Risk Of Biliary Tract Cancer Research Articles

BN SO24 - Predicting incidental gallbladder cancer: A protocol for identifying predictive factors of incidentally detected gallbladder cancer and prospective validation of a scoring system to allow selective histological analysis of the gallbladder

Abstract Background Incidental Gallbladder Cancer (iGBC) is a rare complication of cholecystectomy, with a UK incidence of 0.14-0.3%. Despite its rarity, most gallbladder specimens are analysed histologically. Some comparable countries undertake Selective Histological Analysis (SHA), selecting high-risk specimens for histology based on clinical judgement or postoperative inspection. However, evidence suggests a third of diagnoses can be missed with these approaches. Swedish and Dutch diagnostic scores incorporate few risk factors and are not generalisable to the UK. We present a protocol for a UK study aiming to develop a detailed diagnostic score for iGBC to reliably stratify patients by their risk of iGBC. Method This UK multicentre, cross-sectional, trainee-led study includes adult patients undergoing cholecystectomy for benign indications. It incorporates a feasibility study and an adaptive design, and has been submitted for ethical review. A parallel qualitative study will explore attitudes towards the risk of iGBC and the acceptability of SHA among patients and healthcare professionals. The feasibility phase will include 500 patients over six months, collecting data on patient risk factors for iGBC, preoperative investigations, operative findings, and histology results. Exclusion criteria include cholecystectomy as a secondary procedure, polyps over 5mm, and conditions known to increase the risk of biliary tract cancers. Results Following the feasibility phase, the recruitment rate and data completeness will be evaluated. Outcomes will be assessed against anticipated values, and collaborators will be surveyed to identify challenges with data collection. Necessary adjustments to the electronic case record form or overall protocol will be made, and the recruitment target will be recalculated based on an updated sample size calculation. When the study meets specified progression criteria, additional sites will be recruited, and data collection will continue to meet the required sample size. A detailed statistical analysis plan will be provided at a later date. Conclusion This protocol describes a UK diagnostic modelling study aimed at developing a risk-stratification score for iGBC in patients undergoing routine cholecystectomy, identifying high-risk patients and facilitating SHA.

Associations between pre-diagnostic plasma metabolites and biliary tract cancer risk in the prospective UK Biobank cohort.

Biliary tract cancer (BTC) is potentially influenced by metabolic dysregulation yet previous metabolomic evaluations are limited. To address this gap, we prospectively investigated associations of blood metabolites and BTC risk in the UK biobank cohort study. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between 249 plasma metabolites per standard deviation and BTC risk in 232,781 participants. We implemented exploratory factor analyses and evaluated associations between factors and BTC risk. Associations at p-value<0.001 were considered statistically significant after multiple comparison adjustments. In a median follow-up of 11.8 years, we identified 268 first primary incident BTC cases. Of 49 biomarkers significantly associated with BTC risk, 12% were fatty acids, and 49%, 31%, and 8% were cholesterol, triglyceride, and phospholipid to total lipids ratios, respectively. Multiple cholesterol ratios were inversely associated with BTC with HRs (95% CIs) of 0.74 (0.65-0.84), p<6.0x10-6. Conversely, a triglyceride ratio was positively associated with BTC with an HR (95% CI) of 1.40 (1.22-1.61), p=2.5x10-6. Congruently, a factor high in cholesterol measures and low in triglyceride measures was inversely associated with BTC. Multiple metabolite biomarkers were associated with BTC risk, suggesting metabolism has a substantial role in BTC etiology.

Interplay of Cardiometabolic Syndrome and Biliary Tract Cancer: A Comprehensive Analysis with Gender-Specific Insights.

