Kost, kræft og helbred En undersøgelsen til belysning af sammenhængen mellem kost og kræft Anne Tjønneland Kim Overvad Institut for Epidemiologisk Institut for Epidemiologi og Kræftforskning Socialmedicin Kræftens Bekæmpelse Aarhus Universitet Kost, kræft og helbred

Diet, Cancer and Health Organisation Principal investigators Anne Tjønneland Institute of Cancer Epidemiology Danish Cancer Society Kim Overvad Department of Epidemiology and Social Medicine Aarhus University Funding Danish Cancer Society EU NCU Steering Committee Jørn Olsen (Chairman) Britmarie Sandström Per Kragh Andersen Peter Ebbesen Torben Kruse Hans Sjöström Kost, kræft og helbred

Beskrivelse af databasen Demografi Kost Baggrund, livsstil Antropometri/biologiske målinger Biologisk materiale Kost, kræft og helbred

Deltagere En stikprøve af befolkningen 57.054 personer 27.179 mænd 29.875 kvinder Født i Danmark 7% af aldersgruppen 50-64 år Bosiddende i Københavns kommune Frederiksberg kommune Københavns amt Århus amt Ikke tidligere haft en kræftsygdom Kost, kræft og helbred

Kostoplysninger Kostspørgeskema Semikvantitativt fødevare-frekvensspørgeskema Normalkost gennem det sidste år 196 spørgsmål Måltider Fødevarer Kosttilskud Fedtstoffer brugt ved madlavning Tilberedningsmetoder Kost, kræft og helbred

Kost, kræft og helbred

Spørgeskema om risikofaktorer Baggrund og livsstil Spørgeskema om risikofaktorer Rygevaner  Familieoplysninger - tidligere og nuværende  Uddannelse Alkoholvaner  Arbejde - tidligere og nuværende  Kvindeoplysninger Hudtype - menstruationsforhold Fysisk aktivitet - graviditeter Sygdomme - svangerskabsforebyggelse - tidligere og nuværende - hormonbehandling Medicinindtagelse  Mandeoplysninger Afføringsvaner - sterilisationsspørgsmål Vægt - antal børn - tidligere og nuværende Kost, kræft og helbred

Diet, Cancer and Health Questionnaire check * Optically readable * Missing marking. double marking * Limits * Logical checks Diet, Cancer and Health

Antropometri og biologiske målinger  Ståhøjde  Siddehøjde  Vægt  Taljemål  Hoftemål  Bioimpedans  Blodtryk  Totalkolesterol  Urin  blod  protein  sukker Kost, kræft og helbred

Biologisk materiale  Blodprøve 30 ml  filterpapir  serum 4 x 1 ml  plasma 6 x 1 ml  buffy coat 2 x 1 ml  erytrocytter 2 x 1 ml  Urinprøve 4 x 1 ml  Fedtbiopsi  Tånegleklip Kost, kræft og helbred

Diet, Cancer and Health Tube Box Rack Liquid nitrogen container Kost, kræft og helbred

Section of the biological bank Kost, kræft og helbred

Monitoring of the nitrogen containers Kost, kræft og helbred

Spare nitrogen container in case of break down Kost, kræft og helbred

Liquid nitrogen container Kost, kræft og helbred

Kost, kræft og helbred Registerkoblinger hvert år * Det Centrale Personregister (CPR) * Cancerregisteret * Dødsårsagsregisteret * Landspatientregisteret Spørgeskemadata med 3-5 års interval * Ændringer for eksponering * Information om nye eksponeringer * Oplysninger om sygdomsudfald Kost, kræft og helbred

Antal kræfttilfælde blandt deltagerne (primo 2003) Mænd Kvinder Total 1713 2052 3765 Colon/rectum 241 208 Breast 5 836 Lung 234 209 Prostate 325 - Kost, kræft og helbred

EPIC collaborating centres UK: OXFORD CAMBRIDGE NETHERLANDS: UTRECHT RIVM GERMANY: POTSDAM HEIDELBERG FRANCE: PARIS ITALY: TURIN MILAN FLORENCE NAPLES RAGUSA SPAIN OVIEDO SAN SEBASTIAN PAMPLONA MURCIA GRANADA GREECE ATHENS SWEDEN: UMEA MALMO DENMARK: AARHUS COPENHAGEN NORWAY: TROMSO EPIC collaborating centres I.A.R.C. LYON PARIS FLORENCE MILAN RAGUSA TURIN NAPLES

