Key findings

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Key findings

Europe Against Cancer
European Commission

Key findings

Key results and current scientific activity

Summary

Successful follow-up of the 521,000 subjects enrolled in the EPIC cohort, with little loss to follow-up during this time period, and the identification of over 26,000 incident cases and nearly 16,000 deaths.

Colon cancer etiology:

The hypothesis that a diet high in fibre reduces colorectal cancer risk has been corroborated in the EPIC study. Our findings were published in parallel with the results from the PLCO cohort of the NIH-NCI. In that study, a similar protective effect of fibre on colorectal cancer polyps was observed. Together, these results indicate that fibre is protective both for the development of adenomatous polyps and for their malignant transformation.
The hypotheses that consumption of red and processed meat increases colorectal cancer risk while intake of fish decreases risk is strongly supported by the EPIC results.
The combination of these four dietary factors (i.e. fibre, fish, red and processed meats) plays a major role in colorectal cancer etiology in addition to alcohol intake, obesity and low physical activity.

Breast cancer etiology:

The role of endogenous steroid hormones in pre- and post-menopausal breast cancer has been investigated in EPIC in the largest studies conducted to date on this topic. We have shown that both estrogens and androgens increase breast cancer risk while SHBG decreases risk after menopause. In parallel, overweight and low physical activity increase breast cancer risk after menopause. On the contrary, before menopause, androgens increase breast cancer risk, progesterones decrease risk and SHBG and obesity are not associated with risk. These findings provide strong clues for further investigations of the metabolic and hormonal factors specifically related to pre- and post-menopausal breast cancer.
We found that the consumption of fruit and vegetables is not associated with breast cancer risk. This is an important finding as it helps to narrow down the factors potentially involved in breast cancer etiology and prevention.

Prostate cancer etiology:

We have shown that similarly to breast cancer, prostate cancer risk is not related to fruit and vegetable consumption.

Genetic factors:

We have initiated a very large systematic investigation of the role of polymorphisms in genes involved in the metabolism of steroid hormones and growth factors that have a role in the etiology of breast and prostate cancers in combination with lifestyle and metabolic factors.

Incident tumours by major cancer sites for EPIC study population, 2004

Cancer Site	Number of Incident Cases	Men	Women
Colon-rectum	1910	810	1100
Breast	6218	-	6218
Prostate	1547	1547	-
Lung	1292	686	606
Endometrium	779	-	779
Ovary	620	-	620
Gastric (stomach+oesophagus)	541	338	203
Upper Gastrointestinal Tract (including oesophagus and larynx)	497	359	138
Kidney	366	196	170
Bladder	679	486	193
Cervix	649	-	649
Pancreas	374	174	200
Other	10619	2838	7781
Total	26091	8054	18037

Summary of Scientific Activity on Breast Cancer in the EPIC Study

Abstracts of the publications listed below can be accessed from the publications database (See Menu/Publications)

Topic	Publications	Main results
Fruits and vegetables	JAMA 2005, van Gils CH et al	No statistically significant decreased risks for fruits and vegetables
Body size	Int J Cancer 2004, Lahmann PH et al	Statistically significant increased risk for post-menopausal but not for pre-menopausal breast cancer. In post-menopausal breast cancer cases the effect is limited to women not using HRT
Adult weight gain	Onland-Moret NC et al, submitted 2004	Statistically significant increased risk
Endogenous hormones, pre- menopause	JNCI Kaaks R et al, in press 2004	Increased serum androgens clearly increase pre-menopausal breast cancer risk independent of body weight. Serum progesterone decreases risk.
Endogenous hormones, post- menopause	Kaaks R et al, submitted 2004	Increased levels of serum estradiol and testosterone increase post-menopausal breast cancer risk while increased SHBG decrease risk
Hormone replacement therapy	Int J Cancer 2004, Fournier A et al	Synthetic progestins increase breast cancer risk but no increased risk for natural micronized progesterone (results from French EPIC cohort). Analyses on full EPIC cohort on-going
Phytoestrogens	Cancer Epidemiol Biomarkers Prev 2004 Grace et al.; Am J Clin Nutr 2004 Keinan-Boker et al.	One study found positive association with isoflavones in EPIC-Norfolk cohort and the other found no association with these phytoestrogens in EPIC-Utrecht cohort. Analyses with pooled data set are still on-going.

Summary of Scientific Activity on Colon Cancer in the EPIC Study

Abstracts of the publications listed below can be accessed from the publications database (See Menu/Publications)

