Obesity, inflammatory markers and endometrial cancer risk: results from the EPIC study

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1 WCRF conference: Nutrition, Physical Activity and Cancer Prevention September 2010 Obesity, inflammatory markers and endometrial cancer risk: results from the EPIC study Laure Dossus Division of Cancer Epidemiology

2 Inflammation and cancer Coussens and Werb, Nature, 2002

3 Inflammation and cancer Promotion of angiogenesis Cell proliferation Increased production of free radicals leading to DNA damage tumor initiation and development

4 Prospective studies One major maker: C-reactive protein Heikkila et al., 2009

5 Prospective studies Other markers: IL-6 Heikkila et al., 2009

6 Prospective studies Other markers: TNF-α Studies Cancer Cases Markers RR Krajcik et al., 2003 Breast 142 TNF- α N.S. + receptors Il yasova et al., 2005 Overall 296 TNF-α N.S.

7 Inflammation and EC

8 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 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

10 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

11 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)

12 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 Age at diagnosis Lag time (years) Body mass index (kg/m 2 ) Age at menopause Number of FTP 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%

13 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 0% 5% 6% stnf-rii 0% 5% 7%

14 Correlation with BMI adjusted for age at blood donation and laboratory batch CRP IL-6 IL-1Ra TNF-α stnf-ri stnf-rii

15 Inflammatory markers & risk of EC CRP (ng/ml) < > 2285 Cases/ Controls 68/152 67/152 89/ /152 OR Ptrend Crude OR Ptrend Adj for BMI IL-6 (pg/ml) < > /150 66/151 75/ / IL-1Ra (pg/ml) / / /98 > /

16 Inflammatory markers & risk of EC TNF-α (pg/ml) < > 1.33 Cases/ Controls 57/128 59/127 54/127 97/127 OR Ptrend Crude OR Ptrend Adjusted stnfr1 (pg/ml) < / / /127 > / stnfr2 (pg/ml) < / / /128 > /

17 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

18 Obesity, Inflammation and EC OBESITY Peripheral aromatization Inflammation cytokines IGFBP-1 IGFBP-2 Bio-active IGF-I OVARY Androgens Progesterone Insulin SHBG Estrogens (post only) ENDOMETRIAL CARCINOGENESIS

19 Obesity, Inflammation and EC For 258 cases & 452 controls, data were available on: C-peptide (a marker of pancreatic insulin secretion) Estrone

20 Obesity, Inflammation & EC in EPIC Obese vs. normal weight women

21 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)

22 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)

23 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

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