Dietary Fatty acids and Cancer: is there a link?

Transcription

1 Dietary Fatty acids and Cancer: is there a link? Veronique Chajes, PhD International Agency for Research on Cancer & Isabelle Romieu, MD, MPH, ScD Instituto Nacional de Salud Publica 1

2 Declaración de Intereses: No tengo ningún interés que declarar 2

3 Fatty acids: their effects on human health Cardiovascular diseases Type 2 diabetes Inflammatory diseases Cancer Calder, JPEN J Parenteral Enteral Nutr

4 Fatty acids and cancer development: Biological plausibility Diet Fatty acids Endogenous metabolism Membrane fluidity Signal transduction Regulation of bioactive lipid mediators Inflammation Cell survival and proliferation Transcription factors Gene expression Inflammation Insulin sensitivity Fatty acid metabolism DNA repair Apoptosis Calder, JPEN J Parenter Enteral

5 Total fat, individual fatty acids and cancer risk: first evidence Total fat intake and cancer mortality Experimental studies Carroll et al, Cancer Res stimulation inhibition Carroll et al, Cancer

6 Total fat, individual fatty acids and cancer risk: first evidence Total fat intake and cancer mortality Carroll et al, Cancer Res Willett, BMJ 1995 Biomarkers 6

7 EPIC: blood collection for biomarkers Fatty acids 1996 First GC IARC IARC 22 plasma/serum phospholipid fatty acids 60 plasma/serum phospholipid fatty acids 7

8 What biomarkers of FA may offer? Long-term biomarker Adipose tissue (gluteal, breast, etc.) Triglycerides 2 years Erythrocytes or platelets Membrane phospholipids 3 months Lipid fractions in serum or plasma Phospholipids weeks to months Cholesterol esters weeks Triglycerides hours Total serum? Short-term biomarker 8

9 Fatty acids and Breast Cancer 9

10 Fatty acids and breast cancer: meta-analysis of prospective cohort studies Fatty acids Nb cases Categories Overall risk estimates (95%CI) Dietary questionnaires Saturated fatty acids (SFA) 38,262 Highest vs lowest 1.08 ( ) 1 ER+PR+ -studies in Europe 1.18 ( ) 1 Monounsaturated fatty acids (MUFA) 38,262 Highest vs lowest 1.08 ( ) 1 Polyunsaturated fatty acids (PUFA) 38,262 Highest vs lowest 1.05 ( ) 1 Long-chain n-3 PUFA 16,178 Highest vs lowest 0.86 ( ) 2 Serum fatty acids (%) SFA 1,334 Highest vs lowest 1.00 ( ) 1 MUFA 1,334 Highest vs lowest 1.41 ( ) 1 Total n-6 PUFA 1,334 Highest vs lowest 0.84 ( ) 1 Total n-3 PUFA 1,334 Highest vs lowest 0.81 ( ) 1 Total PUFA 1,334 Highest vs lowest 0.59 ( ) 1 1 Cao et al, Int J Cancer 2016; 2 Zheng et al, BMJ

11 Fatty acids and breast cancer: the EPIC Study Authors Nb Nb cases/controls Exposure Categories Risk estimates categories Risk estimate (95%CI) Sieri et al, JNCI 2014 Pala et al, JNCI 2001 Chajès et al, Am J Epidemiol 2008 Chajès et al, Ann Oncol ,062 Dietary questionnaires SFA 71/142 ORDET 363/726 E3N-EPIC 2,982/2,982 EPIC Quintile 5 vs Q1 ER+PR ( ) Erythrocyte membrane Desaturation index Tertile 3 vs T ( ) Serum phospholipids Desaturation index Industrial trans fatty acids Plasma phospholipids Desaturation index Industrial trans fatty acids Quintile 5 vs Q ( ) 1.75 ( ) Quartile 4 vs Q1 Tertile 3 vs T1 ER-PR ( ) 2.01 ( ) Desaturation index (SCD-1) = Ratio MUFA/SFA Adjustment factors: date of blood collection, body mass index, years of education, height, menopausal hormone use at baseline, alcohol intake at recruitment, age at first birth and parity combined, energy intake, and family history of 11 breast cancer.

