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Primary and Secondary Prevention of Pancreatic Cancer

  • Cancer Epidemiology (MB Terry, Section Editor)
  • Published:
Current Epidemiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Pancreatic cancer remains one of the most lethal of malignancies with 5-year survival of only 8%. A number of reasons account for the high fatality rate including few known modifiable risk factors, no effective screening tools, and lack of early diagnostic symptoms. Therefore, in this review, we aim to summarize existing evidence from major studies concerning (1) risk factors for risk assessment and risk stratification, and (2) screening modalities and early detection markers to better understand the ways to prevent pancreatic cancer or identify it at earlier stages. Improvements in primary and secondary prevention of pancreatic cancer are critical to reduce the morbidity and mortality of this deadly disease.

Recent Findings

We searched the published literature and identified studies of pancreatic cancer risk published prior to September 30, 2018, with an emphasis on manuscripts publicized during the last 5–10 years. Known and suspected risk factors include familial and genetic risk, smoking, obesity, alcohol, poor diet including sugary sweetened beverages, diabetes, and periodontal disease. Recent advances have identified potential early detection markers (e.g., ctDNA, circulating cancer cells, metabolites, and miRNA).

Summary

Currently, pancreatic cancer has few known and suspected risk factors, and risk assessment tools have limited utility given their modest discriminatory power. Although emerging evidence suggests blood-based biomarkers may be useful as early detection markers, findings need to be confirmed in prospective studies. Due to the rarity of disease, future studies should consider a two-tiered approach in which risk assessment is used to identify high-risk individuals for screening, and then effective imaging and biomarkers in pathways known to affect pancreatic cancer risk are employed; these combination approaches may reduce false positives and mortality compared with just risk assessment or screening alone.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. Globocan 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. Lyon: International Agency for Research on Cancer; 2016. http://globocan.iarc.fr/. Accessed 06 May 2019.

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29. https://doi.org/10.3322/caac.20138.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387.

    Article  PubMed  Google Scholar 

  4. American Cancer Society. Survival rates for exocrine pancreatic cancer. 2018. https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html. Accessed 17 May 2019.

  5. Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER cancer statistics review, 1975–2015. National Cancer Institute Bethesda, MD, https://www.seercancergov/csr/1975_2015/, based on November 2017 SEER data submission, posted to the SEER web site, April 2018.

  6. Molina-Montes E, Gomez-Rubio P, Marquez M, Rava M, Lohr M, Michalski CW, et al. Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives. Int J Epidemiol. 2018;47(2):473–83. https://doi.org/10.1093/ije/dyx269.

    Article  CAS  PubMed  Google Scholar 

  7. Ghadirian P, Liu G, Gallinger S, Schmocker B, Paradis AJ, Lal G, et al. Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. Int J Cancer. 2002;97(6):807–10.

    Article  CAS  PubMed  Google Scholar 

  8. Fehringer G, Gallinger S, Borgida A, Zhang LR, Adams L, Liu G, et al. The association of family history of cancer and medical history with pancreatic cancer risk. Pancreas. 2014;43(5):812–4. https://doi.org/10.1097/mpa.0000000000000126.

    Article  PubMed  Google Scholar 

  9. Permuth-Wey J, Egan KM. Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis. Familial Cancer. 2009;8(2):109–17. https://doi.org/10.1007/s10689-008-9214-8.

    Article  PubMed  Google Scholar 

  10. • Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog. 2012;51(1):14–24. https://doi.org/10.1002/mc.20855 A comprehensive review article on genetic susceptibility and pancreatic cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. • Klein AP, Wolpin BM, Risch HA, Stolzenberg-Solomon RZ, Mocci E, Zhang M, et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun. 2018;9(1):556. https://doi.org/10.1038/s41467-018-02942-5 This article identified five new susceptibility loci for pancreatic cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hruban RH, Canto MI, Goggins M, Schulick R, Klein AP. Update on familial pancreatic cancer. Adv Surg. 2010;44:293–311.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Petersen GM. Familial pancreatic cancer. Semin Oncol. 2016;43(5):548–53. https://doi.org/10.1053/j.seminoncol.2016.09.002.

    Article  PubMed  PubMed Central  Google Scholar 

  14. McWilliams RR, Rabe KG, Olswold C, De Andrade M, Petersen GM. Risk of malignancy in first-degree relatives of patients with pancreatic carcinoma. Cancer. 2005;104(2):388–94. https://doi.org/10.1002/cncr.21166.

    Article  PubMed  Google Scholar 

  15. • Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of meta-analytical studies. Int J Epidemiol. 2015;44(1):186–98. https://doi.org/10.1093/ije/dyu240 A comprehensive review article on the epidemiology of pancreatic cancer.

    Article  PubMed  Google Scholar 

  16. Wittel UA, Momi N, Seifert G, Wiech T, Hopt UT, Batra SK. The pathobiological impact of cigarette smoke on pancreatic cancer development (review). Int J Oncol. 2012;41(1):5–14. https://doi.org/10.3892/ijo.2012.1414.

    Article  CAS  PubMed  Google Scholar 

  17. Zheng Z, Zheng R, He Y, Sun X, Wang N, Chen T, et al. Risk factors for pancreatic cancer in China: a multicenter case-control study. J Epidemiol. 2016;26(2):64–70. https://doi.org/10.2188/jea.JE20140148.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang Y, Duan H, Yang X, Guo J. Cigarette smoking and the risk of pancreatic cancer: a case-control study. Med Oncol. 2014;31(10):184. https://doi.org/10.1007/s12032-014-0184-4.

    Article  CAS  PubMed  Google Scholar 

  19. Bosetti C, Lucenteforte E, Silverman DT, Petersen G, Bracci PM, Ji BT, et al. Cigarette smoking and pancreatic cancer: an analysis from the international pancreatic cancer case-control consortium (Panc4). Ann Oncol. 2012;23(7):1880–8. https://doi.org/10.1093/annonc/mdr541.

    Article  CAS  PubMed  Google Scholar 

  20. Zou L, Zhong R, Shen N, Chen W, Zhu B, Ke J, et al. Non-linear dose-response relationship between cigarette smoking and pancreatic cancer risk: evidence from a meta-analysis of 42 observational studies. Eur J Cancer. 2014;50(1):193–203. https://doi.org/10.1016/j.ejca.2013.08.014.

    Article  CAS  PubMed  Google Scholar 

  21. Gapstur SM, Gann P. Is pancreatic cancer a preventable disease? JAMA. 2001;286(8):967–8.

    Article  CAS  PubMed  Google Scholar 

  22. Elena JW, Steplowski E, Yu K, Hartge P, Tobias GS, Brotzman MJ, et al. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control. 2013;24(1):13–25. https://doi.org/10.1007/s10552-012-0078-8.

    Article  PubMed  Google Scholar 

  23. Meinhold CL, Berrington de Gonzalez A, Albanes D, Weinstein SJ, Taylor PR, Virtamo J, et al. Predictors of fasting serum insulin and glucose and the risk of pancreatic cancer in smokers. Cancer Causes Control. 2009;20(5):681–90. https://doi.org/10.1007/s10552-008-9281-z.

    Article  PubMed  Google Scholar 

  24. Michaud DS. Epidemiology of pancreatic cancer. Minerva Chir. 2004;59(2):99–111.

    CAS  PubMed  Google Scholar 

  25. Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1199–209 e4. https://doi.org/10.1053/j.gastro.2013.02.007.