Subject Recruitment in the EPIC Study

Expected Cancer Cases in the EPIC Study after 5 and 10 Years’ Follow-up

EPIC data on diet Two dietary measurements: Dietary questionnaire on usual diet from all 470.000 subjects Very detailed, 150 to 300 foods per questionnaire To relate diet to cancer risk One day “actual” diet from a 7% sample of subjects (32.000) Computerized, 3000 foods and 700 recipes per country To calibrate dietary measurements between countries

EPIC Database on ORACLE system Estimated final size of the database = 150 giga bytes. 90 screens have been developed to facilitate the transfer, standardization, control and export of the data 500.000 subjects * 2000 common variables  1 Billion values to be stored

Diet and cancer hypothesis 1: FOODS Increased risk Meat (red?) Processed meat Salted food Sweets and sugar Reduced risk Vegetables Fruits Whole grain cereals Oily fish

Diet and cancer hypothesis 2 :NUTRIENTS Reduced Risk Poly Unsaturated Fats. Fibre Vitamins and minerals Various non-nutrient components Increased Risk Total fat Saturated fat (Animal) protein Sugars Cooking products

Diet/Nutrition and cancer hypothesis 3 : ENERGY BALANCE Increased risk Overweight Abdominal obesity Sedentary life Reduced risk Normal weight Low waist/hip ratio Physical activity

Diet/Nutrition and cancer hypothesis 4 : Endogenous hormones Androgens, Estrogens, Insulin, Growth Factors (IGFs) and their binding proteins

Hypotheses 5 : GENETIC FACTORS Focused on genetic polymorphisms, e.g. genes involved in hormones metabolism, DNA repair, carcinogens metabolisms, prostaglandins synthesis… Interactions between genes, lifestyle and environment Rare mutations in cancer associated genes (e.g. BRCA1, BRCA2, HNPCC)

EPIC Biorepository

EPIC BIOREPOSITORY: TUBES AND GOBLETS USED TO HOLD PLASTIC STROWS

EPIC BIOREPOSITORY AT IARC-WHO

EPIC BUILDING, LYON, IARC-WHO

Total fruit consumption (grams/day) in EPIC adjusted for age, season and day of the week : MEN 500 450 u 400 350 300 grams/day 250 200 150 100 50 Murcia Ragusa Trin Umea Florence Granada Varese Oviedo Greece Malmo Pamplona Potsdam Aarhus Heidelberg Bilthoven San Sebastian Copenhagen UK - Health conscious UK: General population centres

Variations of biomarkers of diet between EPIC cohorts

Variations of biomarkers of diet between EPIC cohorts Lycopene, men 45-64 years 100 90 80 70 60 microg/dl 50 40 30 20 10 Murcia Umeå Florence Greece Granada Cambridge Heidelberg Potsdam Denmark Malmö Varese/Turin Oxford (*Veg) Ragusa/Naples The Netherlands Northern Spain

Dietary patterns associated with participating countries Country 150% or greater than mean overall intake Italy Vegetables, fruits, cereal products, vegetable oils, sauces Greece Vegetable, legumes, vegetable oils Spain Vegetables, fruits, legumes, vegetable oils, milk, eggs, fresh meat, fish France Sugars, butter, dairy products Bingham & Riboli, 2004 Kost, kræft og helbred

Dietary patterns associated with participating countries Country 150% or greater than mean overall intake Germany Butter, processed meat, coffee, juices The Netherlands Potatoes, margarines, dairy products, processed meat, tea, coffee United Kingdom Potatoes, cakes, sugar, margarine, butter, tea, soft drinks Denmark Sugars, margarines, tea, coffee, soft drinks, alcohol Sweden, Norway Potatoes, cakes, sugars, margarine, dairy products, coffee, soft drinks Bingham & Riboli, 2004 Kost, kræft og helbred

Lifestyle factors and risk of breast cancer in postmenopausal women 326 prevalent cancers 55 missing information (alcohol) 4,844 premenopausal 24,650 postmenopausal 872 excluded due to missing information on co-factors 23,778 Follow up – 31 December 2000 - 425 cases of postmenopausal breast cancer Kost, kræft og helbred

Delprojekter i brystkræftstudiet Kohortestudier Indtag af alkohol Indtag af frugt og grøntsager Indtag af kulhydrater/GI/GL Indtag af fisk Fysisk aktivitet Kropssammensætning Brug af hormoner i forbindelse med overgangsalderen Kost, kræft og helbred

