Risk Of Pancreatic Cancer Research Articles

Occupational exposure to silica and risk of gastrointestinal cancers: a systematic review and meta-analysis of cohort studies.

Although silica is a proven lung carcinogen, there is no convincing evidence linking crystalline silica to gastrointestinal malignancies. We detailedly searched studies on the link between gastrointestinal malignancies and occupational silica exposure. Studies published between 1987 and 2023 were found by searching PubMed, Scopus, Cochrane Library, and Web of Science databases. Further studies were included from reference searching. We conducted a meta-analysis of the incidence and mortality of gastrointestinal malignancies and occupational silica exposure. We computed pooled-risk estimates using random effects models. Egger's regression asymmetry test and a funnel plot were used to identify publication bias. Moreover, sensitivity analysis and subgroup analysis were out. We identified 40 research with individuals from 13 different countries. The results indicate that occupational silica exposure raises the risk of gastric and esophageal cancer incidence, with pooled standardized incidence ratio of 1.35 (95% CI 1.21-1.51, p < 0.001), 1.31 (95% CI 1.04-1.65, p = 0.023), respectively, but there was a lack of statistically significant relationship between standardized mortality ratio. In addition, we found that silica exposure did not increase the risk of colorectal and pancreatic cancers. Occupational silica exposure was found to increase the risk of liver cancer, with pooled SIR and SMR of 1.19 (95% CI 1.04-1.35, p = 0.009), 1.24 (95% CI 1.03-1.49, p = 0.026), respectively. We discovered a link between occupational silica exposure and gastrointestinal malignancies, with cancers of the liver, stomach, and esophagus being the most prevalent. Colorectal and pancreatic cancer were not linked to occupational silica exposure.

Pro-Inflammatory Food, Gut Microbiota, and Cardiovascular and Pancreatic Diseases.

Recent studies have shown that a pro-inflammatory diet and dysbiosis, especially a high level of trimethylamine-N-oxide (TMAO), are associated with various adverse health conditions. Cardiovascular diseases and pancreatic diseases are two major morbidities in the modern world. Through this narrative review, we aimed to summarize the association between a pro-inflammatory diet, gut microbiota, and cardiovascular and pancreatic diseases, along with their underlying mechanisms. Our review revealed that TMAO is associated with the development of cardiovascular diseases by promoting platelet aggregation, atherosclerotic plaque formation, and vascular inflammation. TMAO is also associated with the development of acute pancreatitis. The pro-inflammatory diet is associated with an increased risk of pancreatic cancer and cardiovascular diseases through mechanisms that include increasing TMAO levels, activating the lipopolysaccharides cascade, and the direct pro-inflammatory effect of certain nutrients. Meanwhile, an anti-inflammatory diet decreases the risk of cardiovascular diseases and pancreatic cancer.

Long-term use of anti-cholesterol drugs and cancer risks in a Japanese population

Several studies have investigated the association between the use of anti-cholesterol drugs and cancer risks, of which results have been inconsistent. This study included 67,768 participants from the Japan Public Health Center-based Prospective Study. The data on anti-cholesterol drug use was collected using three questionnaires of the survey conducted every five years. We divided the participants into three groups according to the duration of the anti-cholesterol drug use. Multivariable-adjusted Cox proportional hazard regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). During the 893,009 person-years of follow-up from the 10-year follow-up survey, 8,775 participants (5,387 men and 3,388 women) were newly diagnosed with cancers. The duration of anti-cholesterol drug use was significantly associated with a decreased risk of liver cancer (HR:0.26, 95% CI 0.11–0.64 in > 5 y group) and with an increased risk of pancreatic cancer (HR:1.59, 95% CI 1.03–2.47 in > 5 y group). Moreover, a different trend was observed between men and women in the association with the risk of lung cancer. This study suggested that long-term use of anti-cholesterol drugs may have associations with a decreased incidence of liver cancer and with an increased incidence of pancreatic cancers.