    Article  CAS  PubMed  Google Scholar 

  26. Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-de-Mesquita HB, et al. Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan). Arch Intern Med. 2010;170(9):791–802. https://doi.org/10.1001/archinternmed.2010.63.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Jiao L, Berrington de Gonzalez A, Hartge P, Pfeiffer RM, Park Y, Freedman DM, et al. Body mass index, effect modifiers, and risk of pancreatic cancer: a pooled study of seven prospective cohorts. Cancer Causes Control. 2010;21(8):1305–14. https://doi.org/10.1007/s10552-010-9558-x.

    Article  PubMed  PubMed Central  Google Scholar 

  28. • Genkinger JM, Kitahara CM, Bernstein L, Berrington de Gonzalez A, Brotzman M, Elena JW, et al. Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies. Ann Oncol. 2015;26(11):2257–66. https://doi.org/10.1093/annonc/mdv355 This pooled analysis, representing one of the largest studies to date, observed an association between central obesity and pancreatic cancer mortality.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Genkinger JM, Spiegelman D, Anderson KE, Bernstein L, van den Brandt PA, Calle EE, et al. A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk. Int J Cancer. 2011;129(7):1708–17. https://doi.org/10.1002/ijc.25794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. • Diet, nutrition, physical activity and cancer: a global perspective. Washington, DC: World Cancer Research Fund and the American Institute for Cancer Research; 2018. This report is a systematic review of the associations between diet, nutrition, obesity and physical activity and risk of site-specific cancers (e.g., pancreatic).

  31. Foster JR, Idle JR, Hardwick JP, Bars R, Scott P, Braganza JM. Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis. J Pathol. 1993;169(4):457–63.

    Article  CAS  PubMed  Google Scholar 

  32. Go VL, Gukovskaya A, Pandol SJ. Alcohol and pancreatic cancer. Alcohol. 2005;35(3):205–11.

    Article  CAS  PubMed  Google Scholar 

  33. Poschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol. 2004;39(3):155–65.

    Article  CAS  PubMed  Google Scholar 

  34. Ulrich CM, Bigler J, Bostick R, Fosdick L, Potter JD. Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Res. 2002;62(12):3361–4.

    CAS  PubMed  Google Scholar 

  35. Bouchardy C, Clavel F, La Vecchia C, Raymond L, Boyle P. Alcohol, beer and cancer of the pancreas. Int J Cancer. 1990;45(5):842–6.

    Article  CAS  PubMed  Google Scholar 

  36. Bueno de Mesquita HB, Maisonneuve P, Moerman CJ, Runia S, Boyle P. Lifetime consumption of alcoholic beverages, tea and coffee and exocrine carcinoma of the pancreas: a population-based case-control study in the Netherlands. Int J Cancer. 1992;50(4):514–22.

    Article  CAS  PubMed  Google Scholar 

  37. Clavel F, Benhamou E, Auquier A, Tarayre M, Flamant R. Coffee, alcohol, smoking and cancer of the pancreas: a case-control study. Int J Cancer. 1989;43(1):17–21.

    Article  CAS  PubMed  Google Scholar 

  38. Falk RT, Pickle LW, Fontham ET, Correa P, Fraumeni JF Jr. Life-style risk factors for pancreatic cancer in Louisiana: a case-control study. Am J Epidemiol. 1988;128(2):324–36.

    Article  CAS  PubMed  Google Scholar 

  39. Ferraroni M, Negri E, La Vecchia C, D'Avanzo B, Franceschi S. Socioeconomic indicators, tobacco and alcohol in the aetiology of digestive tract neoplasms. Int J Epidemiol. 1989;18(3):556–62.

    Article  CAS  PubMed  Google Scholar 

  40. Haines AP, Moss AR, Whittemore A, Quivey J. A case-control study of pancreatic carcinoma. J Cancer Res Clin Oncol. 1982;103(1):93–7.

    Article  CAS  PubMed  Google Scholar 

  41. Ji BT, Chow WH, Dai Q, McLaughlin JK, Benichou J, Hatch MC, et al. Cigarette smoking and alcohol consumption and the risk of pancreatic cancer: a case-control study in Shanghai, China. Cancer Causes Control. 1995;6(4):369–76.

    Article  CAS  PubMed  Google Scholar 

  42. Kalapothaki V, Tzonou A, Hsieh CC, Toupadaki N, Karakatsani A, Trichopoulos D. Tobacco, ethanol, coffee, pancreatitis, diabetes mellitus, and cholelithiasis as risk factors for pancreatic carcinoma. Cancer Causes Control. 1993;4(4):375–82.

    Article  CAS  PubMed  Google Scholar 

  43. Lyon JL, Mahoney AW, French TK, Moser R Jr. Coffee consumption and the risk of cancer of the exocrine pancreas: a case-control study in a low-risk population. Epidemiology. 1992;3(2):164–70.

    Article  CAS  PubMed  Google Scholar 

  44. Lyon JL, Slattery ML, Mahoney AW, Robison LM. Dietary intake as a risk factor for cancer of the exocrine pancreas. Cancer Epidemiol Biomarkers Prev. 1993;2(6):513–8.

    CAS  PubMed  Google Scholar 

  45. Mack TM, Yu MC, Hanisch R, Henderson BE. Pancreas cancer and smoking, beverage consumption, and past medical history. J Natl Cancer Inst. 1986;76(1):49–60.

    CAS  PubMed  Google Scholar 

  46. MacMahon B. Risk factors for cancer of the pancreas. Cancer. 1982;50(11 Suppl):2676–80.

    CAS  PubMed  Google Scholar 

  47. Mizuno S, Watanabe S, Nakamura K, Omata M, Oguchi H, Ohashi K, et al. A multi-institute case-control study on the risk factors of developing pancreatic cancer. Jpn J Clin Oncol. 1992;22(4):286–91.

    CAS  PubMed  Google Scholar 

  48. Nkondjock A, Krewski D, Johnson KC, Ghadirian P. Dietary patterns and risk of pancreatic cancer. Int J Cancer. 2005;114(5):817–23.

    Article  CAS  PubMed  Google Scholar 

  49. Silverman DT. Risk factors for pancreatic cancer: a case-control study based on direct interviews. Teratog Carcinog Mutagen. 2001;21(1):7–25.

    Article  CAS  PubMed  Google Scholar 

  50. Silverman DT, Brown LM, Hoover RN, Schiffman M, Lillemoe KD, Schoenberg JB, et al. Alcohol and pancreatic cancer in blacks and whites in the United States. Cancer Res. 1995;55(21):4899–905.

    CAS  PubMed  Google Scholar 

  51. Soler M, Chatenoud L, La Vecchia C, Franceschi S, Negri E. Diet, alcohol, coffee and pancreatic cancer: final results from an Italian study. Eur J Cancer Prev. 1998;7(6):455–60.

    Article  CAS  PubMed  Google Scholar 

  52. Tavani A, Pregnolato A, Negri E, La Vecchia C. Alcohol consumption and risk of pancreatic cancer. Nutr Cancer. 1997;27(2):157–61.

    Article  CAS  PubMed  Google Scholar 

  53. Villeneuve PJ, Johnson KC, Hanley AJ, Mao Y. Alcohol, tobacco and coffee consumption and the risk of pancreatic cancer: results from the Canadian enhanced surveillance system case-control project. Canadian Cancer registries epidemiology research group. Eur J Cancer Prev. 2000;9(1):49–58.

    Article  CAS  PubMed  Google Scholar 

  54. Zatonski WA, Boyle P, Przewozniak K, Maisonneuve P, Drosik K, Walker AM. Cigarette smoking, alcohol, tea and coffee consumption and pancreas cancer risk: a case-control study from Opole, Poland. Int J Cancer. 1993;53(4):601–7.