Delprojekter i brystkræftstudiet Nestede case-control studier Enterolactone i plasma Oxiadation af lipider og proteiner i plasma Estrogenmetabolitter (16a-OHE1 + 2-OHE) i urin DNA-reparationsprodukter i urin IGF1+2 samt IGFBP2+3 i serum Estradiol, SHBG, estron og FSH i serum Kost, kræft og helbred

Delprojekter i brystkræftstudiet Nestede case-control studier, fortsat Antioxidant enzymer i røde blodlegemer Genetiske polymorfier vedr. metaboliske enzymer Genetiske polymorfier vedr. reparations enzymer Organochloriner i fedtvæv Kost, kræft og helbred

Risikofaktorer for brystkræft (internt justerede) IRR (95% CI) En ekstra fødsel 0.87 (0.77-1.00) Alder ved første fødsel (5 års stigning) 1.02 (0.89-1.16) Tidligere benign brystsygdom 1.65 (1.30-2.09) Skolegang  7 år 1 8-10 år 1.00 (0.80-1.26)  11 år 1.35 (1.02-1.79) HRT Tidligere 1.10 (0.80-1.51) Nuværende 1.97 (1.50-2.58) Varighed af HRT (5 års stigning) 1.07 (0.97-1.19) BMI (5 kg/m2 stigning) 1.07 (0.96-1.20) Kost, kræft og helbred

Frugt og grøntsager De kræftforebyggende effekter af frugt og grøntsager har været tilskrevet en række vitaminer, mineraler og andre fytokemikalier Antioxidative effekter har været i fokus Kost, kræft og helbred

Epidemiologisk baggrund En lang række case-kontrol studier Primære fund: beskyttende effekt 11 kohorte studier Ingen association til brystkræft Kost, kræft og helbred

Olsen, J. Nutr. 2004 Kost, kræft og helbred

Olsen, J. Nutr. 2004 Kost, kræft og helbred

Olsen, J. Nutr. 2004 Kost, kræft og helbred

Konklusion Ingen sammenhæng mellem indtag af frugt og grøntsager og risiko for brystkræft - I overensstemmelse med alle tidligere kohortestudier Måske forskellige effekter for ER+ og ER- brystkræft? Kost, kræft og helbred

Enterolactone Enterolactone er det primære fytoøstrogen i den danske kost Enterolactone tilskrives antioxidative effekter og har været relateret til reducerende effekter vedr. tumor progression og metastaseren Forskningen er dog yderst begrænset og stammer fra in vitro og dyreeksperimentelle studier Kost, kræft og helbred

Enterolactone Enterolactone stammer fra plantelignaner der indgår som en del af fiberkomponenten i planters cellevægge Lignanerne fermenteres i tyktarmen og optages som enterolactone Kost, kræft og helbred

Kilder til enterolactone Fuldkornsprodukter   Grøntsager  Kaffe  Rygning   Fedt   BMI  Johnsen & Hausner 2003 Kost, kræft og helbred

Epidemiologisk baggrund

Olsen, CEBP. 2004 Kost, kræft og helbred

Enterolactone og brystkræft, kvartiler Olsen, CEBP 2004 Kost, kræft og helbred

Hvorfor reference i 2. Kvartil? Enterolactoneniveauet afhænger af fermentering i tyktarmen Antibiotikabehandling ødelægger tarmfloraen De kvinder der er i laveste kvartil er måske en blanding af kvinder med ”sande” lave enterolactoneniveauer og kvinder med akut lave niveauer pga. nylig antibiotikabehandling Kost, kræft og helbred

Konklusion Der er lavere incidens af brystkræft blandt kvinder med høje niveauer er enterolactone i plasma Den beskyttende effekt ses primært i forhold til ER- brystkræft Skyldes den øgede risiko for brystkræft ved langvarigt forbrug af antibiotika en nedsat produktion af enterolactone? Kost, kræft og helbred

Hvorfor ER- brystkræft? Hypoteser Den beskyttende effekt af enterolactone er primær antioxidativ. Effekten på ER+ bliver ”overskygget” af østrogene risikofaktorer (fra enterolactone eller andet)? ER- brystkræft er et senere stadie af ER+ brystkræft. Enterolactone ”bremser” progressionen fra ER+ til ER- brystkræft? Kost, kræft og helbred