GLP-1RA: no increased risk of pancreatic cancer

GLP-1RA: no increased risk of pancreatic cancer

The Causal Effects of Cholelithiasis on Acute Pancreatitis and Pancreatic Cancer: A Large Sample Size Mendelian Randomization Analysis.

The aim of two-sample Mendelian randomization (MR) with a large sample size was to explore the causal cholelithiasis impact on acute pancreatitis and pancreatic cancer. We performed the two-sample MR analysis with two models. Publicly available summary- level information for cholelithiasis was acquired from the Genome-Wide Summary Association Studies (GWAS) of FinnGen Biobank. The inverse variance weighted (IVW) method was the main method to obtain the MR estimates. Other methods were also used as supplementary methods, including MR-Egger, maximum likelihood, MR-Robust Adjusted Profile Score (MR-RAPS), weighted median, penalised weighted median method, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) method. After the selection of genetic instrumental variables (IVs), 11 single nucleotide polymorphisms (SNPs) (Model 1) and 22 SNPs (Model 2) were used to explore the effect of cholelithiasis on acute pancreatitis, and 10 SNPs (Model 1) and 24 SNPs (Model 2) on pancreatic cancer. The findings obtained by the fixed-effect IVW method with both Model 1 and Model 2 showed that genetically predicted cholelithiasis was significantly related to the elevated acute pancreatitis risk (Model 1: OR: 1.001, 95% CI: 1.000-1.002, p <0.001; Model 2: OR: 1.001, 95% CI: 1.000-1.002, p <0.001). Moreover, cholelithiasis would also raise the pancreatic cancer risk (Model 1: OR: 1.676, 95% CI: 1.228-2.288, p = 0.001; Model 2: OR: 1.432, 95% CI: 1.116-1.839, p = 0.005). Genetically predicted cholelithiasis was significantly related to the elevated risk of acute pancreatitis and pancreatic cancer. More attention should be paid to patients with cholelithiasis for the primary prevention of pancreatic-related diseases.

Fateful fat: Intra-pancreatic lipids cause pancreatic cancer

In a Mendelian randomization and prospective cohort study,1 intra-pancreatic fat increases the risk of pancreatic cancer. This provides persuasive human evidence of causal relation between lipids and cancer in the pancreas, which confirms a prediction of the PANDORA hypothesis.

A Clinical Prediction Model to Assess Risk for Pancreatic Cancer Among Patients With Acute Pancreatitis.

We aimed to develop and validate a prediction model as the first step in a sequential screening strategy to identify acute pancreatitis (AP) individuals at risk for pancreatic cancer (PC). We performed a population-based retrospective cohort study among individuals 40 years or older with a hospitalization for AP in the US Veterans Health Administration. For variable selection, we used least absolute shrinkage and selection operator regression with 10-fold cross-validation to identify a parsimonious logistic regression model for predicting the outcome, PC diagnosed within 2 years after AP. We evaluated model discrimination and calibration. Among 51,613 eligible study patients with AP, 801 individuals were diagnosed with PC within 2 years. The final model (area under the receiver operating curve, 0.70; 95% confidence interval, 0.67-0.73) included histories of gallstones, pancreatic cyst, alcohol use, smoking, and levels of bilirubin, triglycerides, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin. If the predicted risk threshold was set at 2% over 2 years, 20.3% of the AP population would undergo definitive screening, identifying nearly 50% of PC associated with AP. We developed a prediction model using widely available clinical factors to identify high-risk patients with PC-associated AP, the first step in a sequential screening strategy.

Major Stressful Life Events and the Risk of Pancreatic, Head and Neck Cancers: A Case-Control Study.

