history of cancer in one of their first-degree relatives, 21.99% were smokers, 13.9% were opium users, and 11.7% had a history of diabetes. Aspirin was used by 22.77% of PDAC patients and 18.25% of the controls. Ever aspirin use (OR: 1.01, 95% CI: 0.89 - 1.14) was not associated with PDAC. Overall, aspirin use was not associated with a reduced risk of PDAC.

Cytokeratin 6 identifies basal-like subtypes of pancreatic ductal adenocarcinoma with decreased survival

PurposeRising incidence of pancreatic ductal adenocarcinoma (PDAC) bind with insufficient therapy options showcases a great medical challenge. Further biomarkers are required to identify patients, who will benefit from more aggressive therapy.Methods320 patients were included by the PANCALYZE study group. Cytokeratin 6 (CK6) immunohistochemical staining as a putative marker for the basal-like subtype of PDAC was performed. The correlation between CK6 expression patterns and survival data, as well as various markers of the (inflammatory) tumor microenvironment, were analyzed.ResultsWe divided the study population based on the expression pattern of CK6. Patients with a high CK6 tumor expression had a significantly shorter survival (p = 0.013), confirmed in a multivariate cox regression model. CK6-expression is an independent marker for a decreased overall survival (HR = 1.655, 95% CI 1.158–2.365, p = 0.006). In addition, the CK6-positive tumors showed significantly less plasma cell infiltration and more cancer-associated fibroblasts (CAFs) expressing Periostin and SMA.ConclusionsCK6 could be considered as an independent biomarker for a shorter overall survival. CK6 is a clinically easily accessible biomarker for the identification of the basal-like subtype of PDAC. Therefore, it could be taken into consideration in deciding for the more aggressive therapy regimes. Prospectively, studies addressing the chemosensitive characteristics of this subtype are required.

Phase I study of trifluridine/tipiracil in combination with gemcitabine (gem) and nab-paclitaxel (nab-P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC).

731 Background: The incidence of PDAC is on the rise and it is predicted to be the 2nd leading cause of cancer related mortality in the next decade. Most patients present with advanced disease at diagnoses with limited systemic treatment options. Fluoropyrimidines are active in PDAC. Lonsurf (L) is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Preclinical data demonstrate Lonsurf may have activity in 5-FU resistant malignancies. This phase I study combines Gem, nab-P, and L. Methods: Gem and nab-P are dosed on days 1 and 15 IV on a 28 day cycle. L (20-30mg/m2) is dosed twice daily on days 2-6 and 16-20 (table 1). Dose escalation is by 3+3 design. Key eligibility include pts with untreated locally advanced or metastatic PDAC, ECOG 0-1, and adequate hepatic and bone marrow function. Results: 14 pts (median age 62 yrs [range 43-74]) have been enrolled. Dose was initiated at DL1. The first 3 pts were treated without DLT. DL2 exceeded the MTD with 1 patient experiencing grade 3 infection (cholangitis). Dose expansion to 7 patients was completed at DL 1 with no further DLTs. The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. Of the 10 patients with evaluable disease, 2 (20%) had PR and 7 (70%) had SD. Pts were on study a median of 14 months (range 4 -31+). Most common grade 3/4 AEs include fatigue (46%,) neutropenia (38%), anemia (31%) anorexia (15%), nausea (15%), vomiting (15%), abdominal pain (15%), hyperglycemia (15%). No grade 5 events occurred. Conclusions: The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. This combination was well tolerated with expected toxicities of myelosuppression with prolonged responses seen. Clinical trial information: NCT04046887 . [Table: see text]

Abstract C026: Pharmacogenetics of pancreatic ductal adenocarcinoma: A review of racial disparities