    Article  CAS  PubMed  Google Scholar 

  55. Cuzick J, Babiker AG. Pancreatic cancer, alcohol, diabetes mellitus and gall-bladder disease. Int J Cancer. 1989;43(3):415–21.

    Article  CAS  PubMed  Google Scholar 

  56. Hassan MM, Bondy ML, Wolff RA, Abbruzzese JL, Vauthey JN, Pisters PW, et al. Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol. 2007;102(12):2696–707.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lu XH, Wang L, Li H, Qian JM, Deng RX, Zhou L. Establishment of risk model for pancreatic cancer in Chinese Han population. World J Gastroenterol. 2006;12(14):2229–34.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Olsen GW, Mandel JS, Gibson RW, Wattenberg LW, Schuman LM. A case-control study of pancreatic cancer and cigarettes, alcohol, coffee and diet. Am J Public Health. 1989;79(8):1016–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Partanen TJ, Vainio HU, Ojajarvi IA, Kauppinen TP. Pancreas cancer, tobacco smoking and consumption of alcoholic beverages: a case-control study. Cancer Lett. 1997;116(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  60. Pfeffer F, Avilas Rosas H, Vargas F, Villalobos JJ. Smoking, consumption of alcoholic beverages and coffee as factors associated with the development of cancer of the pancreas. Rev Investig Clin. 1989;41(3):205–8.

    CAS  Google Scholar 

  61. Ghadirian P, Simard A, Baillargeon J. Tobacco, alcohol, and coffee and cancer of the pancreas. A population-based, case-control study in Quebec, Canada. Cancer. 1991;67(10):2664–70.

    Article  CAS  PubMed  Google Scholar 

  62. Inoue M, Tajima K, Takezaki T, Hamajima N, Hirose K, Ito H, et al. Epidemiology of pancreatic cancer in Japan: a nested case-control study from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). Int J Epidemiol. 2003;32(2):257–62.

    Article  PubMed  Google Scholar 

  63. Gold EB, Gordis L, Diener MD, Seltser R, Boitnott JK, Bynum TE, et al. Diet and other risk factors for cancer of the pancreas. Cancer. 1985;55(2):460–7.

    Article  CAS  PubMed  Google Scholar 

  64. Harnack LJ, Anderson KE, Zheng W, Folsom AR, Sellers TA, Kushi LH. Smoking, alcohol, coffee, and tea intake and incidence of cancer of the exocrine pancreas: the Iowa Women's health study. Cancer Epidemiol Biomarkers Prev. 1997;6(12):1081–6.

    CAS  PubMed  Google Scholar 

  65. Isaksson B, Jonsson F, Pedersen NL, Larsson J, Feychting M, Permert J. Lifestyle factors and pancreatic cancer risk: a cohort study from the Swedish twin registry. Int J Cancer. 2002;98(3):480–2.

    Article  CAS  PubMed  Google Scholar 

  66. Kato I, Nomura AM, Stemmermann GN, Chyou PH. Prospective study of the association of alcohol with cancer of the upper aerodigestive tract and other sites. Cancer Causes Control. 1992;3(2):145–51.

    Article  CAS  PubMed  Google Scholar 

  67. Lin Y, Tamakoshi A, Kawamura T, Inaba Y, Kikuchi S, Motohashi Y, et al. Risk of pancreatic cancer in relation to alcohol drinking, coffee consumption and medical history: findings from the Japan collaborative cohort study for evaluation of cancer risk. Int J Cancer. 2002;99(5):742–6.

    Article  CAS  PubMed  Google Scholar 

  68. Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Coffee and alcohol consumption and the risk of pancreatic cancer in two prospective United States cohorts. Cancer Epidemiol Biomarkers Prev. 2001;10(5):429–37.

    CAS  PubMed  Google Scholar 

  69. Ye W, Lagergren J, Weiderpass E, Nyren O, Adami HO, Ekbom A. Alcohol abuse and the risk of pancreatic cancer. Gut. 2002;51(2):236–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zheng W, McLaughlin JK, Gridley G, Bjelke E, Schuman LM, Silverman DT, et al. A cohort study of smoking, alcohol consumption, and dietary factors for pancreatic cancer (United States). Cancer Causes Control. 1993;4(5):477–82.

    Article  CAS  PubMed  Google Scholar 

  71. • Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, van den Brandt PA, et al. Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies. Cancer Epidemiol Biomark Prev. 2009;18(3):765–76. https://doi.org/10.1158/1055-9965.EPI-08-0880. One of the largest analyses of prospective data on the association between alcohol intake and pancreatic cancer.

    Article  CAS  Google Scholar 

  72. • Lucenteforte E, La Vecchia C, Silverman D, Petersen GM, Bracci PM, Ji BT, et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the international pancreatic cancer case-control consortium (PanC4). Ann Oncol. 2012;23(2):374–82. https://doi.org/10.1093/annonc/mdr120. One of the largest analyses of retrospective data on the association between alcohol consumption and pancreatic cancer.

    Article  CAS  PubMed  Google Scholar 

  73. • Michaud DS, Vrieling A, Jiao L, Mendelsohn JB, Steplowski E, Lynch SM, et al. Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan). Cancer Causes Control. 2010;21(8):1213–25. https://doi.org/10.1007/s10552-010-9548-z. One of the largest analyses of prospective data on the association between alcohol and pancreatic cancer risk.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Coughlin SS, Calle EE, Patel AV, Thun MJ. Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control. 2000;11(10):915–23.

    Article  CAS  PubMed  Google Scholar 

  75. Larsson SC, Hakansson N, Giovannucci E, Wolk A. Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. J Natl Cancer Inst. 2006;98(6):407–13.

    Article  CAS  PubMed  Google Scholar 

  76. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  77. Koushik A, Spiegelman D, Albanes D, Anderson KE, Bernstein L, van den Brandt PA, et al. Intake of fruits and vegetables and risk of pancreatic cancer in a pooled analysis of 14 cohort studies. Am J Epidemiol. 2012;176(5):373–86. https://doi.org/10.1093/aje/kws027.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Genkinger JM, Wang M, Li R, Albanes D, Anderson KE, Bernstein L, et al. Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies. Ann Oncol. 2014. https://doi.org/10.1093/annonc/mdu019.

  79. Genkinger J, Li R, Spiegelman D, Anderson KE, Albanes D, Bergkvist L, et al. Coffee, tea and sugar-sweetened carbonated soft drink intake and pancreatic cancer risk: a pooled analysis of 14 cohort studies. Cancer Epidemiol Biomarkers Prev. 2012;21(2):305–18. https://doi.org/10.1158/1055-9965.EPI-11-0945-T.

    Article  CAS  PubMed  Google Scholar 

  80. Bray GA, Benfield JR. Intestinal bypass for obesity a summary and perspective. Am J Clin Nutr. 1977;30(1):121–7.

    Article  CAS  PubMed  Google Scholar 

  81. Inoue-Choi M, Flood A, Robien K, Anderson K. Nutrients, food groups, dietary patterns, and risk of pancreatic cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2011;20(4):711–4. https://doi.org/10.1158/1055-9965.EPI-11-0026.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Nothlings U, Murphy SP, Wilkens LR, Boeing H, Schulze MB, Bueno-de-Mesquita HB, et al. A food pattern that is predictive of flavonol intake and risk of pancreatic cancer. Am J Clin Nutr. 2008;88(6):1653–62. https://doi.org/10.3945/ajcn.2008.26398.