BTC overall incidence is globally increasing. CCA, including its subtypes, is a form of BTC. MetS, obesity, MASLD, and diabetes are all linked to CCA in interconnected ways. The link between obesity and CCA is less well-defined in Eastern countries as compared to Western. Although more research is needed to determine the relationship between MASLD and extrahepatic CCA (eCCA), MASLD may be a concurrent risk factor for intrahepatic CCA, particularly in populations with established or unidentified underlying liver disease. Interestingly, the risk of biliary tract cancer (BTC) seemed to be higher in patients with shorter diabetes durations who were not treated with insulin. Therefore, early detection and prevention of chronic liver disease, as well as additional intervention studies, will undoubtedly be required to determine whether improvements to MetS, weight loss, and diabetes therapy can reduce the risk and progression of BTC. However, further studies are needed to understand how reproductive hormones are involved in causing BTC and to develop consistent treatment for patients. Finally, it is critical to carefully assess the cardiological risk in BTC patients due to their increased intrinsic cardiovascular risk, putting them at risk for thrombotic complications, cardiovascular death, cardiac metastasis, and nonbacterial thrombotic endocarditis. This review aimed to provide an updated summary of the relation between the abovementioned cardio-metabolic conditions and BTC.

Immune cells mediate the causal pathway linking circulating complements to cancer: A Mendelian randomization study.

The role of complement in cancer remains controversial. Whether immune cells and inflammatory factors mediate the pathway from complement to cancer has not been fully elucidated. We conducted bidirectional Mendelian randomization (MR) analysis to explore the causal association between complement components and cancer. Meta-analysis was conducted to enhance the robustness of the results. We further explored the mediation roles of immune cells and inflammatory factors in these associations. Our study identified causal associations between 11 complement components and 12 types of cancer. Furthermore, we identified five immune cells as potential mediators: BAFF-R on IgD + CD38- naive B cell mediated 7.434% of the increased risk for liver cancer from C3; CD4 on CD39 + activated CD4 regulatory T cell mediated 12.384% of the increased risk for biliary tract cancer from CD93; CD25 + + CD45RA + CD4 not regulatory T cell and Basophil %CD33dim HLA DR- CD66b- mediated 7.721% and 7.986% of the increased risk of colorectal cancer from MASP1, respectively; CD45RA on resting CD4 regulatory T cell mediated 11.444% of the increased risk of skin cancer from MASP1. This study revealed the causal relationships between complement components and certain cancers, with five immune cells as potential mediators.

N-glycan signatures identified in the serum from biliary tract cancer patients: Association with clinical diagnosis and prognosis.

Changes in the expression of genes related to glycosyltransferases may lead to alterations in N-glycan structure abundance, potentially acting as markers for diagnosis and prognosis in biliary tract cancer (BTC). This study was divided into cross-sectional and longitudinal approaches. The cross-sectional study included 316 BTC and 301 non-BTC. Propensity score matching was applied to adjust for sex and age differences between BTC and non-BTC. Univariate and multivariate logistic regression identified independent risk factors for BTC and constructed the BTC-G model. The ROC curve was used to validate the diagnostic performance of BTC-G. Longitudinal follow-up studies included postoperative (N = 50) and immunotherapy (N = 43) follow-up cohorts. Cox regression analysis identified N-glycan structures impacting BTC prognosis postoperative and immunotherapy, with further confirmation through Kaplan-Meier curves. Univariate and multivariate analyses identified Peak3 (OR: 0.790, 95% CI: 0.658-0.949), Peak9 (OR: 1.646, 95% CI: 1.409-1.922), and Peak9p (OR: 2.467, 95% CI: 1.267-4.804) as independent BTC risk factors, leading to the creation of the BTC-G. The ROC curve confirmed that BTC-G performed well in training (AUC: 0.753, 95% CI: 0.703-0.799), validation (AUC: 0.811, 95% CI: 0.740-0.870), and CA19-9 negative cohorts (AUC: 0.717, 95% CI: 0.664-0.767). Cox regression analysis and Kaplan-Meier curves established that Peak12 (HR: 5.578, 95% CI: 1.145-27.170) and Peak11 (HR: 1.104, 95% CI: 0.611-1.994) are independent risk factors for BTC prognosis following surgery and immunotherapy, respectively. Our NGFP technology supplements BTC diagnostics, distinguishing survival and recurrence subtypes for postoperative and immunotherapy, thereby supporting the development of treatment strategies.