12 Fatty acids and breast cancer: the EPIC Study Authors Nb cases/controls Exposure Categories Risk estimates (95%CI) Sieri et al, JNCI 2014 Pala et al, JNCI 2001 Chajès et al, Am J Epidemiol 2008 Chajès et al, Ann Oncol ,062 Dietary questionnaires SFA 71/142 ORDET 363/726 E3N-EPIC 2,982/2,982 EPIC Quintile 5 vs Q1 ER+PR ( ) Erythrocyte membrane Desaturation index Tertile 3 vs T ( ) Serum phospholipids Desaturation index Industrial trans fatty acids Plasma phospholipids Desaturation index Industrial trans fatty acids Quintile 5 vs Q ( ) 1.75 ( ) Quartile 4 vs Q1 Tertile 3 vs T1 ER-PR ( ) 2.01 ( ) 12

13 Endogenous synthesis of fatty acids and breast cancer Desaturation index 16 Categories Cases/Controls OR 95%CI P for trend on means Q-value (FDR corrected p-value) <0.018 [ [ [ [ >= / / / / p=.002 p= Increased endogenous synthesis of MUFA and dietary SFA may increase risk of breast cancer? ER+PR+ Chajès et al., Ann Oncol

14 Industrial trans fatty acids and ER-PR- breast cancer High intake of industrial trans fatty acids may increase risk of ER-PR- breast cancer Replication in the American CPS-2 prospective study 14 Chajès et al., Ann Oncol 2017

15 Fatty acids and Colon Cancer 15

16 Fatty acids (n-3 PUFA) and colon cancer: metaanalysis of prospective studies Dietary questionnaires (n=14 cohort studies; 8,775 cases) N-3 LC PUFA Risk estimates (95%CI) Colon cancer 0.98 ( ) Latency time <13y 1.03 ( ) Latency time 13y 0.79 ( ) Proximal colon cancer 0.81 ( ) Distal colon cancer 1.38 ( ) Chen et al, Cancer Causes Control 2015 n-3 long-chain PUFA Blood and tissue levels (%) Yang et al, PLoS One

17 n-3 PUFA and colon cancer: the EPIC study Authors Aglago, Murphy, Chajès, Gunter; ongoing study Nb cases/controls Exposure Categories Risk estimates (95%CI) 6,291 Dietary questionnaires N-3 LC PUFA Quintile 5 vs Q1 Colon Proximal Distal 0.86 ( ) 0.86 ( ) 0.86 ( ) 461/461 Plasma phospholipids N-3 LC PUFA Quartile 4 vs Q1 Colon Proximal Distal 0.94 ( ) 0.55 ( ) 1.54 ( ) Adjusted for energy, BMI, height, physical activity, smoking, education, alcohol consumption, red and processed meat consumption, fibre consumption, dairy products consumption. Aglago, Murphy et al, ms in preparation 17

18 Conclusion/perspectives Dietary questionnaires Saturated fatty acids Plasma/serum phospholipid fatty acids Ratio palmitoleic acid/palmitic acid Cancer ER+PR+ Breast cancer PUFA n-3?? EPA, DHA Colon cancer itfa?? Elaidic acid (18:1n-9t), total itfa ER-PR- Breast cancer 18

19 Dietary Fatty acids and breast cancer Latin American studies 19

20 The CAMA Study: Setting-up Case control study Main health care systems North IMSS Cases n = 1000 ISSSTE Center South SS Controls n = 1074 IMSS SS Cases 200 Controls

21 The CAMA Study: Methods Health Diet Physical activity Anthropometric measurements Blood samples 21

22 Dietary intake of PUFA at baseline Controls Cases n=1,000 n=1,074 p for trend -3 PUFA (g/d) ( ) ( ) -6 PUFA (g/d) ( ) ( ) -3 / -6 PUFA ( ) ( ) 22

23 PUFA and breast cancer stratified by menopausal status Premenopausal women Postmenopausal women PUFA Tertiles Cases/Controls OR 95%CI PUFA Tertiles Cases/Controls OR 95%CI OMEGA6 OMEGA6 1 63/ / / / OMEGA / P = 0.02 OMEGA / P = / / / / Omega3/Omega / P = 0.30 Omega3/Omega / P = / / / / / P = / P = Chaves et al. Cancer Epidemiol 1 Biomarkers Prev. 2012;21(2):

24 PUFA and breast cancer stratified by BMI Normoweight Overweight Obese PUFA Tertiles OR 95%CI Tertiles OR 95%CI Tertiles OR 95%CI OMEGA6 OMEGA P = P = P = 0.93 Omega3/Omega P = P = P = P = P = P = Chaves et al. Cancer Epidemiol Biomarkers Prev. 2012;21(2):

25 Discussion Protective effect of w3 fatty acids on breast cancer risk among obese women? Biological plausibility Decrease estrogen synthesis, via down-regulation of aromatase expression Increase plasma levels of adiponectin and decrease plasma levels of leptin Decrease fatty acid synthesis via down-regulation of Acetyl-CoA carboxylase-alpha (ACCA), Fatty acid synthase (FAS), Stearoyl-CoA-desaturase-1 (SCD-1). These enzymes are over expressed in models of obese rats, and supplementation with w3 PUFA decreased gene expression and led to weight loss. Reduced inflammatory processes in adipose tissue 25