    Article  PubMed  Google Scholar 

  83. Bosetti C, Bravi F, Turati F, Edefonti V, Polesel J, Decarli A, et al. Nutrient-based dietary patterns and pancreatic cancer risk. Ann Epidemiol. 2013;23(3):124–8. https://doi.org/10.1016/j.annepidem.2012.12.005.

    Article  PubMed  Google Scholar 

  84. Chan JM, Gong Z, Holly EA, Bracci PM. Dietary patterns and risk of pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area. Nutr Cancer. 2013;65(1):157–64. https://doi.org/10.1080/01635581.2012.725502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Michaud DS, Skinner HG, Wu K, Hu F, Giovannucci E, Willett WC, et al. Dietary patterns and pancreatic cancer risk in men and women. J Natl Cancer Inst. 2005;97(7):518–24.

    Article  PubMed  Google Scholar 

  86. Arem H, Reedy J, Sampson J, Jiao L, Hollenbeck AR, Risch H, et al. The healthy eating index 2005 and risk for pancreatic cancer in the NIH-AARP study. J Natl Cancer Inst. 2013;105(17):1298–305. https://doi.org/10.1093/jnci/djt185.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Bosetti C, Turati F, Dal Pont A, Ferraroni M, Polesel J, Negri E, et al. The role of Mediterranean diet on the risk of pancreatic cancer. Br J Cancer. 2013;109(5):1360–6. https://doi.org/10.1038/bjc.2013.345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lu PY, Shu L, Shen SS, Chen XJ, Zhang XY. Dietary patterns and pancreatic cancer risk: a meta-analysis. Nutrients. 2017;9(1). https://doi.org/10.3390/nu9010038.

  89. • Zheng J, Guinter MA, Merchant AT, Wirth MD, Zhang J, Stolzenberg-Solomon RZ, et al. Dietary patterns and risk of pancreatic cancer: a systematic review. Nutr Rev. 2017;75(11):883–908. https://doi.org/10.1093/nutrit/nux038. A comprehensive review on dietary patterns and pancreatic cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Behrens G, Jochem C, Schmid D, Keimling M, Ricci C, Leitzmann MF. Physical activity and risk of pancreatic cancer: a systematic review and meta-analysis. Eur J Epidemiol. 2015;30(4):279–98. https://doi.org/10.1007/s10654-015-0014-9.

    Article  PubMed  Google Scholar 

  91. Brenner DR, Wozniak MB, Feyt C, Holcatova I, Janout V, Foretova L, et al. Physical activity and risk of pancreatic cancer in a central European multicenter case-control study. Cancer Causes Control. 2014;25(6):669–81. https://doi.org/10.1007/s10552-014-0370-x.

    Article  PubMed  Google Scholar 

  92. Hanley AJ, Johnson KC, Villeneuve PJ, Mao Y. Physical activity, anthropometric factors and risk of pancreatic cancer: results from the Canadian enhanced cancer surveillance system. Int J Cancer. 2001;94(1):140–7. https://doi.org/10.1002/ijc.1446.

    Article  CAS  PubMed  Google Scholar 

  93. Calton BA, Stolzenberg-Solomon RZ, Moore SC, Schatzkin A, Schairer C, Albanes D, et al. A prospective study of physical activity and the risk of pancreatic cancer among women (United States). BMC Cancer. 2008;8:63. https://doi.org/10.1186/1471-2407-8-63.

    Article  PubMed  PubMed Central  Google Scholar 

  94. • Farris MS, Mosli MH, McFadden AA, Friedenreich CM, Brenner DR. The association between leisure time physical activity and pancreatic cancer risk in adults: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2015;24(10):1462–73. https://doi.org/10.1158/1055-9965.Epi-15-0301. A comprehensive review on leisure-time physical activity and pancreatic cancer.

    Article  PubMed  Google Scholar 

  95. Berrington de Gonzalez A, Spencer EA, Bueno-de-Mesquita HB, Roddam A, Stolzenberg-Solomon R, Halkjaer J, et al. Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2006;15(5):879–85.

    Article  PubMed  Google Scholar 

  96. Nothlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN. Body mass index and physical activity as risk factors for pancreatic cancer: the multiethnic cohort study. Cancer Causes Control. 2007;18(2):165–75.

    Article  PubMed  Google Scholar 

  97. Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev. 2005;14(2):459–66.

    Article  PubMed  Google Scholar 

  98. Stolzenberg-Solomon RZ, Adams K, Leitzmann M, Schairer C, Michaud DS, Hollenbeck A, et al. Adiposity, physical activity, and pancreatic cancer in the National Institutes of Health-AARP diet and health cohort. Am J Epidemiol. 2008;167(5):586–97. https://doi.org/10.1093/aje/kwm361.

    Article  PubMed  Google Scholar 

  99. Andren-Sandberg A, Hoem D, Backman PL. Other risk factors for pancreatic cancer: hormonal aspects. Ann Oncol. 1999;10(Suppl 4):131–5.

    Article  PubMed  Google Scholar 

  100. Robles-Diaz G, Duarte-Rojo A. Pancreas: a sex steroid-dependent tissue. Isr Med Assoc J. 2001;3(5):364–8.

    CAS  PubMed  Google Scholar 

  101. Sumi C, Brinck-Johnsen T, Longnecker DS. Inhibition of a transplantable pancreatic carcinoma by castration and estradiol administration in rats. Cancer Res. 1989;49(23):6687–92.

    CAS  PubMed  Google Scholar 

  102. Sumi C, Longnecker DS, Roebuck BD, Brinck-Johnsen T. Inhibitory effects of estrogen and castration on the early stage of pancreatic carcinogenesis in Fischer rats treated with azaserine. Cancer Res. 1989;49(9):2332–6.

    CAS  PubMed  Google Scholar 

  103. Andersson G, Borgquist S, Jirstrom K. Hormonal factors and pancreatic cancer risk in women: the Malmo diet and Cancer study. Int J Cancer. 2018;143(1):52–62. https://doi.org/10.1002/ijc.31302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Prizment AE, Anderson KE, Hong CP, Folsom AR. Pancreatic cancer incidence in relation to female reproductive factors: Iowa Women's health study. JOP. 2007;8(1):16–27.

    PubMed  Google Scholar 

  105. Skinner HG, Michaud DS, Colditz GA, Giovannucci EL, Stampfer MJ, Willett WC, et al. Parity, reproductive factors, and the risk of pancreatic cancer in women. Cancer Epidemiol Biomarkers Prev. 2003;12(5):433–8.

    PubMed  Google Scholar 

  106. Navarro Silvera SA, Miller AB, Rohan TE. Hormonal and reproductive factors and pancreatic cancer risk: a prospective cohort study. Pancreas. 2005;30(4):369–74.

    Article  PubMed  Google Scholar 

  107. Luo AJ, Feng RH, Wang XW, Wang FZ. Older age at first birth is a risk factor for pancreatic cancer: a meta-analysis. Hepatobiliary Pancreat Dis Int. 2016;15(2):125–30.

    Article  PubMed  Google Scholar 

  108. Stevens RJ, Roddam AW, Green J, Pirie K, Bull D, Reeves GK, et al. Reproductive history and pancreatic cancer incidence and mortality in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2009;18(5):1457–60. https://doi.org/10.1158/1055-9965.Epi-08-1134.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Lujan-Barroso L, Zhang W, Olson SH, Gao YT, Yu H, Baghurst PA, et al. Menstrual and reproductive factors, hormone use, and risk of pancreatic Cancer: analysis from the international pancreatic cancer case-control consortium (PanC4). Pancreas. 2016;45(10):1401–10. https://doi.org/10.1097/mpa.0000000000000635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kirkegard J, Cronin-Fenton D, Heide-Jorgensen U, Mortensen FV. Acute pancreatitis and pancreatic cancer risk: a Nationwide matched-cohort study in Denmark. Gastroenterology. 2018;154(6):1729–36. https://doi.org/10.1053/j.gastro.2018.02.011.