Causal relationship between immune cell phenotypes and risk of biliary tract cancer: evidence from Mendelian randomization analysis.

Biliary tract cancer stands as a prevalent illness, posing significant risks to human health, where immune cells are pivotal in both its development and recovery processes. Due to the diverse functionalities exhibited by different immune cell phenotypes within the organism, and the relatively limited research on their relationship with biliary tract cancer, this study employed Mendelian randomization (MR) to explore their potential association, thereby aiding in a better understanding of the causal link between immune cell phenotypes and biliary tract cancer. In this study, the causative association of 731 immunophenotype with biliary tract cancer was established using publicly accessible genome-wide association study (GWAS) genetic data through two-sample MR analysis. Sensitivity analyses assess horizontal pleiotropy and heterogeneity of the study findings. Among the 731 immunophenotypes examined, a total of 26 immune cell phenotypes were found to exhibit positive results, indicating a significant association with the risk of biliary tract cancer. We confirmed that among these 26 types of immune cells, there are primarily 13 types of B cells; three types of classical dendritic cells (CDCs), including CD80 on myeloid DC, HLA DR on myeloid DC, and Myeloid DC %DC; one type of mature stage T cell,CD4RA on TD CD4+; six types of regulatory T cells; and three types of myeloid cells.

Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis.

People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.

Dietary intake, obesity, and physical activity in association with biliary tract cancer risk: Results from meta-analyses of individual-level data from prospective cohort studies of 723,326 adults.

Biliary tract cancer (BTC) is a rare and aggressive malignancy with increasing incidence. Most BTC cases are diagnosed with metastatic disease which carries a 5-year survival rate of <5%. Physical activity, diet, and obesity might be associated with BTC risk, but studies have been limited particularly in African descendants. We addressed this knowledge gap by evaluating associations of BTC risk with obesity, physical activity, and dietary intakes in 723,326 adult participants in four cohort studies conducted in China, the United Kingdom, and the United States. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) in each cohort; results were combined using meta-analysis. All cohorts had ≥11 median follow-up years with 839 incident BTC cases combined. BTC risk was positively associated with body mass index (BMI) and waist-to-hip ratio (WHR) whereas physical activity, fruit intake, and fish intake were inversely associated. HR and (95% CI) comparing BMI >35.0 to 18.5-24.9: 1.71 (1.26, 2.31), p-trend <.0001; comparing BMI-adjusted WHR top to bottom quartile: 1.20 (0.94, 1.53), p-trend = .05; comparing ≥15-0 metabolic equivalent task-hours/week 0.76 (0.61, 0.94), p-trend = .009; comparing highest to lowest intake tertile for fruit and fish 0.79 (0.66, 0.95), p-trend = .01; 0.82 (0.68, 0.98), p-trend = .04, respectively. Associations were, in general, similar across ancestry groups. Our study provides strong evidence for important roles of obesity, diet, and physical activity in BTC etiology and stresses the need for lifestyle modification to combat the rising incidence of this fatal malignancy.

The effect of metabolism-related lifestyle and clinical risk factors on digestive system cancers in East Asian populations: a two-sample Mendelian randomization analysis