Abstract Background Pancreatic Ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality and is projected to increase in incidence by 2030 in the United States. Compared to Caucasians, African Americans (AA) have a significantly increased risk for PDAC, even after adjusting for risk factors (e.g., SES, obesity and smoking), and worse survival outcomes. Somatic and germline mutations are found in 90% and 10% PDAC cases, respectively. These mutations are known to alter the incidence and therapeutic response of PDAC, and studies show significant differences in genetic expression between AA and Caucasians. Our study focused on the current understanding of genetic mutations that influence the pharmacoethnicity of FDA approved PDAC drugs. Methods For this narrative review, multiple searches were generated from the PubMed database using several variations of the following keywords: pharmacogenetics, pancreatic cancer, race, ethnicity, African, Black, toxicity, and the FDA approved drug names: Fluoropyrimidines, Topoisomerase inhibitors, Gemcitabine, Nab-Paclitaxel, Platinum agents, Pembrolizumab, PARP-inhibitors, and NTRK fusion inhibitors. Names of genes were extracted from studies with established data on pharmacogenetic-related racial disparities. Additional studies were found from the cited section. After searches for PubMed was thoroughly reviewed, the same keywords were imputed in Web of Science. The University of Alabama at Birmingham (UALCAN) database was used to verify if overall survival was significant for the expression of the genes identified in literature. Only genes that were found in the literature and UALCAN database were included. Results The following genes were identified as influencing pharmacogenetic-related disparities and then assessed for significance in overall survival using the UALCAN database: CDA, TYMS, UGT1A1, SLC and ABCB transporters, BRCA 2, PALB2, ERCC1, ERCC2, NTRK 1-3, POLA2, and CY2C8. The following genes were not significant for overall survival: CDA, UGT1A1, PALB2, ERCC1, ECCR2, NTRK 1-3. TYMS (p=0.0052), POLA2 (p=0.022), CYP2C8 (p=0.027), BRCA2 (p=0.027) genes were significant for impacting overall survival outcomes. The UALCAN database has low sample size of African Americans (n=6) therefore, significance for overall survival based on race could not be properly stratified. Conclusion In conclusion, racial differences in gene expression can influence the therapeutic response of PDAC. The UALCAN database provides overall survival for patients with PDAC, but conclusions about race could not be properly stratified due to the low sample size of African Americans. As targeted therapy advancements improve, referrals for genetic testing should also because it can direct treatment course for avoiding toxicities and improving medical precision for AA. Citation Format: Guettchina Telisnor, Esther Frimpong, Edward Agyare, John M. Allen, Sherise C. Rogers. Pharmacogenetics of pancreatic ductal adenocarcinoma: A review of racial disparities [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C026.

Abstract A014: Targeting TAK1 for intercepting PanIN progression to ductal adenocarcinoma in an inducible KC mouse model

Abstract Despite advances in our knowledge of human pancreatic ductal adenocarcinoma (PDAC), targeted therapies have not yet significantly translated to an improved overall survival for patients. Pancreatic tumor microenvironment enriched by infiltrating immune cells and consisting of dense fibrotic stroma is characterized by desmoplasia, the major contributors of tumor-associated inflammation. Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is widely accepted as a key player in the TNF-α and TGF-β -induced signaling, and principal contributor of tumor fibrosis, inflammation and cell proliferation. Here, we show that pancreatic tumors over- express TAK1, and are associated with fibrotic-stroma and infiltrating immune cells. Also, p-TAK1(ser412) expression is correlated with progression of pancreatic intraepithelial neoplasia (PanIN) lesions to PDAC. Thus, we hypothesized TAK1 as an important target for inhibition of the tumor-associated fibrosis, inflammation and PanIN progression to PDAC. To prove above hypothesis, we tested a selective TAK1 inhibitor, Takinib for its toxicity and efficacy against PanIN progression in the inducible Ptf1CreERT.LSL-KrasG12D (KC) mouse model. Takinib was synthesized and fed to wild type C57BL/6J mice (n=6) at 250 ppm and 500ppm in diet for 6 weeks to determine toxicity. Bodyweight gain, organ weights and serum enzyme analysis did not indicate any toxicity at the tested doses. For efficacy study, LSL-KrasG12D mice were bred with Ptf1-CreERTmice. Pups were genotyped and randomized to groups (n=12). PanINs -PDAC was induced in the KC mice by tamoxifen (oral gavage) followed by 250ppm Takinib administration in diet for 20 weeks. After termination, pancreas tissue sections were evaluated for PanIN multiplicity and PDAC incidence/spread. Administration of Takinib led to significant reduction in PanIN 1 by 54% (p&amp;lt;0.02), PanIN 2 by 77% (p&amp;lt;0.001) and PanIN 3 by 80% (p&amp;lt;0.02) in the KC mice compared to untreated mice. PDAC incidence was also reduced with an increase in normal pancreas in Takinib administered KC mice. Taken together our results suggest that TAK1 is a valuable target for PDAC, and Takinib possesses efficacy against the PanIN and PDAC progression in the KC mouse model warranting further studies. (Supported by PHF Team Science grant and Kerley-Cade Endowed Chair). Citation Format: Venkateshwar Madka, Gopal Pathuri, Gaurav Kuma, Anil Singh, Nicole Stratton, Courtney Houchen, Altaf Mohammed, Chinthalapally V. Rao. Targeting TAK1 for intercepting PanIN progression to ductal adenocarcinoma in an inducible KC mouse model [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A014.