Major stressful life events have been shown to be associated with an increased risk of lung cancer, breast cancer and the development of various chronic illnesses. The stress response generated by our body results in a variety of physiological and metabolic changes which can affect the immune system and have been shown to be associated with tumor progression. In this study, we aim to determine if major stressful life events are associated with the incidence of head and neck or pancreatic cancer (HNPC). This is a matched case-control study. Cases (CAs) were HNPC patients diagnosed within the previous 12 months. Controls (COs) were patients without a prior history of malignancy. Basic demographic data information on major stressful life events was collected using the modified Holmes-Rahe stress scale. A total sample of 280 was needed (79 cases, 201 controls) to achieve at least 80% power to detect odds ratios (ORs) of 2.00 or higher at the 5% level of significance. From 1 January 2018 to 31 August 2021, 280 patients were enrolled (CA = 79, CO = 201) in this study. In a multivariable logistic regression analysis after controlling for potential confounding variables (including sex, age, race, education, marital status, smoking history), there was no difference between the lifetime prevalence of major stressful event in cases and controls. However, patients with HNPC were significantly more likely to report a major stressful life event within the preceding 5 years when compared to COs (p = 0.01, OR = 2.32, 95% CI, 1.18-4.54). Patients with head, neck and pancreatic cancers are significantly associated with having a major stressful life event within 5 years of their diagnosis. This study highlights the potential need to recognize stressful life events as risk factors for developing malignancies.

Cardiometabolic risk comorbidities in exocrine pancreatic insufficiency compared to patients with cancer: A single centered observational retrospective cohort study.

642 Background: Exocrine pancreatic insufficiency (EPI) is characterized by inadequate secretion of digestive enzymes. EPI is associated with increased risk for pancreatic cancer as well as increased risk for diabetes and consequently cardiometabolic (CM) risk equivalents. Emerging data suggest patients with cancer also have increased CM risk equivalents. To explore the cardiovascular risk associated with both EPI and cancer, we sought to describe and compare CM comorbidities and surrogates in patients with EPI vs cancer. Methods: A retrospective observational electronic chart analysis was done at Ochsner Health, Louisiana, spanning records from January 2017-2020 comparing two cohorts: patients with EPI (n=677) and patients with Cancer (n=1432). Results: The Cancer cohort was older (65.1 ± 11.9 yrs) than the EPI cohort (54.2 ± 17.6 yrs) (p &lt; 0.05). The Cancer cohort had higher AST levels (63.2 ± 106.2 U/L [nl 8-33 U/L] at start, 84.9 ± 447.3 U/L at end) vs the EPI cohort (50.2 ± 86.9 U/L at start, 65.4 ± 368.9 U/L at end) (p &lt; 0.05). The Cancer cohort also had higher ALT levels (69 ± 111.4 U/L (nl 7-55 U/L) at start, 58.5 ± 141.2 U/L at end) vs the EPI cohort (48.7 ± 79.5 U/L at start, 41.4 ± 100.3 U/L at end) (p &lt; 0.05). No significant differences were seen in Cancer cohort vs EPI cohort for A1c, TG, amylase, lipase, cholesterol, uric acid, tobacco/alcohol use, or blood pressure levels. Within the Cancer cohort, there was an increase in neuropathy (11% at the start vs 26.9% at end [p &lt; 0.05]), CHF (3.63% at the start vs 11.5% at end [p &lt; 0.05]), and HTN prevalence (29.9% at the start vs 66.1% at end [p &lt; 0.05]). Cancer patients also had decreased weight (175.2 ± 46.5 lbs at start, 163.8 ± 43.4 lbs at end [p &lt; 0.05]) and BMI (27.3 ± 6.5 at start, 25.7 ± 6.4 at end [p &lt; 0.05]). Among the general cancer cohort, no statistically different changes were seen in hypoglycemia, DKA, retinopathy, nephropathy, ESRD, dialysis, HLD, NAFLD, OSA, CAD, CVD, PAD, hyperuricemia, or gout prevalence over the period of observation or in comparison to EPI cohort. Conclusions: Patients in the Cancer cohort in this study have some indices of greater CM risk compared to those with EPI. Though older, they had significantly higher AST and ALT levels compared to EPI cohort. Over the 3 years of observation, cancer patients developed a statistically significant increase in neuropathy, CHF, and HTN prevalence, and decrease in weight and BMI. These changes may reflect consequent morbidity related both to natural disease progression and/or effects of cancer treatments such as chemotherapy.

Epidemiological characteristics of patients with pancreatic cancer with and without diabetes mellitus: A retrospective cohort study.

