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Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
Kaaks opac2013
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Kaaks opac2013

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  • 1. Excess body weight, metabolic riskfactors and pancreatic cancerRudolf KaaksDept. of Cancer Epidemiology
  • 2. Page 2 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerIncidence rates of pancreas cancer (men, all ages)
  • 3. Page 3 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerRisk factors of pancreatic cancer• Smoking• Chronic pancreatitis• Excess body weight• Diabetes mellitus• Allergies
  • 4. Page 4 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerBMI and pancreas cancer risk –meta-analysis of prospective cohort studiesAune et al., Ann Oncol 2012 Overall summary RR = 1.10, for 5 kg/m2
  • 5. Page 5 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerAune et al., Ann Oncol 2012BMI and pancreas cancer risk –meta-analysis of prospective cohort studies
  • 6. Page 6 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerDiabetes mellitus and pancreas cancer risk – meta-analysis ofprospective cohort studiesBen et al., Eur J Cancer, 2011Overall Summary RR ≈ 2.0Duration(yrs)# studies RR<1 3 5.381-4 5 1.955-9 4 1.49≥10 4 1.47>1 14 1.96>5 11 1.83
  • 7. Page 7 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerAssociations (odds ratios) between BMI, type-2 diabetesand pancreas cancer risk (EPIC, nested case-control study)Pancreatic CancerExcess Body Weight Type 2 Diabetes MellitusBMI 25-30 : 2.40 ♂ / 3.92 ♀BMI ≥ 30 : 6.74 ♂ / 12.41 ♀1.82BMI 25-30: 1.09 ♂ / 1.29 ♀BMI ≥ 30: 1.50 ♂ / 1.46 ♀(among non smokers)
  • 8. Page 8 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerRelative risks of cancer, by quintiles/quartiles of fasting serumglucose -- large prospective cohort studiesKorea; Jee et al. JAMA 2005 P-trendPancreas (M) 1.0 1.08 1.34 1.37 2.09 0.03Pancreas (F) 1.0 1.27 1.39 1.99 1.67 0.04Liver (M) 1.0 1.01 1.16 1.45 1.72 0.01Kidney(M) 1.0 1.08 1.07 1.24 1.26 0.02Austria; Rapp et al. Diabetologia 2006 P-trendLiver (M) 1.59 1.00 2.63 3.50 4.58 0.001Biliary tract (M+F) 0.92 1.00 1.90 3.74 3.35 0.0002Endometrium (F) 0.78 1.00 1.63 0.84 1.62 0.05Sweden; Stattin et al., Diabetes Care, 2007 P-trendPancreas (M+F) 1.0 1.19 1.11 2.49 0.006Kidney (M+F) 1.0 1.35 1.49 2.08 0.09Melanoma (M+F) 1.0 1.41 2.14 2.16 0.013Endometrium (F) 1.0 1.32 1.16 1.86 0.02
  • 9. Page 9 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerRelative risk of pancreas cancer, by levels of fasting glucose, insulin,and insulin resistance – Stratified by follow-up timeStolzenberg-Solomon et al., JAMA 2005
  • 10. Page 10 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerRisk of pancreatic cancer by categories of HbA1c(EPIC cohort)Levelptrend1 2 3 4HbA1c Cut-offs (%) 4.8-5.4 5.5-5.7 5.8-6.0 6.0-11.0Crude 1.0 1.26 1.77 1.83Adj. BMI,smoking1.0 1.28 1.78 1.67Grote et al., Diabetologia 2011
  • 11. Page 11 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerOR for pancreatic cancer by categories of C-peptide (EPIC)overall, excluding diabetic subjects, and by fasting status1 2 3 4 ptrendCases/ControlsAll crude 1.0 1.42 1.38 1.42adj. smoking, BMI 1.0 1.27 1.16 1.15without T2D ** crude 1.0 1.25 1.06 1.15adj. smoking, BMI1.0 1.23 1.00 1.09Non-fasting crude 1.0 1.44 1.21 1.44adj. smoking, BMI1.0 1.45 1.16 1.29Fasting crude 1.0 1.39 1.38 2.20(117/111) adj. smoking, BMI 1.0 1.22 1.22 1.90** at blood donation Grote et al., Diabetologia 2011