Metabolic factors play a critical role in the development of digestive system cancers (DSCs), and East Asia has the highest incidence of malignant tumors in the digestive system. We performed a two-sample Mendelian randomization analysis to explore the associations between 19 metabolism-related lifestyle and clinical risk factors and DSCs, including esophageal, gastric, colorectal, hepatocellular, biliary tract, and pancreatic cancer. The causal association was explored for all combinations of each risk factor and each DSC. We gathered information on the instrumental variables (IVs) from various sources and retrieved outcome information from Biobank Japan (BBJ). The data were all from studies of east Asian populations. Finally, 17,572 DSCs cases and 195,745 controls were included. Our analysis found that genetically predicted alcohol drinking was a strong indicator of gastric cancer (odds ratio (OR) = 0.95; 95% confidence interval (CI): 0.93–0.98) and hepatocellular carcinoma (OR = 1.11; 95% CI: 1.05–1.18), whereas coffee consumption had a potential protective effect on hepatocellular carcinoma (OR = 0.69; 95% CI: 0.53–0.90). Triglyceride was potentially associated with a decreased risk of biliary tract cancer (OR = 0.53; 95% CI: 0.34–0.81), and uric acid was associated with pancreatic cancer risk (OR = 0.59; 95% CI: 0.37–0.96). Metabolic syndrome (MetS) was associated with esophageal and gastric cancer. Additionally, there was no evidence for a causal association between other risk factors, including body mass index, waist circumference, waist-to-hip ratio, educational levels, lipoprotein cholesterol, total cholesterol, glycine, creatinine, gout, and Graves’ disease, and DSCs. The leave-one-out analysis revealed that the single nucleotide polymorphism (SNP) rs671 from the ALDH2 gene has a disproportionately high contribution to the causal association between alcohol drinking and gastric cancer and hepatocellular carcinoma, as well as the association between coffee consumption and hepatocellular carcinoma. The present study revealed multiple metabolism-related lifestyle and clinical risk factors and a valuable SNP rs671 for DSCs, highlighting the significance of metabolic factors in both the prevention and treatment of DSCs.

Protective effect of higher free thyroxine levels within the reference range on biliary tract cancer risk: a multivariable mendelian randomization and mediation analysis.

Hepatobiliary cancer (HBC), including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is currently one of the malignant tumors that mainly cause human death. Many HBCs are diagnosed in the late stage, which increases the disease burden, indicating that effective prevention strategies and identification of risk factors are urgent. Many studies have reported the role of thyroid hormones on HBC. Our research aims to assess the causal effects and investigate the mediation effects between thyroid function and HBC. Utilizing the Mendelian randomization (MR) approach, the study employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to explore causal links between thyroid function [free thyroxine (FT4), thyroid stimulating hormone (TSH), hyperthyroidism and hypothyroidism] and HBC. Data were sourced from the ThyroidOmic consortium and FinnGen consortium. The analysis included univariable and multivariable MR analysis, followed by mediation analysis. The study found a significant causal association between high FT4 levels and the reduced risk of BTC, but not HCC. However, TSH, hyperthyroidism and hypothyroidism had no causal associations with the risk of HBC. Notably, we also demonstrated that only higher FT4 levels with the reference range (FT4-RR) could reduce the risk of BTC because this protective effect no longer existed under the conditions of hyperthyroidism or hypothyroidism. Finally, we found that the protective effect of FT4-RR on BTC was mediated partially by decreasing the risk of metabolic syndrome (MetS) and reducing the waist circumference (WC). The findings suggest that higher FT4-RR may have a protective effect against BTC, which is partially mediated by decreased risk of MetS and a reduction in WC. This study highlights the potential role of FT4 in the pathogenesis of BTC and underscores that MetS and WC may play mediation effects as two mediators in this process.

Exploring the association between acute pancreatitis and biliary tract cancer: A large-scale population-based matched cohort study.