26 Serum phospholipid fatty acids levels and breast cancer in young women: PRECAMA study Preliminary results 26

27 Materials and methods: data collection and analysis Study design: Multicentre, Case-control study among Latin American women <=45years Countries: Chile, Colombia, Costa Rica, and Mexico Questionnaires: Demographic data, Socio-economic data, Personal and family morbidity, Reproductive factors, Physical activity, Smoking status, Dietary consumption Anthropometry: Weight, height, waist, hip ----> BMI, WHR Individual fatty acids expressed as % total fatty acids were used for the analysis Values were log-transformed for analysis Conditional logistic regressions. n=150 cases and 150 controls matched on age, country and place of residence Adjustment for potential confounding factors 27

28 Total PUFA 3 (%) Elaidic acid (%) Total PUFA 6 (%) Fatty acids levels per country Elaidic acid per country Total PUFA 6 per country Chile Colombia Costa Rica Mexico Chile Colombia Costa Rica Mexico Total PUFA 3 per country Chile Colombia Costa Rica Mexico *Red horizontal lines are data from EPIC 28

29 Breast cancer risk by tertiles of serum phospholipid fatty acids (n=150 cases and 150 controls) Unadjusted Adjusted * Q1 Q2 Q3 P trend Q1 Q2 Q3 P trend Saturated fatty acids (SFA) Total SFA ( ) 1.19 ( ) ( ) 2.70 ( ) 0.25 Monounsaturated fatty acids (MUFA) Total cis-mufa ( ) 1.19 ( ) ( ) 1.42 ( ) 0.43 Total trans-mufa ( ) 2.13 ( ) ( ) 2.57 ( ) 0.12 Trans fatty acids 18:1n-9/12 (elaidic acid) ( ) 2.28 ( ) ( ) 2.14 ( ) 0.32 Total trans ruminant fatty acids ( ) 3.33 ( ) ( ) 3.30 ( ) Total trans industrial fatty acids ( ) 2.42 ( ) ( ) 4.77 ( ) Polyunsaturated fatty acids (PUFA) Total long-chain n-6 PUFA ( ) 2.21 ( ) ( ) 3.44 ( ) Total long-chain n-3 PUFA ( ) 7.81 ( ) ( ) 5.72 ( ) Ratio PUFA n-6/n ( ) 0.15 ( ) ( ) 0.13 ( ) Desaturation indexes SCD-16 (16:1n-7cis/16:0) ( ) 0.94 ( ) ( ) 1.15 ( ) 0.81 SCD-18 (18:1n-9cis/18:0) ( ) 0.96 ( ) ( ) 0.81 ( ) 0.63 FADS1 (20:4n-6/20:3n-6) ( ) 1.84 ( ) ( ) 1.48 ( ) 0.36 *Adjusted for Age, smoking, family breast cancer history, breastfeeding, physical activity, oral contraceptive use, age at first menses, education, height and weight 29

30 Discussion 1. Trans fatty acids and breast cancer: ruminant fatty acids The association between dairy fatty acids and breast cancer is inconsistent. Some dietary studies looked at different sources of dietary dairy. Yogurt showed a negative association while cheese showed a positive association. The associations between ruminant Fas and BRC is likely depend on menopausal status, subtype of breast tumor and BMI PUFA and breast cancer Inconsistent results. Most of the studies used questionnaires, or targeted specifically reported fish consumption as primary sources of PUFA n-3 Potential contamination of fish by heavy metals (incl. Hg, Cd, Vd, Pb) from water The association between PUFA and BRC may be modulated by antioxidants levels. In Mexican women, Chajes et al. (2012, study on dietary questionnaire) showed a protective effect of n-3 in obese women and a positive association with n-6 in premenopausal women Several studies have also suggested that the n-6/n-3 might be a more important factor than the individual PUFA n-3 and n-6 with regards to the risks towards BRC McCann et al. Curr Dev Nutr 2017 Pollack et al. Environ Health Perspect Pouchieu et al. PlosOne 2014

31 Conclusion Fatty acids appear to be important in relation to cancer development. More research is needed on their metabolic role and the role of endogenous synthesis ( genetic polymorphisms, epigenetics, interaction with other nutrients). The role of industrial trans-fatty acids has been observed in different cohort studies but more research is need to understand mechanisms Polyunsaturated fatty acids may act differently depending on the host factors such as baseline levels, metabolic disorders and genetic susceptibility Confirmed associations will support dietary recommendations to decrease the burden of cancer 31

32 Acknowledgments Elio Riboli, Imperial college, UK EPIC Investigators IARC team NME Sabina Rinaldi Laure Dossus Carien Biessy Marc Gunter Elom Aglado Neil Murphy Epic Participants and Funding Agencies Gabriela Torres, INSP CAMA research Team CAMA participants Sabina Rinaldi, IARC PRECAMA country Team Gabriela Torres, Mexico Gloria I. Sanchez, Colombia Maria Luisa Garmendia, Chile Carolina Porras, Costa Rica PRECAMA participants 32

33 Gracias! 33

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