    Article  PubMed  Google Scholar 

  111. Ekbom A, McLaughlin JK, Karlsson BM, Nyren O, Gridley G, Adami HO, et al. Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst. 1994;86(8):625–7.

    Article  CAS  PubMed  Google Scholar 

  112. Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol. 2010;24(3):349–58. https://doi.org/10.1016/j.bpg.2010.02.007.

    Article  PubMed  Google Scholar 

  113. Pang Y, Kartsonaki C, Guo Y, Bragg F, Yang L, Bian Z, et al. Diabetes, plasma glucose and incidence of pancreatic cancer: a prospective study of 0.5 million Chinese adults and a meta-analysis of 22 cohort studies. Int J Cancer. 2017;140(8):1781–8. https://doi.org/10.1002/ijc.30599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bosetti C, Rosato V, Li D, Silverman D, Petersen GM, Bracci PM, et al. Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the international pancreatic cancer case-control consortium. Ann Oncol. 2014;25(10):2065–72. https://doi.org/10.1093/annonc/mdu276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Haugvik SP, Hedenstrom P, Korsaeth E, Valente R, Hayes A, Siuka D, et al. Diabetes, smoking, alcohol use, and family history of cancer as risk factors for pancreatic neuroendocrine tumors: a systematic review and meta-analysis. Neuroendocrinology. 2015;101(2):133–42. https://doi.org/10.1159/000375164.

    Article  CAS  PubMed  Google Scholar 

  116. Walker EJ, Ko AH, Holly EA, Bracci PM. Metformin use among type 2 diabetics and risk of pancreatic cancer in a clinic-based case-control study. Int J Cancer. 2015;136(6):E646–53. https://doi.org/10.1002/ijc.29120.

    Article  CAS  PubMed  Google Scholar 

  117. Lu Y, Garcia Rodriguez LA, Malgerud L, Gonzalez-Perez A, Martin-Perez M, Lagergren J, et al. New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer. Br J Cancer. 2015;113(11):1607–14. https://doi.org/10.1038/bjc.2015.353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, Zhu J, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2014;106(1):19–26. https://doi.org/10.1016/j.diabres.2014.04.007.

    Article  CAS  PubMed  Google Scholar 

  119. Hamada T, Khalaf N, Yuan C, Babic A, Morales-Oyarvide V, Qian ZR, et al. Statin use and pancreatic cancer risk in two prospective cohort studies. J Gastroenterol. 2018;53(8):959–66. https://doi.org/10.1007/s00535-018-1430-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chiu HF, Chang CC, Ho SC, Wu TN, Yang CY. Statin use and the risk of pancreatic cancer: a population-based case-control study. Pancreas. 2011;40(5):669–72. https://doi.org/10.1097/MPA.0b013e31821fd5cd.

    Article  CAS  PubMed  Google Scholar 

  121. Walker EJ, Ko AH, Holly EA, Bracci PM. Statin use and risk of pancreatic cancer: results from a large, clinic-based case-control study. Cancer. 2015;121(8):1287–94. https://doi.org/10.1002/cncr.29256.

    Article  CAS  PubMed  Google Scholar 

  122. Cui X, Xie Y, Chen M, Li J, Liao X, Shen J, et al. Statin use and risk of pancreatic cancer: a meta-analysis. Cancer Causes Control. 2012;23(7):1099–111. https://doi.org/10.1007/s10552-012-9979-9.

    Article  PubMed  Google Scholar 

  123. Archibugi L, Arcidiacono PG, Capurso G. Statin use is associated to a reduced risk of pancreatic cancer: a meta-analysis. Dig Liver Dis. 2018. https://doi.org/10.1016/j.dld.2018.09.007.

  124. Shimoda T, Shikata T, Karasawa T, Tsukagoshi S, Yoshimura M, Sakurai I. Light microscopic localization of hepatitis B virus antigens in the human pancreas. Possibility of multiplication of hepatitis B virus in the human pancreas. Gastroenterology. 1981;81(6):998–1005.

    CAS  PubMed  Google Scholar 

  125. Yoshimura M, Sakurai I, Shimoda T, Abe K, Okano T, Shikata T. Detection of HBsAg in the pancreas. Acta Pathol Jpn. 1981;31(4):711–7.

    CAS  PubMed  Google Scholar 

  126. Alvares-Da-Silva MR, Francisconi CF, Waechter FL. Acute hepatitis C complicated by pancreatitis: another extrahepatic manifestation of hepatitis C virus? J Viral Hepat. 2000;7(1):84–6.

    Article  CAS  PubMed  Google Scholar 

  127. Torbenson M, Yeh MM, Abraham SC. Bile duct dysplasia in the setting of chronic hepatitis C and alcohol cirrhosis. Am J Surg Pathol. 2007;31(9):1410–3. https://doi.org/10.1097/PAS.0b013e318053d122.

    Article  PubMed  Google Scholar 

  128. Huang J, Zagai U, Hallmans G, Nyren O, Engstrand L, Stolzenberg-Solomon R, et al. Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort: a nested case-control study. Int J Cancer. 2017;140(8):1727–35. https://doi.org/10.1002/ijc.30590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Xu JH, Fu JJ, Wang XL, Zhu JY, Ye XH, Chen SD. Hepatitis B or C viral infection and risk of pancreatic cancer: a meta-analysis of observational studies. World J Gastroenterol. 2013;19(26):4234–41. https://doi.org/10.3748/wjg.v19.i26.4234.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Krull Abe S, Inoue M, Sawada N, Iwasaki M, Shimazu T, Yamaji T, et al. Hepatitis B and C virus infection and risk of pancreatic cancer: a population-based cohort study (JPHC study cohort II). Cancer Epidemiol Biomarkers Prev. 2016;25(3):555–7. https://doi.org/10.1158/1055-9965.Epi-15-1115.

    Article  PubMed  Google Scholar 

  131. Liu H, Chen YT, Wang R, Chen XZ. Helicobacter pylori infection, atrophic gastritis, and pancreatic cancer risk: a meta-analysis of prospective epidemiologic studies. Medicine. 2017;96(33):e7811. https://doi.org/10.1097/md.0000000000007811.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Schulte A, Pandeya N, Fawcett J, Fritschi L, Risch HA, Webb PM, et al. Association between helicobacter pylori and pancreatic cancer risk: a meta-analysis. Cancer Causes Control. 2015;26(7):1027–35. https://doi.org/10.1007/s10552-015-0595-3.

    Article  PubMed  Google Scholar 

  133. Risch HA, Lu L, Kidd MS, Wang J, Zhang W, Ni Q, et al. Helicobacter pylori seropositivities and risk of pancreatic carcinoma. Cancer Epidemiol Biomarkers Prev. 2014;23(1):172–8. https://doi.org/10.1158/1055-9965.Epi-13-0447.

    Article  CAS  PubMed  Google Scholar 

  134. Fan X, Alekseyenko AV, Wu J, Peters BA, Jacobs EJ, Gapstur SM, et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut. 2018;67(1):120–7. https://doi.org/10.1136/gutjnl-2016-312580.