Biliary tract cancer (BTC) often goes undetected until its advanced stages, resulting in a poor prognosis. Given the anatomical closeness of the gallbladder and bile ducts to the pancreas, the inflammatory processes triggered by acute pancreatitis might increase the risk of BTC. To assess the association between acute pancreatitis and the risk of BTC. Using the Swedish Pancreatitis Cohort (SwePan), we compared the BTC risk in patients with a first-time episode of acute pancreatitis during 1990-2018 to a 1:10 matched pancreatitis-free control group. Multivariable Cox regression models, stratified by follow-up duration, were used to calculate hazard ratios (HRs), adjusting for socioeconomic factors, alcohol use, and comorbidities. BTC developed in 0.94% of 85,027 acute pancreatitis patients and in 0.23% of 814,993 controls. The BTC risk notably increased within 3months of hospital discharge (HR 82.63; 95% CI: 63.07-108.26) and remained elevated beyond 10years of follow-up (HR 1.82; 95% CI: 1.35-2.47). However, the long-term risk of BTC subtypes did not increase with anatomical proximity to the pancreas, with a null association for gallbladder and extrahepatic tumors. Importantly, patients with acute pancreatitis had a higher occurrence of early-stage BTC within 2years of hospital discharge than controls (13.0 vs. 3.6%; p-value <0.01). Our nationwide study found an elevated BTC risk in acute pancreatitis patients; however, the risk estimates for BTC subtypes were inconsistent, thereby questioning the causality of the association. Importantly, the amplified detection of early-stage BTC within 2years after a diagnosis of acute pancreatitis underscores the necessity for proactive BTC surveillance in these patients.

Abstract 3465: Association with total reproductive year and the risk of biliary tract cancer in women

Abstract Background: Many studies have reported that female reproductive factors, such as parity, age at menarche or menopause, breastfeeding, or age at first birth, were associated with or not associated with the development of biliary tract cancer (BTC). Our study was planned to determine whether a long-term rather than transient exposure was associated with the risk of BTC, including total reproductive year, which was defined as the time from menarche to menopause throughout the life cycle. Methods: This nationwide cohort study included 1,059,533 women with natural menopausal women aged 40-69 years who underwent the periodic health check-up provided by the Korean National Health Insurance System in 2009. The median follow-up period was 9.3 years. Cox proportional hazard regression analysis was performed to estimate the risk of BTC based on the female reproductive factors. Results: During the 9,867,152 person-years of follow-up, 4,198 patients (0.4%) were newly diagnosed with BTC. The incidence of BTC was significantly increased in subjects younger than 40 years at menopause compared with those aged 40 years or older (HR 1.341, 95% CI, 1.095-1.642). This trend was consistent even when menopause age was subdivided into 5-year intervals (&amp;lt;40 vs. 40−44, 45−49, 50-54, and ≥ 55 years) for those aged 40 years or older. When compared by categorization into four quartiles, the incidence of BTC tended to be numerically lower than that of the bottom 25% with the lowest age of menopause (designated as Q1 reference group). Compared to those with total reproductive year of 30 years or more, the incidence of BTC increased significantly in the group with less than 30 years of total reproductive year (HR 1.106, 95% CI, 1.014-1.206). This tendency was significantly reproduced in comparison by categorizing the entire group into quartiles. Compared to the lower 25% group (designated as Q1 reference group), the risk of BTC showed a significant linear inverse correlation with the longer total reproductive year. Q1 group has significantly higher incidence of BTC compared to the other groups (p &amp;lt; 0.001). This trend was repeated in various subgroup analysis. Conclusions: In conclusion, this study demonstrated that women under the age of 40 at menopause had an increased risk of BTC compared to those over 40 years of age. Similarly, a longer period of total reproductive year was associated with a lower risk of BTC, suggesting a protective female hormonal effect on BTC. Total reproductive year may be more reliable indicator in that it reflects the actual lifetime exposure to female hormones. Citation Format: Chi Hoon Maeng, Kyungdo Han, Joo-Hyun Park, Jung Yong Hong. Association with total reproductive year and the risk of biliary tract cancer in women [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 3465.