705 Background: Pancreatic cancer accounts for approximately 3% of new cancers diagnosed in the US and more than 8% of all cancer deaths. Despite the increasing incidence, there are few indicated screenings, mostly in patients with genetic mutations. Pancreatic cancer is associated with several risk factors including tobacco use, family history, heavy alcohol use, and diabetes mellitus (DM). In the US, more than 11% of adults have a diagnosis of diabetes and incidence is projected to rise over the coming years. Given the risk of DM associated with pancreatic cancer, establishing preventative measures, early intervention, and appropriate follow up for diabetic control could be an important step in decreasing the risk of pancreatic cancer. This study examines the demographic characteristics of patients with a diagnosis of pancreatic cancer with and without DM. Methods: We used the 2016-2019 Nationwide Inpatient Sample database, the largest all-payer inpatient care database in the US, to stratify all patients admitted with a diagnosis of pancreatic cancer, with and without DM, to further characterize their epidemiological characteristics. Results: Characteristics of patients with and without DM and pancreatic cancer are shown in the table. There were 150,275 patients diagnosed with pancreatic cancer, of which 44,170 (29%) had a concomitant diagnosis of DM. Of patients with both pancreatic cancer and DM, 53% were women (51% in patients without DM), 64% were white (70% in patients without diabetes), and 63% had Medicare for insurance (60% in patients without DM). Conclusions: Of patients with pancreatic cancer 29% had a concomitant diagnosis of DM(p=0.00). Epidemiological characteristics of patients with pancreatic cancers with and without DM such as age, sex, and insurance status were similar between both groups. However, there was a decreased percentage of Caucasian patients with pancreatic cancer and DM compared to those without DM. Given the association of diabetes with pancreatic cancer, and rising incidence of patients with diabetes in the US, emphasis on diabetes prevention and control may be an important factor in reducing the incidence pancreatic cancer. This study also suggests the need for further research to determine if there is utility in screening for pancreatic cancer in patients with diabetes to decrease the burden of pancreatic cancer in the US population.[Table: see text]

Abstract A015: Impact of healthy lifestyles and polygenic risk scores on pancreatic cancer risk: The Multiethnic Cohort Study

Abstract Background: Healthy lifestyles have been observed to reduce the risk of pancreatic cancer. However, it is unknown whether this protective impact varies among individuals with different levels of genetic susceptibility for pancreatic cancer. Methods: We investigated the association between healthy lifestyles, genetic risk, and pancreatic cancer incidence in 70,780 participants (32,783 males, 37,907 females) from the Multiethnic Cohort Study (MEC), a prospective cohort of White, African American, Native Hawaiian, Japanese American, and Latino men and women. We calculated a healthy lifestyle factor score (HLFS) based on smoking status, alcohol intake, body mass index and physical activity. We also estimated genetic risk using an established polygenic risk score (PRS) of 49 pancreatic cancer risk variants. Cox regression was used to assess the independent and joint associations of the HLFS (analyzed as quintiles) and PRS (analyzed as quintiles and high/low categories) with pancreatic cancer risk. Models were adjusted for age at blood draw, sex, race, family history of pancreatic cancer, and in the genetic analyses, the first ten principal components to account for population stratification. Results: The analytical cohort was comprised of 23,643 (33.4%) Japanese Americans, 16,816 (23.8%) Latinos, 14,305 (20.2%) Whites, 10,645 (15.0%) African Americans, and 5,371 (7.6%) Native Hawaiians. There were 721 incident cases of pancreatic cancer from an average follow-up period of 13.7 (SD 4.8) years. Higher levels of the PRS were associated with a 25-62% increase in pancreatic cancer risk, compared to the first PRS quintile. These elevated risks were borderline significant for quintile 2 (HR 1.25, 95% CI 0.97-1.61) and statistically significant for quintile 3 (HR 1.35, 95% CI 1.05-1.73), quintile 4 (HR 1.46, 95% CI 1.15-1.87), and quintile 5 (HR 1.62, 95% CI 1.27-2.06). For the HLFS, higher quintiles were associated with a 10-27% decreased risk of pancreatic cancer, compared to the lowest quintile, but this was only statistically significant for the highest quintile (HR 0.73, 95% CI 0.56-0.94). When evaluating the HLFS by levels of the PRS (low 0-50% vs. high 50-100%), the association between the highest HLFS quintile and pancreatic cancer was more pronounced among those in the high PRS group (HR 0.64, 95% CI 0.45-0.91), compared to those in the low PRS group (HR 0.80, 95% CI 0.55-1.18). However, this difference in effect by PRS levels was not statistically significant (p-interaction=0.43). Conclusions: Our study demonstrates that including information on healthy lifestyles and genetic risk may improve the risk stratification of pancreatic cancer for multiethnic populations. In addition, it is possible that healthy lifestyles could provide more benefit to individuals at higher genetic risk. Citation Format: Brian Huang, Adelynn Paik, David Bogumil, Fei Chen, Peggy Wan, Lynne Wilkens, Loic Le Marchand, David Conti, Christopher Haiman, Veronica Wendy Setiawan. Impact of healthy lifestyles and polygenic risk scores on pancreatic cancer risk: The Multiethnic Cohort Study [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 A015.