Topic	Publications	Main results
Fibre	Lancet 2003, Bingham S et al	Inverse relation of dietary fibre with colorectal cancer incidence with the greatest protective effect in the left colon, and least in the rectum. No food source of fibre is significantly more protective than others.
Fibre 2	Bingham S et al, submitted 2004	Confirmation of the above findings after adjustment for folate and with a longer follow-up.
Nuts	Cancer Epidemiol Biomarkers Prev 2004, Jenab et al	Higher nut and seed intake is not significantly associated to the risk of colorectal, colon, and rectal cancers in men but did show an inverse association with colon cancer in women.
Meat, fish, poultry	Norat T et al, provisionally accepted 2004	High consumption of processed and/or red meat is associated with an increase in colorectal cancer risk, not explained by the substitution of fish by red meat and is less apparent in high fibre consumers. Fish consumption is significantly inversely associated with risk while there is no association with poultry.
Dairy foods	Riboli E et al, Paper in preparation	Intake of milk and cheese was significantly associated with reduced colorectal cancer risk. The data suggested an inverse association for yogurt. Dietary calcium and calcium from dairy products are also significantly inversely associated.
Hormone replace-ment therapy, oral contraceptives and reproductive factors	Ongoing analysis	Among postmenopausal women, ever use of hormone replacement therapy was significantly associated with a reduction in risk of colorectal cancer.
Current alcohol intake	Ongoing analysis	Preliminary results indicate that current alcohol intake is significantly positively associated with risk of rectal, but not of colon cancer.
Lifestyle, insulin, IGF-I	Grant approved	Nested case-control study (C-peptide, IGF-1 and IGFBP-1 and IGFBP-2, and HbA1c)
Inflammatory markers and adipo-cytokines & lifestyle	Proposed study	Nested case-control study (C- reactive protein, leptin, adiponectin, variants of the PPARγ and adiponectin gene)
Folate, 1 carbon methyl nutrients, gene variants and colon cancer	Grant approved	Nested case-control study (Folate, vitamins B, homocysteine, gene variants)

Summary of Scientific Activity on Prostate Cancer in the EPIC Study

Abstracts of the publications listed below can be accessed from the publications database (See Menu/Publications)

Topic	Publications	Main results or objectives
Rates and hypotheses	IARC Sci Publ 156 2002, Key TJ.	Threefold variation in rates across EPIC countries
Fruit and vegetables	Int J Cancer 2004, Key T et al	No association of fruit and vegetables with prostate cancer risk.
Foods and nutrients	Ongoing analysis	Preliminary results indicate that major foods and nutrients are not associated with overall prostate cancer risk; analyses for localized and advanced disease to follow
Serum sex hormones and IGF system	Grant approved	Nested case-control study (androgens, estrogens, IGF-I and IGF binding proteins)
Genetic polymorphisms for sex hormones and IGF system	Ongoing analysis	Nested case-control study (polymorphisms for hormone synthesis and catabolism genes, and hormone receptors)
Nutritional biomarkers	Grant approved	Nested case-control study (plasma fatty acids, carotenoids, tocopherols, vitamin D, folate, vitamin B12, homocysteine, selenium and phytoestrogens)
Biomarkers of infections	Grant approved	Nested case-control study (HPV 16 and 18, herpes simplex virus-2, gonorrhoea, chlamydia, syphilis)

Summary of Scientific Activity on Gastric Cancer in the EPIC Study

Abstracts of the publications listed below can be accessed from the publications database (See Menu/Publications)

Topic	Publication	Main results
Tobacco	Int J Cancer 2003, Gonzalez CA et al	Confirm that smoking is causally associated with GC risk in European population
Meat, nitrosamines and nitrites	Ongoing analysis	Preliminary results indicate that red and preserved meat increase GC risk
Fruit and vegetables intake	Ongoing analysis	Preliminary results indicate that fruit reduces GC risk and vegetable is not associated. Analyses will be redone with more cases and separately by histological type and cardia and non-cardia site
Body mass index and the risk	Ongoing analysis	Preliminary results indicate that BMI is associated with adenocarcinoma of oesophagus
Alcohol intake	Ongoing analysis	Preliminary results indicate that alcohol is not associated with gastric cancer risk
Diet diversity	Ongoing analysis	Preliminary results indicate that diet diversity is negatively associated with gastric cancer risk
Helicobacter pylori infection	Ongoing analysis	Preliminary results indicate that the OR associated with Hp is 3, being higher in Mediterranean countries but lower in Northern European countries
Tobacco smoking, Helicobacter pylori infection, polymorphism of metabolic genes	Ongoing analysis	Preliminary analysis show an interaction between smoking and some variants in metabolic genes
Helicobacter pylori infection, smoking, inflammatory responses genes	Ongoing analysis	Preliminary analysis show an interaction between Hp infection and some variants in inflammatory genes
Prevalence of Helicobacter pylori infection and CagA positive strain in 10 European countries.	Ongoing analysis	Preliminary results indicate that the prevalence of Hp is higher in Mediterranean countries and lower in Northern European countries

Summary of Scientific Activity on Lung Cancer in the EPIC Study and GenAir

Ongoing Studies

Data on several analyses are mature for publication including meat, cholesterol, physical activity, smoking and occupational exposures. An assessment of the dose-response relation between lung cancer risk and tobacco smoking by means of biomarkers, such as cotinine in plasma and possibly carcinogenic components of tobacco that can be measured in blood, are planned. DNA adducts are being excluded because they require large amounts of DNA, but specific adducts could be measured in subgroups. Work on bio-mathematical cancer modelling on the induction of lung cancer by smoking is on-going with an assessment of the two-mutation-carcinogenesis model currently being done.