Hvor ofte drikker De den angivne mængde? Alkoholoplysninger Kostspørgeskema Hvor ofte drikker De den angivne mængde? - Lys øl (flaske) - Almindelig øl (flaske) - Stærk øl (flaske) - Vin (rød, hvid,rosé) (glas) - Hedvin (ex. portvin) (genstand) - Spiritus (ex. snaps) (genstand) Angives i kategorier fra aldrig til 8 gange/dag Kost, kræft og helbred

Alkoholoplysninger Livsstilsskema Hvor ofte drikker De almindeligvis alkohol (øl, vin, hedvin eller spiritus)? - Aldrig - Mindre end 1 gang om måneden - 1-3 gange om måneden - 1 gang om ugen - 2-4 gange om ugen - 5-6 gange om ugen - Hver dag Kost, kræft og helbred

Characteristics of 23,778 women in the Danish Diet, Cancer and Health cohort, 1993-2000 No. of cases = 426 (%) No. of cohort = 23,778 (%) Alcohol groups Abstainers 1 10 (2.3) 560 (2.4) Occasional drinkers 2 437 (1.8) Drinkers (grams per day) 0 to 6 122 (28.6) 7,875 (33.1) >6 to <12 89 (20.9) 5,812 (24.4) 12 to 24 93 (21.8) 4,903 (20.6) >24 to <60 3,794 (16.1) 60 9 (2.1) 357 (1.7) Kost, kræft og helbred

Median (5-95 percentiles) Median (5-95 percentiles) Characteristics of 23,778 women in the Danish Diet, Cancer and Health cohort, 1993-2000 Median (5-95 percentiles) Median (5-95 percentiles) Age (years) 57 (51-64) Age at first birth (years) 23 (18-32) 23 (18-31) BMI + 24.8 (19.7-33.6) 24.9 (19.9-33.8) Alcohol (grams per day) * 11.5 (1.3-43.8) 9.7 (0.8-42.1) Alcohol from different types of beverages Wine 5.5 (1.3-43.8) 5.4 (0.4-30.7) Beer 1.1 (0-12.7) 1.0 (0-12.2) Spirits 0.3 (0-7.8) * Abstainers and occasional drinkers not included + Weight (kg)/height (m2) Kost, kræft og helbred

Rate ratio for increases of 10 g alcohol per day by type of alcohol among 23,778 women in the Danish Diet, Cancer and Health cohort, 1993-2000 Type of alcohol Adjusted* Rate ratio (95% CI) Mutually adjusted** P for similar effect Total alcohol 1.10 (1.04-1.16) - Wine 1.14 (1.06-1.22) 1.13 (1.06-1.22) Beer 1.01 (0.87-1.17) 0.98 (0.50-1.14) 0.21 Spirits 1.15 (0.92-1.43) 1.09 (0.87-1.36) * Rate ratio were adjusted for parous/nulliparous and number of births (continuous), age at first birth (in years), benign breast tumour removed (yes/no), years at school categorized, (7, 8-10, >10), use of HRT (never, past, current), duration of HRT (in years), and BMI (continuous) ** The beverage specific estimates were in addition adjusted for each other (wine, beer, spirits) Tjønneland, CCC 2003 Kost, kræft og helbred

Intake (g/day) (5-95% percentile) Rate ratio* (RR) in each category of drinking pattern among 23,778 women in the Danish Diet, Cancer and Health cohort, 1993-2000 Drinking occasions n Intake (g/day) (5-95% percentile) RR (95% CI) Every day 3,188 (12-70) 1.02 (0.72-1.44) 5-6 times/week 2,471 (10-47) 0.96 (0.68-1.35) 2-4 times/week 7,443 (5-32) 1 Once/week 3,467 (2-15) 0.99 (0.73-1.35) Less than once/week 6,212 (0.35-8) 0.87 (0.65-1.15) * Adjusted for total alcohol intake as well as for parous/nulliparous and number of births (continuous), age at first birth (in years), benign breast tumour removed (yes/no), years at school categorized, (7, 8-10, >10), use of HRT (never, past, current), duration of HRT (in years), and BMI (continuous) * Adjusted for total alcohol intake as week as well as Tjønneland, CCC 2003 Kost, kræft og helbred

Rate ratio of breast cancer by frequency of alcohol consumption Tjønneland, CCC 2003 Kost, kræft og helbred

