Petersen, Gloria M.

Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3% of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls in a largely white population (>96%). Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake had a modest effect size, but was significantly inversely associated with pancreatic cancer (odds ratio (OR) = 0.99, p < 0.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.

Abstract Background: Epidemiologic associations of leukocyte telomere length (LTL) and pancreatic ductal adenocarcinoma (PDAC) have been inconsistent owing, in part, to variation in telomere length (TL) assessment across studies. To overcome this limitation and address concerns of potential reverse causation, we used carriage of telomere-related alleles to genetically predict TL and examined its association with PDAC. Methods: A case–control study of 1,500 PDAC cases and 1,500 controls, frequency-matched on age and sex was performed. Eight of nine polymorphisms previously associated with variation in LTL were analyzed. Genetic risk scores (GRS) consisting of the TL-related polymorphisms were computed as the number of long TL alleles carried by an individual scaled to published kilobase pairs of TL associated with each allele. Participants were further categorized on the basis of the number of short TL alleles they carry across all eight SNPs. Associations were examined in additive and dominant models using logistic regression to calculate ORs and 95% confidence intervals (CI). Results: In age- and sex-adjusted models, one short TL allele (rs10936599, T) was associated with reduced risk, whereas another short TL allele (rs2736100, A) was associated with increased risk, with per-allele ORs of 0.89 (95% CI, 0.79–0.99) and 1.13 (95% CI, 1.01–1.24), respectively. No association was observed with GRS or short TL allele counts, and no associations were observed in the dominant models. Conclusions: Findings suggest that genetically predicted short TL is not associated with PDAC risk. Impact: Common genetic determinants of short TL do not appear to influence PDAC risk. Cancer Epidemiol Biomarkers Prev; 26(6); 971–4. ©2017 AACR.

Abstract In the United States, incidence and mortality rates of pancreatic cancer (PC) have remained largely unchanged since 1973. During 2005-2009, the incidence rate for Whites was 11.6/105 and for African-Americans, 15.2/105. Mortality rates were 10.7/105 for Whites and 13.8/105 for African-Americans. The 5-year survival has been 4-7% for decades. The absolute number of new cases and deaths due to PC has been increasing steadily since 2004 due to the baby-boomer generation reaching the risk window (where median age at diagnosis is 71 years). By 2030, PC will be the second most common cause of cancer mortality, after lung cancer. Already, in 2016 it is estimated to be the third leading cause of cancer death, surpassing deaths from breast cancer. Though the etiology of PC remains to be fully understood, we have learned much in the past decade in a variety of case-control and cohort studies on non-genetic and genetic risk factors. Non genetic factors: Host and lifestyle factors such as cigarette smoking, high body mass index, and heavy alcohol use, and long-standing type II diabetes mellitus and chronic pancreatitis, are associated with increased risk. The range of increased risks among these factors are two- to three fold increased risk over the general population. Other epidemiological investigations have implicated environmental exposures such as pesticides, asbestos, benzene and chlorinated hydrocarbons, with odds ratios in the range of 1.2 to 1.7. Protective effects of factors have been observed with diets rich in fruits and vegetables, dietary fiber, aspirin use, and history of allergies. Genetic factors account for ~10% of all PC cases. The genetic risk factors for PC have been pursued along two lines of inquiry. The first line of inquiry involves studies of high risk families, particularly those kindreds meeting criteria for familial pancreatic cancer (FPC) by containing at least two affected first degree relatives. Family-based studies and new methods for gene discovery, including next generation sequencing, have significantly increased our understanding of low frequency predisposition mutations, and the proportion of patients who carry mutations in genes such as BRCA1, BRCA2, CDKN2A, PALB2, ATM, mismatch repair genes (Lynch syndrome), and PRSS1 and SPINK2 (hereditary pancreatitis). Novel predisposition genes, among them a host of DNA repair genes, continue to be identified and emphasize the genetic heterogeneity of PC. As sporadic case series are being screened for mutations, we are finding that family history of PC is not a necessary requirement to be a PC mutation carrier. Predisposition genetic testing for individuals in FPC kindreds is feasible, and evolving, but typically will consist of sequencing a panel of multiple genes. The second line of inquiry involves large series of sporadic cases and non-cancer controls who are screened agnostically with thousands of single nucleotide polymorphisms (SNPs) that are studied in genome wide association studies (GWAS). Through this approach, numerous low penetrance but common variants have been implicated as contributing to PC risk, including SNPs in genes or regions such as ABO, NR5A2, CLPTMIL-TERT, LINC-PINT, BCAR1/CTRB1/CTRB2, PDX1, ZNRF3, LINC00673, SUGCT, TP63, and ETAA1. In general, these findings have helped generate new lines of inquiry for further understanding of PC etiology. Ongoing research continues to identify new risk factors and gene-environment interactions. Improvements in risk assessment and preventive interventions are increasingly becoming plausible. Citation Format: Gloria M. Petersen.{Authors}. Genetic and non-genetic risk factors of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA03.

