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WCRF conference: Nutrition, Physical Activity and Cancer Prevention 12-13 September 2010 Obesity, inflammatory markers and endometrial cancer risk: results from the EPIC study Laure Dossus Division of Cancer Epidemiology Inflammation and cancer Coussens and Werb, Nature, 2002 9/17/10 | Laure Dossus Division of Cancer Epidemiology Inflammation and cancer • Promotion of angiogenesis • Cell proliferation • Increased production of free radicals leading to DNA damage ► tumor initiation and development 9/17/10 | Laure Dossus Division of Cancer Epidemiology Prospective studies One major maker: C-reactive protein Heikkila et al., 2009 9/17/10 | Laure Dossus Division of Cancer Epidemiology Prospective studies Other markers: IL-6 Heikkila et al., 2009 9/17/10 | Laure Dossus Division of Cancer Epidemiology Prospective studies Other markers: TNF-α 9/17/10 | Studies Cancer Cases Markers RR Krajcik et al., 2003 Breast 142 TNF- α + receptors N.S. Il’yasova et al., 2005 Overall 296 TNF-α N.S. Laure Dossus Division of Cancer Epidemiology Inflammation and EC 9/17/10 | Laure Dossus Division of Cancer Epidemiology Inflammation and EC • Central role of inflammation in the regulation of endometrial mucosa growth and shedding during menstrual cycle • Alterations of cytokine production in endometrial cancer patients • Established risk factors for endometrial cancer are associated with an inflammatory milieu: excess body weight, type-II diabetes, low physical activity 9/17/10 | Laure Dossus Division of Cancer Epidemiology Inflammation and EC in EPIC Study aims: to examine the association between blood concentrations of inflammatory markers and endometrial cancer risk to estimate the extent to which the association between obesity and endometrial cancer is mediated by inflammation 9/17/10 | Laure Dossus Division of Cancer Epidemiology The EPIC study • 521,000 subjects (400,000 with biological samples ) • Detailed questionnaire data on diet, lifestyle, illnesses, medication, reproduction, anthropometry • Follow-up through cancer registries, health insurance, pathology registries, active follow-up 9/17/10 | Laure Dossus Division of Cancer Epidemiology Study population Exclusions: HRT or OC users at blood donation prevalent cancers (except non melanoma skin cancer) hysterectomized women • • • Case selection: incident epithelial endometrial cancer Control selection: up to two controls per case, individually matched on: study center, age, menopausal status, time of the day of blood collection, fasting status, menstrual cycle phase (pre only) 9/17/10 | Laure Dossus Division of Cancer Epidemiology Baseline characteristics Cases (N=342) Controls (N=644) Premenopausal 23.4% 22.4% Postmenopausal 65.8% 66.8% Perimenopausal / Unknown 10.8% 10.9% Age at blood collection 56.5 56.6 Age at diagnosis 59.9 - Lag time (years) 3.5 - Body mass index (kg/m2) 27.6 26.0 Age at menopause 50.9 49.8 Number of FTP 2.3 2.4 Previous OC use 33.6% 43.5% Previous HRT use 29.5% 16.7% Diabetes 4.1% 3.5% Current smokers 14.9% 17.7% 9/17/10 | Laure Dossus Division of Cancer Epidemiology Laboratory measurements < LOQ Intra-batch CVs Inter-batch CVs IL-6 0% 6.3% 8.2% CRP 2% 6.8% 