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10−5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.

An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive digestive malignancy due to frequent late-stage diagnosis, rapid progression and resistance to therapy. With increasing PDAC incidence worldwide, there is an urgent need for new prognostic biomarkers and therapy targets. Recently, RNA methylation has emerged as a new tumorigenic mechanism in different cancers. 5-methylcytosine (m5C) is one of the most frequent RNA modifications and occurs on a variety of RNA species including mRNA, thereby regulating gene expression. Here we investigated the prognostic role of m5C-regulator-associated transcriptional signature in PDAC. We evaluated m5C-regulator status and expression in 239 PDAC samples from publicly available datasets. We used unsupervised consensus clustering analyses to classify PDACs based on m5C-regulator expression. From the resulting signature of differentially expressed genes (DEGs), we selected prognosis-relevant DEGs to stratify patients and build a scoring signature (m5C-score) through LASSO and multivariate Cox regression analyses. The m5C-score represented a highly significant independent prognostic marker. A high m5C-score correlated with poor prognosis in different PDAC cohorts, and was associated with the squamous/basal subtype as well as activated cancer-related pathways including Ras, MAPK and PI3K pathways. Furthermore, the m5C-score correlated with sensitivity to pathway-specific inhibitors of PARP, EGFR, AKT, HER2 and mTOR. Tumors with high m5C-score were characterized by overall immune exclusion, low CD8+ T-cell infiltration, and higher PD-L1 expression. Overall, the m5C-score represented a robust predictor of prognosis and therapy response in PDAC, which was associated with unfavorable molecular subtypes and immune microenvironment.

Postoperative Pancreatic Fistula: Is Minimally Invasive Surgery Better than Open? A Systematic Review and Meta-analysis.

Minimally invasive pancreaticoduodenectomy (PD) is gaining popularity. The aim of this study was to compare the incidence of postoperative pancreatic fistula (POPF) after minimally invasive versus open procedures. Following the PRISMA statement, literature research was conducted focusing on papers comparing the incidence of POPF after open pancreaticoduodenectomy (OPD) versus minimally invasive pancreaticoduodenectomy (MIPD). Twenty-one papers were included in this meta-analysis, for a total of 4,448 patients. A total of 2,456 patients (55.2%) underwent OPD, while 1,992 (44.8%) underwent MIPD. Age, ASA score III patients, incidence of pancreatic ductal adenocarcinoma and duct diameter were significantly lower in the MIPD group. No statistically significant differences were found between the OPD and MIPD regarding the incidence of major complications (15.6% vs. 17.0%, respectively, p=0.55), mortality (3.7% vs. 2.4%, p=0.81), and POPF rate (14.3% vs. 12.9%, p=0.25). MIPD and OPD had comparable rates of postoperative complications, postoperative mortality, and POPF.

Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma: Where Do We Go?

The incidence of pancreatic ductal adenocarcinoma (PDAC) has been on the rise in recent years; however, its clinical diagnosis and treatment remain challenging. Although surgical resection remains the only chance for long-term patient survival, the likelihood of initial resectability is no higher than 20%. Neoadjuvant therapy (NAT) in PDAC aims to transform the proportion of inoperable PDACs into operable cases and reduce the likelihood of recurrence to improve overall survival. Ongoing phase 3 clinical trial aims to validate the role of NAT in PDAC therapy, including prolongation of survival, increased R0 resection, and a higher proportion of negative lymph nodes. Controversies surrounding the role of NAT in PDAC treatment include applicability to different stages of PDAC, chemotherapy regimens, radiation, duration of treatment, and assessment of effect. This review aims to summarize the current progress and controversies of NAT in PDAC.