  • 12. Page 12 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerRelative risk for pancreatic cancer by quartiles of plasma C-peptide;HPFS, NHS, PHS and WHI cohortsAll cases /controls46 / 1441.0040 / 1410.8236 / 1430.7875 / 1431.52 (0.87 – 2.64)Ptrend = 0.005> 4 yearsfollow-up29 / 1031.0030 / 911.1027 / 1070.9951 / 981.90 (0.97 – 3.73)Ptrend = 0.01FastingNon-fasting1.001.000.791.210.810.861.21 (0.66 – 2.24)4.24 (1.30 – 13.8)Ptrend = 0.19Ptrend < 0.001Michaud et al., CEBP 2007
  • 13. Page 13 Rudolf Kaaks Obesity, Metabolism and Pancreatic Cancerbreast pancreascolorectal prostateCurrie et al., Diabetologia, 2009Metformin onlyMetformin +sulfonylureaSulfonylurea onlyInsulin-basedMetformin onlyMetformin + sulfonylureaInsulin-basedSulfonylurea onlyProgression to solid tumor cancers in diabetics receivingdifferent glucose-lowering therapies.UK General Practices study
  • 14. Page 14 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerAdiponectin and pancreas cancer risk (prospective studies)study cases / controls 1 2 3 4 5 ptrendATBC 311/510 1.00 0.76 1.12 1.08 1.00 0.78adj. smoking 0.96 0.69 0.80 0.65 0.04EPIC 452/452 1.00 0.94 1.07 0.67 0.045Adj. BMI 1.00 1.20 0.77 0.20adj. smoking 0.96 1.11 0.72 0.11Never smokers 1.02 0.92 0.44 0.0055 UScohorts468/1080adj. smoking(matched)1.00 0.60 0.57 0.55 0.60 0.004Stolzenberg-Solomon et al., Am J Epidemiol, 2008;Grote et al., Int J Cancer, 2012;Bao et al., JNCI, 2013
  • 15. Page 15 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerInflammation markers and pancreas cancer risk –EPIC cohortNo associations for:• CRP• IL-6• sTNF-R1Grote et al., Br J Cancer 2012sTNF-R2
  • 16. Page 16 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerSerum CML (Nε-carboxymethyl-lysine) and pancreas cancer risk – EPICGrote et al., Cancer Epidemiol Biomarkers Prev, 2012
  • 17. Page 17 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerSerum esRAGE and pancreas cancer risk – EPICGrote et al., Cancer Epidemiol Biomarkers Prev, 2012
  • 18. Page 18 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerSerum CML (Nε-carboxymethyl-lysine), sRAGE and pancreascancer risk – ATBC cohortstudy cases / controls 1 2 3 4 5 ptrendCML 255/485 1.00 0.49 0.48 0.60 0.46 0.003adj. smoking, BMI 0.49 0.47 0.58 0.45 0.003sRAGE 255/485 1.00 0.75 0.69 0.35 0.39 0.0001adj. smoking, BMI 0.72 0.69 0.36 0.40 0.0002CML / sRAGEratio255/485 1.00 1.45 1.30 1.38 2.02 0.01adj. smoking, BMI 1.46 1.30 1.39 2.02 0.02Jiao et al., Cancer Res, 2011
  • 19. Page 19 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerConclusions – Interpretation (i)• BMI significantly, but not strongly associated with pancreas cancer risk,and only among non-smokers.• Pancreas cancer is associated with pre-existing, increased glycemia anddiabetes (mostly adult-onset); associations with serum insulin still unclear• BMI correlates strongly with fasting insulin/insulin resistance, but onlyweakly with blood glucose. Insulin resistance may not generally be the major cause of deterioratedglucose metabolism interaction between insulin resistance and other (“host”) factors indevelopment of pancreatic beta-cell insufficiency.
  • 20. Page 20 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerRelationships between insulin sensitivity and pancreatic β-cellfunction, in normal and impaired glucose tolerance
  • 21. Page 21 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerConclusions – Interpretation (ii)• Diabetes as cause, effect, or epi-phenomenon of pancreas cancer ?• Is pancreas cancer associated with “pancreatogenic” (“type 3c”) diabetes?• Role of inflammatory processes in (diabetes preceding) pancreas cancer?• Causes for the large international differences in pancreas cancerincidence are not well-understood.
  • 22. Page 22 Rudolf Kaaks Obesity, Metabolism and Pancreatic CancerThank you for your attention

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