    Article  CAS  PubMed  Google Scholar 

  135. Huang J, Roosaar A, Axell T, Ye W. A prospective cohort study on poor oral hygiene and pancreatic cancer risk. Int J Cancer. 2016;138(2):340–7. https://doi.org/10.1002/ijc.29710.

    Article  CAS  PubMed  Google Scholar 

  136. • Michaud DS, Izard J, Wilhelm-Benartzi CS, You DH, Grote VA, Tjonneland A, et al. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut, 2013;62(12):1764–70. https://doi.org/10.1136/gutjnl-2012-303006. This study found that periodontal disease may increase the risk of pancreatic cancer.

  137. Michaud DS, Joshipura K, Giovannucci E, Fuchs CS. A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst. 2007;99(2):171–5. https://doi.org/10.1093/jnci/djk021.

    Article  PubMed  Google Scholar 

  138. Humans IWGotEoCRt. Arsenic, metals, fibres, and dusts. IARC Monogr Eval Carcinog Risks Hum. 2012;100(PT C):11.

    Google Scholar 

  139. • IARC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC Monogr Eval Carcinog Risks Hum. 1993;58:1–415 This article identified compounds in occupational settings as carcinogens.

    Google Scholar 

  140. Ojajarvi IA, Partanen TJ, Ahlbom A, Boffetta P, Hakulinen T, Jourenkova N, et al. Occupational exposures and pancreatic cancer: a meta-analysis. Occup Environ Med. 2000;57(5):316–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Alguacil J, Porta M, Kauppinen T, Malats N, Kogevinas M, Carrato A. Occupational exposure to dyes, metals, polycyclic aromatic hydrocarbons and other agents and K-ras activation in human exocrine pancreatic cancer. Int J Cancer. 2003;107(4):635–41. https://doi.org/10.1002/ijc.11431.

    Article  CAS  PubMed  Google Scholar 

  142. Carrigan PE, Hentz JG, Gordon G, Morgan JL, Raimondo M, Anbar AD, et al. Distinctive heavy metal composition of pancreatic juice in patients with pancreatic carcinoma. Cancer Epidemiol Biomarkers Prev. 2007;16(12):2656–63. https://doi.org/10.1158/1055-9965.Epi-07-0332.

    Article  CAS  PubMed  Google Scholar 

  143. Adams SV, Passarelli MN, Newcomb PA. Cadmium exposure and cancer mortality in the Third National Health and Nutrition Examination Survey cohort. Occup Environ Med. 69(2):153–6.

  144. Sawada N, Iwasaki M, Inoue M, Takachi R, Sasazuki S, Yamaji T, et al. Long-term dietary cadmium intake and cancer incidence. Epidemiology. 2012;23(3):368–76. https://doi.org/10.1097/EDE.0b013e31824d063c.

    Article  PubMed  Google Scholar 

  145. Amaral AF, Porta M, Silverman DT, Milne RL, Kogevinas M, Rothman N, et al. Pancreatic cancer risk and levels of trace elements. Gut. 2012;61(11):1583–8. https://doi.org/10.1136/gutjnl-2011-301086.

    Article  CAS  PubMed  Google Scholar 

  146. Elinder CG, Kjellstrom T, Hogstedt C, Andersson K, Spang G. Cancer mortality of cadmium workers. Br J Ind Med. 1985;42(10):651–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Garcia-Esquinas E, Pollan M, Tellez-Plaza M, Francesconi KA, Goessler W, Guallar E, et al. Cadmium exposure and cancer mortality in a prospective cohort: the strong heart study. Environ Health Perspect. 2014;122(4):363–70. https://doi.org/10.1289/ehp.1306587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Garcia-Esquinas E, Pollan M, Umans JG, Francesconi KA, Goessler W, Guallar E, et al. Arsenic exposure and cancer mortality in a US-based prospective cohort: the strong heart study. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1944–53. https://doi.org/10.1158/1055-9965.EPI-13-0234-T.

    Article  CAS  PubMed  Google Scholar 

  149. Jarup L, Bellander T, Hogstedt C, Spang G. Mortality and cancer incidence in Swedish battery workers exposed to cadmium and nickel. Occup Environ Med. 1998;55(11):755–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kriegel AM, Soliman AS, Zhang Q, El-Ghawalby N, Ezzat F, Soultan A, et al. Serum cadmium levels in pancreatic cancer patients from the East Nile Delta region of Egypt. Environ Health Perspect. 2006;114(1):113.

    Article  CAS  PubMed  Google Scholar 

  151. Liu-Mares W, Mackinnon JA, Sherman R, Fleming LE, Rocha-Lima C, Hu JJ, et al. Pancreatic cancer clusters and arsenic-contaminated drinking water wells in Florida. BMC Cancer. 2013;13:111. https://doi.org/10.1186/1471-2407-13-111.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Luckett BG, Su LJ, Rood JC, Fontham ET. Cadmium exposure and pancreatic cancer in South Louisiana. J Environ Public Health. 2012;2012:180186. https://doi.org/10.1155/2012/180186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Yorifuji T, Tsuda T, Grandjean P. Unusual cancer excess after neonatal arsenic exposure from contaminated milk powder. J Natl Cancer Inst. 2010;102(5):360–1. https://doi.org/10.1093/jnci/djp536.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Chen C, Xun P, Nishijo M, Sekikawa A, He K. Cadmium exposure and risk of pancreatic cancer: a meta-analysis of prospective cohort studies and case-control studies among individuals without occupational exposure history. Environ Sci Pollut Res Int. 2015;22(22):17465–74. https://doi.org/10.1007/s11356-015-5464-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Antwi SO, Eckert EC, Sabaque CV, Leof ER, Hawthorne KM, Bamlet WR, et al. Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer. Cancer Causes Control. 2015;26(11):1583–91. https://doi.org/10.1007/s10552-015-0652-y.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Current cigarette smoking among adults - United States, 2011. MMWR Morbid Mortal Wkly Rep. 2012;61(44):889–94.

  157. Ng M, Freeman MK, Fleming TD, Robinson M, Dwyer-Lindgren L, Thomson B, et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA. 2014;311(2):183–92. https://doi.org/10.1001/jama.2013.284692.

    Article  CAS  PubMed  Google Scholar 

  158. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295(13):1549–55. https://doi.org/10.1001/jama.295.13.1549.

    Article  CAS  PubMed  Google Scholar 

  159. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–81. https://doi.org/10.1016/s0140-6736(14)60460-8.

    Article  PubMed  PubMed Central  Google Scholar 

  160. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998;21(9):1414–31.

    Article  CAS  PubMed  Google Scholar 

  161. Ghadirian P, Lynch HT, Krewski D. Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev. 2003;27(2):87–93.

    Article  CAS  PubMed  Google Scholar 

  162. Lowenfels AB, Maisonneuve P. Risk factors for pancreatic cancer. J Cell Biochem. 2005;95(4):649–56.

    Article  CAS  PubMed  Google Scholar 

  163. Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006;20(2):197–209.

    Article  PubMed  Google Scholar 

  164. Food, Nutrition, Physical activity and the prevention of cancer: a global perspective. Washington, DC: World Cancer Research Fund and the American Institute for Cancer Research; 2007.