Rate ratio (RR) of breast cancer according to an increase of 10 grams of alcohol intake for different exposure periods among postmenopausal women in the “Diet, Cancer and Health” cohort, 1993-2000 Exposure period RR 1 (95% CI) RR 2 (95% CI) Twenties 0.97 (0.79-1.20) 0.97 (0.78-1.20) Thirties 0.94 (0.79-1.11) 0.94 (0.79-1.12) Forties 1.01 (0.88-1.16) 1.01 (0.88-1.16) Fifties – baseline 1.11 (1.00-1.24) 1.04 (0.91-1.19) Cumulative intake 3 1.03 (0.99-1.07) 4 0.99 (0.94-1.04) Adjusted for parity, age at first birth, benign breast tumour, years of school education, HRT use, duration of HRT use, BMI, total alcohol intake in other exposure periods 2. Further adjusted for current alcohol intake 3. Cumulative intake, calculated from year 20 to baseline, excluding periods without drinking alcohol 4. Rate ratio of breast cancer according to an increase of 1 drink/day/year  1 drink-year of alcohol intake. Adjusted for the same variables as in 1) except adjustment for other exposure periods Tjønneland, J. Nutr. 2004 Kost, kræft og helbred

Age at drinking start RR (95% CI) Rate ratio of breast cancer per 10 g/day of alcohol intake according to age at drinking start among 21,901 postmenopausal women in the “Diet, Cancer and Health” cohort, 1993-2000 Age at drinking start RR (95% CI) <16 0.84 (0.55-1.28) 17-18 1.00 19-20 0.99 (0.75-1.32) 21-25 1.06 (0.79-1.42) 26-30 1.38 (0.96-1.99) >30 1.01 (0.72-1.43) Adjusted for parous/nulliparous, no. of births, age at first birth, benign breast tumour removed, school education, use of HRT, duration of HRT and BMI Tjønneland, J. Nutr. 2004 Kost, kræft og helbred

- app. at the same time of 1st birth 56/3,136 1.10 (0.81-1.49) Rate ratio of breast cancer per 10 g/day of alcohol intake according to drinking start among 21,901 postmenopausal women in the “Diet, Cancer and Health” cohort, 1993-2000 Started drinking: Cases/ cohort RR (5-95% CI) - before 1st birth 203/11,409 1.00 - app. at the same time of 1st birth 56/3,136 1.10 (0.81-1.49) - after the 1st birth 135/7,356 1.11 (0.84-1.46) Rate ratios were adjusted for parous/nullliparous, no. of births, age at first birth, benign breast tumour removed, years at school, use of HRT, duration of HRT, and BMI; current alcohol intake and mutually adjusted Tjønneland, J. Nutr. 2004 Kost, kræft og helbred

Incidence Rate Ratio 1 of breast cancer per each additional 10 g/d of average daily alcohol intake according to categories for cumulative average intake of total folate among 388 cases and 388 controls, nested in the Danish “Diet, Cancer and Health” cohort Median Total folate intake 5-95% percentiles Unit 300 301-350 <351-400 400 P for interaction Alcohol intake 11.0 (0.8-43.8) 10 g 1.21 (1.01-1.45) 1.12 (0.84-1.48) 1.02 (0.83-1.25) 1.03 (0.86-1.22) 0.48 1 Adjusted for vitamin C (food-frequency questionnaire and supplements), school education (low, median, high), body mass index (linear), parous/nulliparous and number of births (linear), age at birth of first child (linear), history of benign breast tumour surgery (yes/no). Tjønneland,subm 2004 Kost, kræft og helbred

Incidence Rare Ratio of breast cancer by total folate and alcohol intake among 388 cases and 388 controls, nested in the Danish “Diet, Cancer and Health” cohort. The reference group for all comparisons was women who consumed 300 mcg/d or less total folate and 15 g/d or less alcohol. The Incidence Rate Ratio was adjusted for vitamin C, school education (low, median, high), body mass index (linear), parous/nulliparous and number of births (linear), age at first child (linear), history of benign breast tumor surgery (yes/no). Kost, kræft og helbred

Konklusion Alkoholindtagelse øger risikoen for brystkræft med 10% for hver gang indtagelsen øges med 10 g/dag Drikkemønsteret har ikke betydning for risikoen Tidlig drikkestart øger ikke risikoen for brystkræft blandt postmenopausale kvinder Kost, kræft og helbred