9.3% IL-1Ra 50% 15.0% 27.7% TNF-α 21% 16.7% 27.0% sTNF-RI sTNF-RII 0% 0% 5% 5% 6% 7% 9/17/10 | Laure Dossus Division of Cancer Epidemiology Correlation with BMI adjusted for age at blood donation and laboratory batch CRP IL-6 0.36 9/17/10 | 0.33 Laure Dossus IL-1Ra 0.20 TNF-α sTNF-RI sTNF-RII 0.07 Division of Cancer Epidemiology 0.14 0.18 Inflammatory markers & risk of EC Crude Cases/ CRP (ng/mL) Controls < 581 68/152 581-1127 67/152 1128-285 89/152 > 2285 102/152 1.00 1.03 1.40 1.66 IL-6 (pg/mL) < 0.85 0.85-1.20 1.21-1.78 > 1.78 71/150 66/151 75/152 115/150 1.00 0.94 1.10 1.76 IL-1Ra (pg/mL) ≤ 16.0 159/325 16.1-58.0 36/100 58.1-135.4 58/98 > 135.4 82/104 1.00 0.79 1.34 1.83 OR Ptrend OR Ptrend 0.004 1.00 0.92 1.20 1.12 0.36 0.002 1.00 0.84 0.91 1.30 0.17 0.002 1.00 0.69 1.12 1.47 0.07 0.5 9/17/10 | Laure Dossus Adj for BMI 1 2 Division of Cancer Epidemiology 0.5 1 2 Inflammatory markers & risk of EC Cases/ Controls TNF-α (pg/mL) < 0.59 57/128 0.60-0.95 59/127 0.96-1.33 54/127 > 1.33 97/127 1.00 1.10 1.04 1.82 sTNFR1 (pg/mL) < 856.4 54/128 856.5-987.7 60/129 987.8-1124.4 62/127 > 1124.5 92/127 1.00 1.13 1.26 1.96 sTNFR2 (pg/mL) < 1583.4 56/128 1583.5-1815.9 50/128 1816.0-2147.8 78/128 > 2147.9 84/127 1.00 0.90 1.45 1.67 OR Ptrend OR Ptrend 0.005 1.00 0.98 1.02 1.73 0.01 0.005 1.00 1.21 1.21 1.68 0.07 0.01 1.00 0.86 1.42 1.53 0.03 0.5 9/17/10 | Laure Dossus Crude 1 2 Division of Cancer Epidemiology Adjusted 0.5 1 2 Inflammation and EC in EPIC Study aims: to examine the association between blood concentrations of inflammatory markers and endometrial cancer risk to estimate the extent to which the association between obesity and endometrial cancer is mediated by inflammation 9/17/10 | Laure Dossus Division of Cancer Epidemiology Obesity, Inflammation and EC OBESITY Inflammation cytokines↑ Peripheral aromatization ↑ Insulin ↑ IGFBP-1 ↓ IGFBP-2 ↓ SHBG↓ Bio-active IGF-I ↑ OVARY Androgens↑ Progesterone↓ ENDOMETRIAL CARCINOGENESIS 9/17/10 | Laure Dossus Division of Cancer Epidemiology Estrogens ↑ (post only) Obesity, Inflammation and EC For 258 cases & 452 controls, data were available on: • C-peptide (a marker of pancreatic insulin secretion) • Estrone 9/17/10 | Laure Dossus Division of Cancer Epidemiology Obesity, Inflammation & EC in EPIC Obese vs. normal weight women 9/17/10 | Laure Dossus Division of Cancer Epidemiology Summary • Elevated inflammatory markers are associated with endometrial cancer risk • Possible mediators of the association between obesity and endometrial cancer • Also direct role in endometrial cancer development, independently of BMI (TNF-α) 9/17/10 | Laure Dossus Division of Cancer Epidemiology Possible mechanisms • Indirect obesity-related effects: o Modulation of the aromatase activity by cytokines within the adipose tissue o Development of insulin resistance • Direct effect on endometrial carcinogenesis (NF-kB pathway) 9/17/10 | Laure Dossus Division of Cancer Epidemiology Acknowledgments Rudolf Kaaks Annie Lukanova Susen Becker Sigrid Henke Britta Lederer Sabina Rinaldi David Achaintre Thomas Cler Bertrand Hemon EPIC colleagues & participants The study was funded by the WCRF grant 2007/13 9/17/10 | Laure Dossus Division of Cancer Epidemiology