Pancreatic Cancer Surveillance in Carriers of a Germline CDKN2A Pathogenic Variant: Yield and Outcomes of a 20-Year Prospective Follow-Up.

Pancreatic cancer surveillance in high-risk individuals may lead to detection of pancreatic ductal adenocarcinoma (PDAC) at an earlier stage and with improved survival. This study evaluated the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants (PVs) in CDKN2A. Prospectively collected data were analyzed from individuals participating in pancreatic cancer surveillance. Surveillance consisted of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound. Three hundred forty-seven germline PV carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years. A total of 36 cases of PDAC were diagnosed in 31 (8.9%) patients at a median age of 60.4 (interquartile range 51.3-64.1) years. The cumulative incidence of primary PDAC was 20.7% by age 70 years. Five carriers (5 of 31; 16.1%) were diagnosed with a second primary PDAC. Thirty (83.3%) of 36 PDACs were considered resectable at the time of imaging. Twelve cases (12 of 36; 33.3%) presented with stage I disease. The median survival after diagnosis of primary PDAC was 26.8 months, and the 5-year survival rate was 32.4% (95% CI, 19.1 to 54.8). Individuals with primary PDAC who underwent resection (22 of 31; 71.0%) had an overall 5-year survival rate of 44.1% (95% CI, 27.2 to 71.3). Nine (2.6%; 9 of 347) individuals underwent surgery for a suspected malignant lesion, which proved to not be PDAC, and this included five lesions with low-grade dysplasia. This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in CDKN2A. This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.

Responses to immune checkpoint inhibition among MSI-H pancreatic ductal adenocarcinoma: A multi-institutional case series.

4145 Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death. Outcomes remain poor, due to irresectability at diagnosis for many and sub-optimal responses to systemic therapy. Cytotoxic chemotherapy remains the standard of care. High microsatellite instability (MSI-H) predicts response to immune checkpoint inhibition (ICI) in many cancers. Detecting high MSI is rare in PDAC (incidence &lt;2%), but case reports demonstrate potential therapeutic benefit with ICI. Here, we present multi-institutional data to characterize the clinical behavior of MSI-H PDAC, with special attention to response to ICI. Methods: Cases of MSI-H PDAC were obtained by reviewing data of all PDAC patients from our tertiary cancer center who had undergone genomic sequencing by one commercially available platform. The resulting cohort was supplemented with MSI-H PDAC cases identified by GI oncology specialists at multiple institutions. De-identified patient data were compiled and analyzed. Results: 15 MSI-H PDAC patients were identified. 20% had stage II disease at diagnosis, 27% stage III, and 53% stage IV. 73% of patients received ICI (n=11); 40% as 1st line and 33% as 2nd line. These patients demonstrated 100% overall response rate; 45% complete response (1 pathologic CR, 4 radiographic CR) and 55% partial response. No patient that received ICI had lost response or died after a median follow-up of 18 months (range 6-89 mos). 1 patient had oligoprogression of a single hepatic lesion after 7 mos that was then irradiated; this patient retained radiographic CR for 17 subsequent mos (ongoing). In this cohort, we observe poor responses to cytotoxic chemotherapy. In total, 12 regimens were trialed among 9 patients. Overall response rate was 0%. 42% achieved disease stability, with median duration of response of 2 mos; only 2 cases maintained disease stability for &gt;5 mos. 4 patients did not receive ICI; all patients died, with a median survival of 7.5 mos. Conclusions: MSI-H PDAC represents a rare but important subtype of PDAC with unique clinical behavior. Given its rarity, large-scale analyses and trials are unlikely to be performed, making case series such as ours crucial. In our cohort, we observe impressive, durable responses to ICI, along with very poor responses to cytotoxic chemotherapy. Our data argues for consideration of ICI in any patient presenting with MSI-H PDAC, including in the first-line and neoadjuvant settings.