Abstract 4442: Associations between pre-diagnostic plasma metabolites and biliary tract cancer risk in the prospective UK Biobank cohort

Abstract Background Annually, approximately 200,000 people are diagnosed with biliary tract cancer (BTC). Most present with metastatic disease which encompasses a 5-year survival rate of &amp;lt;5%. Etiology is poorly understood though some studies suggest metabolic dysregulation may contribute to development. Previous evaluations of metabolites and BTC risk have primarily been limited to case-control studies, few metabolites, or post-diagnostic blood samples. Methods We evaluated 248,285 adult participants with metabolite data in the UK Biobank, a prospective cohort study. Participants were excluded (6.2%) primarily due to a baseline history of cancer. To reduce potential influences of reverse causation, those who developed cancer or died within one year after baseline blood collection were also removed. Metabolites were trimmed to two standard deviations, log-transformed (ln[x+0.5]), z-scored, and evenly divided into tertiles. Cox proportional hazards regression was implemented to evaluate associations of BTC risk per 1-standard deviation (SD) and across tertiles with hazard ratios (HR) and 95% confidence intervals (95% CI). Models were adjusted for age, sex, education, income, fasting time, and statin use. A p-value of 0.001 was considered statistically significant after multiple comparison adjustment (0.05 divided by 50, the number of independent tests). Results The analyzed cohort includes 232,781 UKB participants with a median age of 58, a median follow-up time of 11.8 years, and 268 first primary incident BTC cases. Multiple metabolites were significantly associated with BTC risk using continuous variables (per 1-SD increment). High triglyceride to total lipid ratios were associated with higher BTC risk, and the strongest association was for intermediate-density lipoproteins (the HR (95% CI) was 1.33 (1.15-1.54), p=0.0001). On the other hand, high cholesterol to total lipid ratios were associated with lower BTC risk, and the strongest association was for the free cholesterol to total lipids in small very-low-density lipoproteins (VLDL) (0.76 (0.66-0.88), p =0.0002). High glutamine was associated with lower BTC risk (0.68 (0.69-0.89), p =0.0003) as was the phospholipid to total lipid ratio in small VLDL (0.75 (0.65-0.87), p =0.0002). Analysis by tertile identified additional significant associations, including a higher polyunsaturated fatty acid to total fatty acid ratio being associated with lower BTC risk (the HR (95% CI) comparing the highest to lowest tertile, 0.50 (0.35-0.71), p-trend=0.0001). Notably, within polyunsaturated fatty acids, a higher omega-6 to omega-3 ratio trended toward higher risk (1.32 (0.94-1.85), p-trend=0.11). Conclusion These findings indicate circulating metabolites may be biomarkers for BTC and suggest that triglycerides, cholesterols, fatty acids, phospholipids, and glutamine may be involved in BTC etiology. Citation Format: Valerie Gunchick, Guochong Gia, Wei Zheng. Associations between pre-diagnostic plasma metabolites and biliary tract cancer risk in the prospective UK Biobank cohort [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 4442.

The causal relationship between gut microbiota and biliary tract cancer: comprehensive bidirectional Mendelian randomization analysis.

Growing evidence has shown that gut microbiome composition is associated with Biliary tract cancer (BTC), but the causality remains unknown. This study aimed to explore the causal relationship between gut microbiota and BTC, conduct an appraisal of the gut microbiome's utility in facilitating the early diagnosis of BTC. We acquired the summary data for Genome-wide Association Studies (GWAS) pertaining to BTC (418 cases and 159,201 controls) from the Biobank Japan (BBJ) database. Additionally, the GWAS summary data relevant to gut microbiota (N = 18,340) were sourced from the MiBioGen consortium. The primary methodology employed for the analysis consisted of Inverse Variance Weighting (IVW). Evaluations for sensitivity were carried out through the utilization of multiple statistical techniques, encompassing Cochrane's Q test, the MR-Egger intercept evaluation, the global test of MR-PRESSO, and a leave-one-out methodological analysis. Ultimately, a reverse Mendelian Randomization analysis was conducted to assess the potential for reciprocal causality. The outcomes derived from IVW substantiated that the presence of Family Streptococcaceae (OR = 0.44, P = 0.034), Family Veillonellaceae (OR = 0.46, P = 0.018), and Genus Dorea (OR = 0.29, P = 0.041) exerted a protective influence against BTC. Conversely, Class Lentisphaeria (OR = 2.21, P = 0.017), Genus Lachnospiraceae FCS020 Group (OR = 2.30, P = 0.013), and Order Victivallales (OR = 2.21, P = 0.017) were associated with an adverse impact. To assess any reverse causal effect, we used BTC as the exposure and the gut microbiota as the outcome, and this analysis revealed associations between BTC and five different types of gut microbiota. The sensitivity analysis disclosed an absence of empirical indicators for either heterogeneity or pleiotropy. This investigation represents the inaugural identification of indicative data supporting either beneficial or detrimental causal relationships between gut microbiota and the risk of BTC, as determined through the utilization of MR methodologies. These outcomes could hold significance for the formulation of individualized therapeutic strategies aimed at BTC prevention and survival enhancement.