Abstract A009: Association between unstable diabetes mellitus and risk of pancreatic cancer

Abstract Worsening of hyperglycemia in people with pre-existing diabetes mellitus may be an indicator of undiagnosed pancreatic cancer. However, there is limited evidence from longitudinal studies regarding the association between deterioration of diabetes and pancreatic cancer in people with previously stable diabetes. The size of the association between deterioration of diabetes and pancreatic cancer, and how the association changes over time, needs further investigation. A population-based matched cohort study was conducted within Australian women with stable diabetes mellitus. Unstable diabetes, the exposure of interest, was defined as change in the type of antidiabetic medication or addition of another antidiabetic medication after at least 24 months of stable antidiabetic medication use. The date of exposure was defined as the index date. Each woman with unstable diabetes was matched to 4 women with stable diabetes by birth year (±1 year) at the index date. Flexible parametric survival models were used to estimate hazard ratios (HR) (overall and at different times) and 95% confidence intervals (CI), and absolute risk in both groups at different time points. We identified 134,954 women with unstable diabetes; these were matched to women who had not developed unstable diabetes at the index date. The mean age of the cohort was 68 years. Over a median follow-up period of 2.8 years, 1,315 pancreatic cancer cases were diagnosed. Overall, women who experienced deterioration in glycemic control had a 2.5-fold increased risk of developing pancreatic cancer (HR 2.55; 95% CI 2.29 – 2.85). The risk was very high during the initial few months [HRs at 3 months (5.76; 95% CI 4.72 – 7.04), 6 months (4.56; 95% CI 3.81 – 5.46), and 12 months (3.33; 95% CI 2.86 – 3.89)]. The risk then progressively declined with time. Worsening of glycemic control in those with previously stable diabetes may be an early clinical manifestation of pancreatic cancer. Further research is warranted to differentiate this pancreatic cancer-associated deterioration of glycemic control from other causes. The longer-term (3-7 years) weaker association between pancreatic cancer and deterioration of glycemic control suggests that poorly controlled hyperglycemia is a predisposing factor for pancreatic cancer. Citation Format: Sitwat Ali, Michael Coory, Peter Donovan, Renhua Na, Nirmala Pandeya, Sallie-Anne Pearson, Katrina Spilsbury, Louise Stewart, Bridie Thompson, Karen Tuesley, Mary Waterhouse, Penelope Webb, Susan Jordan, Rachel Neale. Association between unstable diabetes mellitus and risk of pancreatic cancer [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 A009.