Abstract Individuals from pancreatic cancer families are at increased risk, not only of pancreatic cancer, but also of melanoma, breast, ovarian, and colon cancers. While some of the increased risk may be due to mutations in high-penetrance genes (i.e., BRCA2, PALB2, ATM, p16/CDKN2A or DNA mismatch repair genes), common genetic variants may also be involved. In a high-risk population of cases with either a family history of pancreatic cancer or early-onset pancreatic cancer (diagnosis before the age of 50 years), we examined the role of genetic variants previously associated with risk of pancreatic, breast, ovarian, or prostate cancer. We genotyped 985 cases (79 early-onset cases, 906 cases with a family history of pancreatic cancer) and 877 controls for 215,389 SNPs using the iSelect Collaborative Oncological Gene-Environment Study (iCOGS) array with custom content. Logistic regression was performed using a log-linear additive model. We replicated several previously reported pancreatic cancer susceptibility loci, including recently identified variants on 2p13.3 and 7p13 (2p13.3, rs1486134: OR = 1.36; 95% CI, 1.13–1.63; P = 9.29 × 10−4; 7p13, rs17688601: OR = 0.76; 95% CI, 0.63–0.93; P = 6.59 × 10−3). For the replicated loci, the magnitude of association observed in these high-risk patients was similar to that observed in studies of unselected patients. In addition to the established pancreatic cancer loci, we also found suggestive evidence of association (P &lt; 5 × 10−5) to pancreatic cancer for SNPs at HDAC9 (7p21.1) and COL6A2 (21q22.3). Even in high-risk populations, common variants influence pancreatic cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 25(7); 1185–91. ©2016 AACR.

Purpose The inclusion of metformin in the treatment arms of cancer clinical trials is based on improved survival that has been demonstrated in retrospective epidemiologic studies; however, unintended biases may exist when analysis is performed by using a conventional Cox proportional hazards regression model with dichotomous ever/never categorization. We examined the impact of metformin exposure definitions, analytical methods, and patient selection on the estimated effect size of metformin exposure on survival in a large cohort of patients with pancreatic ductal adenocarcinoma (PDAC). Patients and Methods Of newly diagnosed patients with PDAC with diabetes, 980 were retrospectively included, and exposure to metformin documented. Median survival was assessed by using Kaplan-Meier and log-rank methods. Hazard ratios (HR) and 95% CIs were computed to compare time-varying covariate analysis with conventional Cox proportional hazards regression analysis. Results Median survival of metformin users versus nonusers was 9.9 versus 8.9 months, respectively. By the time-varying covariate analysis, metformin use was not statistically significantly associated with improved survival (HR, 0.93; 95% CI, 0.81 to1.07; P = .28). There was no evidence of benefit in the subset of patients who were naïve to metformin at the time of PDAC diagnosis (most representative of patients enrolled in clinical trials; HR, 1.01; 95% CI, 0.80 to 1.30; P = .89); however, when the analysis was performed by using the conventional Cox model, an artificial survival benefit of metformin was detected (HR, 0.88; 95% CI, 0.77 to 1.01; P = .08), which suggested biased results from the conventional Cox analysis. Conclusion Our findings did not suggest the benefit of metformin use after patients are diagnosed with PDAC. We highlight the importance of patient selection and appropriate statistical analytical methods when studying medication exposure and cancer survival.