Can NPC1L1 inhibitors reduce the risk of biliary tract cancer? Evidence from a mendelian randomization study

Background & AimsOxysterols have been implicated in biliary tract cancer (BTC), and Niemann-Pick C1–like 1 (NPC1L1) has been associated with oxysterol uptake in biliary and intestinal cells. Thus, our study aims to investigate the potential causal link between genetically proxied NPC1L1 inhibitors and the risk of BTC. MethodsIn this study, we employed two genetic instruments as proxies for NPC1L1 inhibitors, which included LDL cholesterol-associated genetic variants located within or in close proximity to the NPC1L1 gene, as well as expression quantitative trait loci (eQTLs) of the NPC1L1 gene. Effect estimates were calculated using the Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) methods. ResultsIn MR analysis using the IVW method, both proxy instruments from the UK Biobank and the GLGC demonstrated a positive association between NPC1L1-mediated LDL cholesterol and BTC risk, with odds ratios (OR) of 10.30 (95% CI = 1.51–70.09; P = 0.017) and 5.61 (95% CI = 1.43–21.91; P = 0.013), respectively. Moreover, SMR analysis revealed a significant association between elevated NPC1L1 expression and increased BTC risk (OR = 1.19, 95% CI = 1.04–1.37; P = 0.014). ConclusionsThis MR study suggests a causal link between NPC1L1 inhibition and reduced BTC risk. NPC1L1 inhibitors, like ezetimibe, show potential for chemoprevention in precancerous BTC patients, requiring further clinical investigation.

Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts.

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.

Effects of Metformin on Prevention and Treatment of Biliary Tract Cancer: A Meta-analysis of Observational Studies

Background and objectivesDiabetes mellitus (DM) is an established risk for biliary tract cancer (BTC). Metformin, an anti-diabetes medication, has been reported for its association with a reduced risk of BTC. However, the controversy about metformin’s benefit among epidemiological studies is unresolved. This study is to investigate metformin’s effects on the development and progression of BTC.

Abstract 3026: Dietary intakes and biliary tract cancer risk: Results from cohort studies including 638,860 Chinese and European adults