Abstract B048: Targeting PPARG to block obesity-associated pancreatic cancer progression

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-related death in the United States and one of the few cancers for which incidence is increasing. This trend in increased incidence has been attributed in part to obesity. Obesity is associated with increased risk of pancreatic cancer and advanced disease stage in patients, concordant with rodent studies showing that obesity accelerates tumorigenesis and metastasis. Although studies have largely focused on the role of inflammation in obesity-associated pancreatic cancer, the cancer cell-autonomous mechanisms by which lipid availability in obesity impacts tumorigenesis remain quite poorly understood. Given the abundant evidence for dysregulated lipid metabolism in tumors, I hypothesized that cancer cells are primed to exploit exogenous lipids in obesity, accelerating disease progression. By mapping lipid-protein interactions in tumor and metastasis-enriched RNA-seq networks, I identified the nuclear hormone receptor PPARG as a potential mediator of obesity-associated lipid signaling in pancreatic cancer. PPARG is an attractive prospective mediator of obesity-associated PDA progression because it is a metabolic regulator activated by a broad set of lipid ligands, suggesting a dual role in lipid sensing and metabolic control. PPARG is also positioned at an interesting junction in PDA etiology; PPARG agonists are used to treat diabetes (a PDA risk factor) and have previously been studied for anti-cancer effects. However, PPARG agonists have seen little clinical success in and recent work has suggested that their use may even increase bladder cancer risk. PPARG is overexpressed in pancreatic tumors where it is associated with poor prognosis, further casting doubt on its anti-tumorigenic function. In my own studies, I found that PPARG agonists had no effect on tumor viability, while the PPARG antagonist T0070907 reduced organoid viability in vitro. Modeling the convergent effects of PPARG and obesity, I supplemented organoids with a mixture of lipids in the presence of PPARG antagonist and found that lipids boosted the viability of both tumor and metastatic organoids dependent on PPARG activity in vitro. These results suggest that PPARG can mediate the pro-tumorigenic function of exogenous lipids. As the incidence of both obesity and pancreatic cancer continue to rise, defining the role of PPARG in PDA could have significant implications for the development of new strategies to treat or prevent obesity-associated cancer. Citation Format: L. Paige Ferguson. Targeting PPARG to block obesity-associated pancreatic cancer progression [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 B048.

Tryptophan intake and pancreatic cancer: findings from a case-control study.

Pancreatic cancer is a leading cause of cancer-related death worldwide. Tryptophan plays a vital role in cell growth and maintenance as a building block of protein and coordination of organismal responses to environmental and dietary cues. Animal model study showed that dietary tryptophan improved treatment response in those who received chemotherapy or immune checkpoint inhibitors. Limited data are available assessing the association between tryptophan intake and risk of pancreatic cancer. We aimed to evaluate this association in a case-control study in Vietnam. We analyzed data from a case-control study, including 3759 cancer cases and 2995 control subjects of whom 37 with pancreatic cancer cases. Tryptophan intake was derived from food frequency questionnaire. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for different levels of tryptophan intake with pancreatic cancer risk. Overall, tryptophan intake was inversely associated with pancreatic cancer risk in a dose-dependent manner. The ORs and 95% CIs of pancreatic cancer were 0.51 (0.29-0.92) for continuous scale, 0.27 (0.10-0.73) for tertile 2 and 0.34 (0.11-1.06) for tertile 3, compared with tertile 1 (the lowest intake) ( Ptrend = 0.02). In stratified analysis, this inverse association pattern was present among those with BMI < 23 kg/m 2 and ever drinkers. A diet with a higher intake of tryptophan was significantly associated with a lower incidence of pancreatic cancer among Vietnamese population. These suggest that dietary modification may be an effective strategy for primary prevention of pancreatic cancer development.

Pancreatic Carcinoma: Exploring its Relationship with Diabetes and the Potential Chemopreventive Effects of Metformin

Objective: We aim to study the association between Pancreas cancer and Type2 Diabetes Mellitus and chemo-protective role of metformin. Method: We conducted a comprehensive systematic search for studies across various databases, including PubMed, Web of Science, Cochrane Library using the keywords “metformin” OR “biguanide” AND “pancreatic cancer” OR “pancreatic tumor” in “Title/ Abstract”AND “diabetes mellitus” was done. Result: An overall analysis of 18 articles by use of random effect model showed that compared with no use of metformin, the use of metformin could reduce the risk of pancreatic cancer in patients with type 2 diabetes. Conclusion: In this review, we delve into the intricate and symbiotic relationship between diabetes and PC (pancreatic cancer) by examining the fundamental mechanisms driving their coexistence. Utilizing metformin among individuals with diabetes appears to lower the risk of pancreatic cancer when compared to those who do not use metformin.