  165. • Klein AP, Lindstrom S, Mendelsohn JB, Steplowski E, Arslan AA, Bueno-de-Mesquita HB, et al. An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PloS one. 2013;8(9):e72311. https://doi.org/10.1371/journal.pone.0072311 This study developed an absolute risk model for men and women of European descent using non-genetic and genetic factors to identify individuals at high-risk of pancreatic cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. • Wang W, Chen S, Brune KA, Hruban RH, Parmigiani G, Klein AP. PancPRO: risk assessment for individuals with a family history of pancreatic cancer. J Clin Oncol. 2007;25(11):1417–22. https://doi.org/10.1200/jco.2006.09.2452. PancPRO, a mendelian risk prediction model for pancreatic cancer in individuals with familial pancreatic cancer, was developed and validated within this study.

    Article  PubMed  Google Scholar 

  167. Nakatochi M, Lin Y, Ito H, Hara K, Kinoshita F, Kobayashi Y, et al. Prediction model for pancreatic cancer risk in the general Japanese population. PLoS One. 2018;13(9):e0203386. https://doi.org/10.1371/journal.pone.0203386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Yu A, Woo SM, Joo J, Yang HR, Lee WJ, Park SJ, et al. Development and validation of a prediction model to estimate individual risk of pancreatic cancer. PLoS One. 2016;11(1):e0146473. https://doi.org/10.1371/journal.pone.0146473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Pfeiffer RM, Park Y, Kreimer AR, Lacey JV Jr, Pee D, Greenlee RT, et al. Risk prediction for breast, endometrial, and ovarian cancer in white women aged 50 y or older: derivation and validation from population-based cohort studies. PLoS Med. 2013;10(7):e1001492. https://doi.org/10.1371/journal.pmed.1001492.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Wenten M, Gilliland FD, Baumgartner K, Samet JM. Associations of weight, weight change, and body mass with breast cancer risk in Hispanic and non-Hispanic white women. Ann Epidemiol. 2002;12(6):435–4.

    Article  PubMed  Google Scholar 

  171. • Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, et al. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013;62(3):339–47. https://doi.org/10.1136/gutjnl-2012-303108 A consortium on screening for pancreatic cancer of high-risk individuals.

    Article  PubMed  Google Scholar 

  172. • Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110(2):223-62; quiz 63. https://doi.org/10.1038/ajg.2014.435. Guidelines on screening of patients with genetic risk of gastrointestinal cancers.

  173. Munoz D, Near AM, van Ravesteyn NT, Lee SJ, Schechter CB, Alagoz O et al. Effects of screening and systemic adjuvant therapy on ER-Specific US breast cancer mortality. J Natl Cancer Instit. 2014;106(11). https://doi.org/10.1093/jnci/dju289.

  174. Usher-Smith JA, Emery J, Kassianos AP, Walter FM. Risk prediction models for melanoma: a systematic review. Cancer Epidemiol Biomarkers Prev. 2014;23(8):1450–63. https://doi.org/10.1158/1055-9965.EPI-14-0295.

    Article  PubMed  Google Scholar 

  175. Wang X, Oldani MJ, Zhao X, Huang X, Qian D. A review of cancer risk prediction models with genetic variants. Cancer Informat. 2014;13(Suppl 2):19–28. https://doi.org/10.4137/CIN.S13788.

    Article  CAS  Google Scholar 

  176. Griffin JF, Poruk KE, Wolfgang CL. Pancreatic cancer surgery: past, present, and future. Chin J Cancer Res. 2015;27(4):332–48. https://doi.org/10.3978/j.issn.1000-9604.2015.06.07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Haab BB, Huang Y, Balasenthil S, Partyka K, Tang HY, Anderson M et al. Definitive characterization of CA 19–9 in resectable pancreatic cancer using a reference set of serum and plasma specimens. Plos One. 2015;10(10). https://doi.org/10.1371/journal.pone.0139049.

  178. O'Brien DP, Sandanayake NS, Jenkinson C, Gentry-Maharaj A, Apostolidou S, Fourkala EO, et al. Serum CA19-9 is significantly upregulated up to 2 years before diagnosis with pancreatic cancer: implications for early disease detection. Clin Cancer Res. 2015;21(3):622–31. https://doi.org/10.1158/1078-0432.ccr-14-0365.

    Article  PubMed  Google Scholar 

  179. Ballehaninna UK, Chamberlain RS. Serum CA 19-9 as a biomarker for pancreatic cancer-a comprehensive review. Indian J Surg Oncol. 2011;2(2):88–100. https://doi.org/10.1007/s13193-011-0042-1.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Wald NJ, Hackshaw AK, Frost CD. When can a risk factor be used as a worthwhile screening test? BMJ. 1999;319(7224):1562–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Barrow TM, Michels KB. Epigenetic epidemiology of cancer. Biochem Biophys Res Commun. 2014;455(1–2):70–83. https://doi.org/10.1016/j.bbrc.2014.08.002.

    Article  CAS  PubMed  Google Scholar 

  182. Cho YH, Shen J, Gammon MD, Zhang YJ, Wang Q, Gonzalez K, et al. Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients. Breast Cancer Res Treat. 2012;131(1):197–205. https://doi.org/10.1007/s10549-011-1712-y.

    Article  CAS  PubMed  Google Scholar 

  183. Zhang P, Zou M, Wen X, Gu F, Li J, Liu G, et al. Development of serum parameters panels for the early detection of pancreatic cancer. Int J Cancer. 2014;134(11):2646–55. https://doi.org/10.1002/ijc.28584.

    Article  CAS  PubMed  Google Scholar 

  184. • Zhou B, Xu JW, Cheng YG, Gao JY, Hu SY, Wang L, et al. Early detection of pancreatic cancer: where are we now and where are we going? Int J Cancer. 2017;141(2):231–41. https://doi.org/10.1002/ijc.30670 A comprehensive review article on the early detection of pancreatic cancer.

    Article  CAS  PubMed  Google Scholar 

  185. Nolen BM, Brand RE, Prosser D, Velikokhatnaya L, Allen PJ, Zeh HJ, et al. Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study. PLoS One. 2014;9(4):e94928. https://doi.org/10.1371/journal.pone.0094928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Nie S, Lo A, Wu J, Zhu J, Tan Z, Simeone DM, et al. Glycoprotein biomarker panel for pancreatic cancer discovered by quantitative proteomics analysis. J Proteome Res. 2014;13(4):1873–84. https://doi.org/10.1021/pr400967x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Kaur S, Smith LM, Patel A, Menning M, Watley DC, Malik SS, et al. A combination of MUC5AC and CA19-9 improves the diagnosis of pancreatic cancer: a multicenter study. Am J Gastroenterol. 2017;112(1):172–83. https://doi.org/10.1038/ajg.2016.482.

    Article  CAS  PubMed  Google Scholar 

  188. Jenkinson C, Elliott VL, Evans A, Oldfield L, Jenkins RE, O'Brien DP, et al. Decreased serum thrombospondin-1 levels in pancreatic cancer patients up to 24 months prior to clinical diagnosis: association with diabetes mellitus. Clinical Cancer Res. 2016;22(7):1734–43. https://doi.org/10.1158/1078-0432.CCR-15-0879.

    Article  CAS  Google Scholar 

  189. Kim J, Bamlet WR, Oberg AL, Chaffee KG, Donahue G, Cao XJ et al. Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med. 2017;9(398). https://doi.org/10.1126/scitranslmed.aah5583.

  190. Song J, Sokoll LJ, Pasay JJ, Rubin AL, Li H, Bach DM, et al. Identification of serum biomarker panels for the early detection of pancreatic cancer. Cancer Epidemiol Biomark Prev. 2018. https://doi.org/10.1158/1055-9965.EPI-18-0483.

  191. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37. https://doi.org/10.1038/nrc3066.