Abstract IntroductionBiliary tract cancer (BTC) is an uncommon, aggressive malignancy with an untreated median overall survival of 2.5-4.5 months for advanced disease. Incidence varies geographically and is generally highest in parts of Asia and South America and lowest in Western countries. Previous dietary risk evaluations have primarily been limited case-control studies with small sample sizes.ObjectiveHere, we prospectively evaluate associations of dietary intakes, BMI, abdominal fat, and physical activity with BTC risk in three cohort studies in two countries, the largest such assessment reported in literature.Methods/Study PopulationWe evaluated 638,816 adults in China and the United Kingdom enrolled in the Shanghai Women’s Health Study (SWHS), Shanghai Men’s Health Study (SMHS), or UK Biobank (UKB). Dietary intake and physical activity information was obtained from study participants at baseline using food frequency and physical activity questionnaires, respectively. All have been validated for these evaluations. Dietary intakes of major food groups were divided into low, middle, and high intake tertiles. BMI was divided by standard cut-offs, and WHR and leisure-time physical activity (measured using MET hours/week) were split into quartiles. Cox regression was used to estimate hazard ratios and 95% confidence intervals for BTC risk in all cohorts. Participants were excluded due to a prior history of cancer, CHD, or stroke at baseline, developing cancer or dying within one year after enrollment, developing cancer after the censor date in UKB, or having extreme energy intakes in SWHS-SMHS.ResultsThe analyzed cohort includes 569,303 participants: 66,944 SWHS, 55,738 SMHS, and 446,621 UKB participants with median enrollment ages of 49, 52, and 57 years old and median follow-up times of 18.1, 12.3, and 11.0 years, respectively. The SWHS observed 206 eligible BTC cases, SMHS 97, and UKB 436. SWHS and SMHS participants were combined for dietary evaluation and the highest tertile of fruit intake showed an inverse association with BTC risk when compared to the lowest tertile: HR (95% CI) 0.65 (0.48-0.89); p-trend 0.008. SWHS-SMHS legume intake was associated with an increased risk: 1.52 (1.13-2.06); p-trend 0.016. In UKB, the highest tertile of fish intake was associated with a reduced risk: opposing tertiles 0.65 (0.49-0.87); p-trend 0.019. A positive relationship between BMI and BTC was observed in all cohorts: pooled analysis 1.66 (1.27, 2.16); p-trend, &amp;lt;0.0001. WHR and BTC were positively associated in pooled analysis: 1.28 (1.01-1.64); p-trend 0.020. Physical activity lacked any association.ConclusionHigh dietary fruit and fish intake might be associated with a reduced risk of BTC. Our study suggests that adiposity and diets may play a role in the etiology of this fatal malignancy. Citation Format: Valerie Gunchick, Wei Zheng. Dietary intakes and biliary tract cancer risk: Results from cohort studies including 638,860 Chinese and European adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3026.

1 Analysis of dietary intake and biliary tract cancer risk in 638,860 Chinese and European adults in three cohort studies

OBJECTIVES/GOALS: Biliary tract cancer is an uncommon, aggressive malignancy. Incidence varies geographically and is highest in East Asia and South America and lowest in Western countries. Previous dietary risk evaluations have primarily been case-control studies. We evaluated associations of dietary intakes with BTC risk in three cohort studies in two countries. METHODS/STUDY POPULATION: We evaluated 638,860 adults in China and the United Kingdom enrolled in the Shanghai Women’s Health Study (SWHS), Shanghai Men’s Health Study (SMHS), or UK Biobank (UKB). Dietary intake information was obtained from study participants at baseline using food frequency questionnaires previously validated for these studies. Dietary intakes of major food groups and macronutrients were divided into low, middle, and high intake tertiles. Cox regression was used to estimate hazard ratios and 95% CIs for biliary tract cancer risk associated with major food groups in all three cohorts and macronutrients in the SWHS and SMHS. Participants were excluded if, at enrollment, they had a history of cancer, CHD, stroke, a total daily Kcal count below 500 or exceeding 3500, or developed cancer or died within one year after enrollment. RESULTS/ANTICIPATED RESULTS: The analyzed cohort includes 558,372 participants: 66,945 SWHS, 55,750 SMHS, and 435,677 UKB participants with median enrollment ages of 49, 52, and 57 years old and median follow-up times of 18.1, 12.3, and 10.3 years, respectively. The SWHS observed 205 eligible BTC cases, SMHS 97, and UKB 366. SWHS and SMHS participants were combined for dietary evaluation and the highest tertile of fruit intake showed an inverse association with biliary tract cancer risk when compared to the lowest tertile: HR 0.74 (95% CI, 0.55-0.99); p-trend 0.044. In UKB, the highest tertile of fish intake was associated with a reduced risk when compared to the lowest tertile: HR 0.76 (95% CI, 0.59-0.98); p-trend 0.034. DISCUSSION/SIGNIFICANCE: High dietary fruit intake was associated with a reduced risk of biliary tract cancer only in SWHS and SMHS. High fish intake was associated with a reduced risk of biliary tract cancer only in UKB. Our findings reflect geographic-based BTC risk variation which we will further explore in our next model accounting for population-specific risk factors.