Abstract B013: A quest for deeper understanding of BRCA2 Variants of Uncertain Significance (VUS)

Abstract Deleterious mutations in homology-directed repair pathway genes impact both future cancer risk and therapeutic intervention options for cancer diagnosis and prognosis. Homology-directed repair pathway is a high-fidelity DNA repair pathway for resolving double-strand breaks (DSBs) throughout the human genome. BRCA2, as a homology-directed repair factor, is essential to ensure genome integrity through an error-free process. Deleterious BRCA2 mutations increase the lifetime risk of breast, ovarian, melanoma, prostate, and pancreatic cancers. Deleterious BRCA2 mutations cover only 25% of the total BRCA2 mutations identified in the population by genetic testing whereas 60% are mutations with unknown connection to the disease called Variants of Uncertain Significance (VUS). The majority of BRCA2 VUS are missense mutations with one point mutation which could potentially alter BRCA2 cellular localization and/or nuclear functions. Thus, evaluating BRCA2 cellular localization and function in BRCA2 missense carriers and tumors is urgently needed to provide clinical guidance regarding cancer risk and treatment options. We have identified a paradoxical relationship between BRCA2 nuclear import and treatment. Deleterious missense mutations in the DNA binding domain of BRCA2 direct the protein to the cytosol which increase sensitivity to PARP inhibitors (PARPi) and platinum drugs. Therefore, although BRCA2 mislocalization might be a cause of cancer, keeping it out of the nucleus allows for much better treatment outcomes. Here, we present how BRCA2 cancer-driver missense mutations lead to cytosolic mislocalization and how BRCA2 localization can be used as a diagnostic tool to stratify patients. Our robust multi-step molecular approach will guide future clinical decision rules surrounding BRCA2 VUS. By providing reliable and accurate functional assays to correctly evaluate the pathogenicity of BRCA2 VUS, our goal is to improve personalized medicine by providing actionable information to patients and their physicians. Citation Format: Cole Niedmann, Judit Jimenez Sainz. A quest for deeper understanding of BRCA2 Variants of Uncertain Significance (VUS) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B013.

Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes

Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Treatment with GLP-1RA was compared with basal insulin. Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. ClinicalTrials.gov Identifier: NCT02072902.

Cancer mortality and morbidity among patients with schizophrenia: A hospital-based cohort study, 1992-2020.

Due to the inconsistency of the evidence about the cancer risk among patients with schizophrenia, the aim of this study was to analyse cancer mortality and morbidity in patients with schizophrenia treated in a single centre in Lithuania during the study period of 1992-2020. A retrospective cohort study was conducted in Vilnius Republican Psychiatric Hospital, the biggest specialised psychiatric hospital in Lithuania, with approximately 5000 hospital admissions annually. The patients' cohort was established by identifying all patients with the diagnosis of schizophrenia (ICD-10 code F20) in the hospital database from 1 January 1992 until 31 December 2017. The cancer cases and cancer deaths in the cohort were identified in the Lithuanian Cancer Register through linkage procedures. The analysis of risk was based on a comparison of observed and expected numbers of cancers and deaths. Expected number of cancer cases were calculated by multiplication of the exact person-years under observation in the cohort by sex, calendar year and a 5-year age-group-specific national incidence and mortality rate. All statistical analyses were carried out using STATA 15 statistical software. During the follow-up, out of 8553 patients, 673 cases of cancer were diagnosed in both sexes. Statistically significantly lower risk for overall cancer incidence was observed in men (SIR 0.74, 95% CI 0.66-0.83), but not in women (SIR 1.07, 95% CI 0.97-1.18). Statistically significant lower overall cancer mortality risk was observed in men (SMR 0.82, 95% CI 0.70-0.96), while in the women's group, risk of cancer deaths was significantly higher compared to the general population (SMR 1.28, 95% CI 1.11-1.48). We observed lower risk for pancreatic cancer (SIR 0.36, 95% CI 0.14-0.96), non-melanoma skin cancer (SIR 0.54, 95% CI 0.33-0.88) and prostate cancer (SIR 0.69, 95% CI 0.55-0.87) in men and higher risk for malignant neoplasm of liver (SIR 2.58, 95% CI 1.53-4.36) and skin melanoma (SIR 2.03, 95% CI 1.12-3.66) in men and for breast cancer (SIR 1.38, 95% CI 1.14-1.66) and corpus uteri cancer (SIR 1.56, 95% CI 1.18-2.07) in women. The current results of our study indicate lower risk of overall cancer incidence and mortality in male patients with schizophrenia, while female patients had a higher mortality risk, alongside variations in the risk of different cancer types. This information is important not only for patients, but for healthcare specialists to develop effective disease-specific preventive interventions and programmes.