    Article  CAS  PubMed  Google Scholar 

  192. di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144(6):1220–9. https://doi.org/10.1053/j.gastro.2013.01.071.

    Article  CAS  PubMed  Google Scholar 

  193. Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014;111(5):817–22. https://doi.org/10.1038/bjc.2014.215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24. https://doi.org/10.1126/scitranslmed.3007094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Cohen JD, Javed AA, Thoburn C, Wong F, Tie J, Gibbs P, et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc Natl Acad Sci U S A. 2017;114(38):10202–7. https://doi.org/10.1073/pnas.1704961114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. • Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926–30. https://doi.org/10.1126/science.aar3247 A cross-sectional study using CancerSEEK assay for detection of pancreatic cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Zippelius A, Pantel K. RT-PCR-based detection of occult disseminated tumor cells in peripheral blood and bone marrow of patients with solid tumors. An overview. Ann N Y Acad Sci. 2000;906:110–23.

    Article  CAS  PubMed  Google Scholar 

  198. Zhou J, Hu L, Yu Z, Zheng J, Yang D, Bouvet M, et al. Marker expression in circulating cancer cells of pancreatic cancer patients. J Surg Res. 2011;171(2):631–6. https://doi.org/10.1016/j.jss.2010.05.007.

    Article  CAS  PubMed  Google Scholar 

  199. Pimienta M, Edderkaoui M, Wang R, Pandol S. The potential for circulating tumor cells in pancreatic cancer management. Front Physiol. 2017;8:381. https://doi.org/10.3389/fphys.2017.00381.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Kulemann B, Pitman MB, Liss AS, Valsangkar N, Fernandez-Del Castillo C, Lillemoe KD, et al. Circulating tumor cells found in patients with localized and advanced pancreatic cancer. Pancreas. 2015;44(4):547–50. https://doi.org/10.1097/mpa.0000000000000324.

    Article  CAS  PubMed  Google Scholar 

  201. Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126(4):1208–15. https://doi.org/10.1172/JCI81135.

    Article  PubMed  PubMed Central  Google Scholar 

  202. Whiteside TL. Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem. 2016;74:103–41. https://doi.org/10.1016/bs.acc.2015.12.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Allenson K, Castillo J, San Lucas FA, Scelo G, Kim DU, Bernard V, et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann Oncol. 2017;28(4):741–7. https://doi.org/10.1093/annonc/mdx004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med. 2013;91(4):431–7. https://doi.org/10.1007/s00109-013-1020-6.

    Article  CAS  PubMed  Google Scholar 

  205. Yang S, Che SP, Kurywchak P, Tavormina JL, Gansmo LB, Correa de Sampaio P, et al. Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. Cancer Biol Ther. 2017;18(3):158–65. https://doi.org/10.1080/15384047.2017.1281499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. • Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523(7559):177–82. https://doi.org/10.1038/nature14581 This study identified Glypican-1 on cancer exosomes as a possible biomarker to detect pancreatic cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Dumstrei K, Chen H, Brenner H. A systematic review of serum autoantibodies as biomarkers for pancreatic cancer detection. Oncotarget. 2016;7(10):11151–64. https://doi.org/10.18632/oncotarget.7098.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Young MR, Wagner PD, Ghosh S, Rinaudo JA, Baker SG, Zaret KS, et al. Validation of biomarkers for early detection of pancreatic cancer: summary of the alliance of pancreatic cancer consortia for biomarkers for early detection workshop. Pancreas. 2018;47(2):135–41. https://doi.org/10.1097/mpa.0000000000000973.

    Article  PubMed  PubMed Central  Google Scholar 

  209. Mirus JE, Zhang Y, Li CI, Lokshin AE, Prentice RL, Hingorani SR, et al. Cross-species antibody microarray interrogation identifies a 3-protein panel of plasma biomarkers for early diagnosis of pancreas cancer. Clin Cancer Res. 2015;21(7):1764–71. https://doi.org/10.1158/1078-0432.CCR-13-3474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Yoneyama T, Ohtsuki S, Honda K, Kobayashi M, Iwasaki M, Uchida Y et al. Identification of IGFBP2 and IGFBP3 as compensatory biomarkers for CA19-9 in early-stage pancreatic cancer using a combination of antibody-based and LC-MS/MS-based proteomics. Plos One. 2016;11(8). https://doi.org/10.1371/journal.pone.0161009.

  211. Gerdtsson AS, Wingren C, Persson H, Delfani P, Nordstrom M, Ren H, et al. Plasma protein profiling in a stage defined pancreatic cancer cohort - implications for early diagnosis. Mol Oncol. 2016;10(8):1305–16. https://doi.org/10.1016/j.molonc.2016.07.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. • Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med. 2014;20(10):1193–8. https://doi.org/10.1038/nm.3686 This study found elevated levels of BCAAs is associated with pancreatic cancer risk, suggesting that whole-body protein breakdown is an early event in the development of PDAC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Davis VW, Schiller DE, Eurich D, Bathe OF, Sawyer MB. Pancreatic ductal adenocarcinoma is associated with a distinct urinary metabolomic signature. Ann Surg Oncol. 2013;20(Suppl 3):S415–23. https://doi.org/10.1245/s10434-012-2686-7.

    Article  PubMed  Google Scholar 

  214. Jenkinson C, Earl J, Ghaneh P, Halloran C, Carrato A, Greenhalf W, et al. Biomarkers for early diagnosis of pancreatic cancer. Exp Rev Gastroenterol Hepatol. 2015;9(3):305–15. https://doi.org/10.1586/17474124.2015.965145.

    Article  CAS  Google Scholar 

  215. Giovannetti E, Funel N, Peters GJ, Del Chiaro M, Erozenci LA, Vasile E, et al. MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Res. 2010;70(11):4528–38. https://doi.org/10.1158/0008-5472.can-09-4467.

    Article  CAS  PubMed  Google Scholar 

  216. Yu J, Li A, Hong SM, Hruban RH, Goggins M. MicroRNA alterations of pancreatic intraepithelial neoplasias. Clin Cancer Res. 2012;18(4):981–92. https://doi.org/10.1158/1078-0432.ccr-11-2347.

    Article  PubMed  Google Scholar 

  217. Munding JB, Adai AT, Maghnouj A, Urbanik A, Zollner H, Liffers ST, et al. Global microRNA expression profiling of microdissected tissues identifies miR-135b as a novel biomarker for pancreatic ductal adenocarcinoma. Int J Cancer. 2012;131(2):E86–95. https://doi.org/10.1002/ijc.26466.

    Article  CAS  PubMed  Google Scholar 

  218. Carlsen AL, Joergensen MT, Knudsen S, de Muckadell OB, Heegaard NH. Cell-free plasma microRNA in pancreatic ductal adenocarcinoma and disease controls. Pancreas. 2013;42(7):1107–13. https://doi.org/10.1097/MPA.0b013e318296bb34.

    Article  CAS  PubMed  Google Scholar 

  219. Lai XY, Wang M, McElyea SD, Sherman S, House M, Korc M. A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer. Cancer Lett. 2017;393:86–93. https://doi.org/10.1016/j.canlet.2017.02.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Poruk KE, Gay DZ, Brown K, Mulvihill JD, Boucher KM, Scaife CL, et al. The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med. 2013;13(3):340–51.

    CAS  PubMed  PubMed Central  Google Scholar 

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Yu, A., Romero, T.A. & Genkinger, J.M. Primary and Secondary Prevention of Pancreatic Cancer. Curr Epidemiol Rep 6, 119–137 (2019). https://doi.org/10.1007/s40471-019-00189-2

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