GenAir

GenAir is a case-control study nested within the EPIC cohort that has the primary aim to study the relation between air pollution or environmental tobacco smoke (ETS) and incident cancers of the bladder, lung, oral cavity, pharynx, larynx or leukaemia and mortality from respiratory diseases (COPD and emphysema).

Publications:

On plasma DNA: Gormally et al, Int J Cancer 2004
On ETS and lung cancer: Vineis P et al, submitted JAMA 2004
On DNA adducts and lung cancer: Peluso M et al, submitted Cancer Res 2004
On validation of laboratory measurements: Peluso M et al, submitted Mutat Res 2004

Summary of Scientific Activity on Endometrial Cancer in the EPIC Study

Several lifestyle factors, including excess weight, lack of physical activity, pre-existing diabetes, and use of exogenous estrogens unopposed by progestins, have been clearly implicated as possible causes of endometrial cancer. Nevertheless, further studies are needed to increase the understanding of the physiological mechanisms leading to this disease (Cancer Epidemiol Biomarkers Prev 2002, Kaaks et al). With over 800 cases of endometrial cancer (about 600 with pre-diagnostic blood samples), the EPIC study provides a unique resource for such studies, including investigations using biomarkers.

Current Ongoing Studies:

Preliminary analyses have confirmed the direct relation between excess weight and endometrial cancer risk. Studies on endogenous hormones have started focusing on the relations between risk with either pre- or postmenopausal blood levels of total and bioavailable androgens and estrogens, insulin, and IGF-binding proteins –1 and –2. In addition, studies are being initiated to examine the relationships of endometrial cancer with physical activity and anthropometry, and with lifetime history of smoking (suspected to be a protective factor among postmenopausal women). Studies on dietary patterns, glycemic index, and use of different types of postmenopausal hormone replacement therapy are ongoing and/or planned.

Summary of Scientific Activity on Ovarian Cancer in the EPIC Study

Ovarian cancer is the fourth most frequent cause of cancer death and the most lethal of all gynecological tumors in women from North America, Northern and Western Europe. Established risk factors for ovarian cancer are age, family history of ovarian cancer and infertility, while increasing parity, oral contraceptive (OC) use, hysterectomy or tubal ligation decrease risk. The protective effect of pregnancy has been uniformly demonstrated in North American, European and Asian populations, with a 10-16% decrease in risk for each additional pregnancy. In contrast, use of exogenous hormones for menopause-related symptoms, especially prolonged use of estrogens unopposed by progestins, could be associated with an increased risk of ovarian cancer incidence or mortality. While excess weight and pre-existing diabetes do not appear to be important risk factors, studies on physical activity have shown variable results, some studies showing a significant increase in risk among the more active women. Animal studies have led to some strong hypotheses about the role of endogenous hormones, particularly gonadotropins, but these have not been supported much by epidemiological studies in women (Cancer Epidemiol Biomarkers Prev, Lukanova & Kaaks, in press).

Current Ongoing Studies:

First analyses of ovarian cancer risk in relation to dietary intake patterns have begun (Nutr Cancer Schultz M, in press 2004) and a first article on fruit and vegetable consumption by Schulz et al. is in its final stages of preparation. Overall consumption of fruit and vegetables was unrelated to risk of ovarian cancer. There was evidence of a protective effect of a high intake of allium vegetables on cancer risk. Separate inspection of the fruit and vegetable-ovarian cancer association by histological subtype indicated some differential effects on ovarian cancer risk. Other analyses planned will focus on the relations between ovarian cancer risk and use of different types of HRT, excess body weight and physical activity, and menstrual and reproductive history.

Other cancer sites are the subject of on-going research, awaiting results.

Near future research activities

The key etiological research planned for the near future will be based on the baseline epidemiological and biological data of EPIC. Major areas of research will include the search for lifestyle, metabolic and genetic causes of cancers of the breast, colorectum, prostate, lung, endometrium, ovary, pancreas, bladder, stomach and upper gastro-intestinal tract. The following major etiological hypotheses will be investigated:

The role of complex interactions between genetic, metabolic, hormonal and lifestyle factors, including diet, overweight, weight gain over lifetime, with particular focus on the "metabolic syndrome" hypothesis. This line of research seems of particular relevance for cancers of the breast, prostate, endometrium and kidney.
The role of diet, as defined by a higher level of complexity that will include dietary patterns, glycaemic index, and some complex pathways such as the 1-carbon metabolism, the fatty acids-eicosonoids metabolism, and their role in inflammatory processes.
The diversity and specificity of different combinations of risk factors in relation to specific subsites of cancers within a given cancer site and histology group. It is foreseeable that the new techniques for classifying tumours by patterns of somatic mutations will become readily available and applicable to the tumour samples that have been, and will be, collected within the EPIC study.

Special interest will continue to be devoted to some specific areas of work such as:

Studies making use of biomarkers of diet and of exposure to exogenous carcinogens.
Tobacco, particularly to the investigation of differences in lifestyle associated with quitting smoking, that can be of major interest for studying how to further prevent cancer in the growing number of middle-aged men and women who become ex-smokers.