Risk of Pancreatic Cancer After Acute Pancreatitis: A Retrospective Analysis of the Korean National Sample Cohort.

Acute pancreatitis may increase the risk of pancreatic cancer, although this association remains unclear. Therefore, we aimed to investigate this association. We retrospectively analyzed the 2002-2019 Korean National Health Insurance Service-National Sample Cohort using 1:3 propensity score matching for sex and age (acute pancreatitis, n = 4,494; matched controls, n = 13,482). We calculated the hazard ratio (HR) for pancreatic cancer risk in patients with acute pancreatitis using Cox proportional hazards regression. Acute pancreatitis was significantly associated with an increased risk of pancreatic cancer throughout the study period (adjusted HR, 7.56 [95% confidence interval, 5.00-11.41]), which persisted for 2, 2-5, and > 5 years post-diagnosis (19.11 [9.60-38.05], 3.46 [1.35-8.33], and 2.73 [1.21-6.15], respectively). This pancreatitis-related pancreatic cancer risk became insignificant beyond 10 years of follow-up (1.24 [0.24-6.49]). Furthermore, this risk notably increased as the number of recurrent acute pancreatitis episodes increased (1 episode: 5.25 [3.31-8.33], 2 episodes: 11.35 [6.38-20.19], ≥ 3 episodes: 24.58 [13.66-44.26]). Following an acute pancreatitis diagnosis, the risk of pancreatic cancer increases significantly in the initial years, with a rapid increase further accentuated with recurrent acute pancreatitis episodes. Additional study is needed to evaluate whether this increased risk of carcinogenesis is attributed to accumulated inflammation.

Gut microbiota and pancreatic cancer risk, and the mediating role of immune cells and inflammatory cytokines: a Mendelian randomization study.

Gut microbiota (GM) influences the occurrence and development of pancreatic cancer (PC), potentially through the involvement of inflammatory cytokines (IC) and immune cells (IM). We aimed to investigate the causal impact of the gut microbiota (GM) on pancreatic cancer (PC) and identify potential IC and IM mediators. The summary statistics data from whole-genome association studies of gut microbiota, immune cells, inflammatory cytokines, and four types of pancreatic tumors (MNP: Malignant neoplasm of pancreas; BNP: Benign neoplasm of pancreas; ADCP: Adenocarcinoma and ductal carcinoma of pancreas; NTCP: Neuroendocrine tumor and carcinoma of pancreas). Two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis were employed to assess the causal relationship between gut microbiota (GM) and pancreatic cancer (PC), as well as potential IC and IM mediators. The two-sample UVMR analysis showed causal relationships between 20 gut microbiota species and pancreatic cancer, with pancreatic cancer affecting the abundance of 37 gut microbiota species. Mediation analysis revealed that Interleukin-6 (IL-6), "CD4 on naive CD4+ T cell" and "SSC-A on HLA DR+ Natural Killer" mediated the causal effects of gut microbiota on pancreatic cancer. This Mendelian randomization study demonstrates causal relationships between several specific gut microbiota and pancreatic cancer, as well as potential mediators (IC, IM).