Evidence Update on the Relationship between Diet and the Most Common Cancers from the European Prospective Investigation into Cancer and Nutrition (EPIC) Study: A Systematic Review

1Worldwide, an estimated 18.1 million new cancer cases (excluding nonmelanoma skin cancer) and nearly 10 million cancer deaths occurred in 2020. In Europe, the 2020 cancer burden was estimated to have ascended to 2.7 million new cases and 1.3 million deaths. Overall, the burden of cancer incidence and mortality is rapidly growing, and although cancer was once considered to be a disease of high-income countries, it is now one of the most important public health problems worldwide. The increasing cancer burden reflects in part the decline in fertility and increase of life expectancy, but also the economic, societal, and lifestyle changes related to globalization and socioeconomic development.

2Cancer is a disease characterized mainly by loss of genetic control of cell growth and proliferation. Therefore, it is a genetic disease but the factors that originate the disease process are mainly attributable to environmental and lifestyle factors. These include tobacco consumption, diet, excessive body weight and obesity, alcohol consumption, physical inactivity, or sun exposure, among others, meaning there is great potential for cancer prevention. In relation to modifiable lifestyle factors, there is overwhelming evidence that nutrition, diet, and other related factors such as alcohol intake, physical activity or obesity have an important impact on cancer risk—even more so than smoking—, and that positive behaviour changes can significantly reduce cancer burden. However, despite several decades of epidemiological research, the scientific evidence of the effect of many specific foods and nutrients on cancer is still inconsistent or insufficient and attempts to draw solid conclusions have been hampered. The European Prospective Investigation into Cancer and Nutrition (EPIC), one of the largest cohort studies in the world, was precisely designed to investigate the relationship between diet and cancer and other chronic diseases with the purpose of overcoming previous limitations and contributing to the scientific body of knowledge.

3EPIC is a multi-centre prospective cohort study of 519,978 participants (366,521 women and 153,457 men), most aged 35–70 years, and recruited mostly between 1992 and 1998. Its main aim has been to investigate the relationship of dietary, genetic, lifestyle, and environmental factors with the incidence of cancer and other chronic diseases. The study was conducted in 23 centres in 10 different European countries: France, Denmark, Germany, Italy, Greece, The Netherlands, Spain, Norway, Sweden, and the UK. Europe is considered an ideal natural laboratory due to the different dietary habits found in the European population. These include Mediterranean diet patterns typical of southern Italy, Greece, the south of France, and Spain; central European food patterns typical of Germany, the Netherlands, and the north of France; and Nordic diet patterns found in Denmark and Sweden. In addition, the incidence of some major cancers varies significantly between countries and even between regions.

4Diet over the previous 12 months was assessed at the time of recruitment using validated country-specific questionnaires: self-administered semiquantitative food-frequency questionnaires (around 260 food items), semi-quantitative food-frequency questionnaires (combined with dietary record), and diet history questionnaires administered through interviews (with more than 600 food items). To calibrate the dietary measurement and to correct the errors produced by overestimation or underestimation of food intake, a 24-h recall was performed by a computerized program (EPICSOFT) in a random subsample of 8% of the cohort. In addition, information about lifestyles, habits, and medical history was collected. Weight, height, and waist and hip circumference were assessed, and 385,747 blood samples were collected for hormonal, biochemical, and genetic analyses. Incident cancer cases (above 109,000 cases so far) are regularly identified through automated links with the databases of population cancer registries, except in Germany, France, and Greece, where a combination of methods is used (including monitoring of health insurance records, hospital registries, and active follow-up of participants). Nutrients are analysed using a standardised Food Composition Table (EPIC Nutrient Database ENDB).

5Altogether, the EPIC cohort is one of the largest worldwide and its findings regularly contribute to international recommendations on cancer prevention. The last review of the evidence based on EPIC regarding the role of diet in cancer prevention was published more than 10 years ago. Multiple publications with longer follow-up and investigating previously unaddressed diet-related exposures have been published ever since, significantly increasing the contribution of EPIC. Thus, the aim of the current review is to summarize the findings derived from the EPIC study regarding the relationship between diet-related exposures and cancer risk and mortality, considering the four most frequent cancer types in the European population: colorectal, breast, lung, and prostate cancer.

6This study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines) (Figure 1) and was registered in the International Prospective Register of Systematic Reviews PROSPERO (Registration number: CRD42021245178).

7We systematically searched MEDLINE (via PubMed), Scopus, and Web of Science to identify prospective studies from the European Prospective Investigation into Cancer and Nutrition (EPIC) study addressing the effect of diet-related factors on the incidence and mortality of colorectal, breast, lung, and prostate cancer. The search strategy included the following terms: (“European prospective investigation into cancer” OR “European prospective investigation into cancer and nutrition” OR “EPIC study”) AND (“lung cancer” OR “prostate cancer” OR “breast cancer” OR “colorectal cancer” OR “colon cancer” OR “rectal cancer”) AND (“diet” OR “intake” OR “nutrients”). The literature search was performed between February and March 2021 by reviewing citations of the articles considered eligible for the systematic review, and the authors were contacted to obtain missing information when necessary. The complete search strategies used for each database are available in Table S1.

8The criteria for including studies were as follows: (i) study design: prospective studies from the EPIC project; (ii) any of the following exposures: food intake/type of diet/nutrient levels/nutritional biomarkers/alcohol consumption; and (iii) outcome: incidence or mortality of colorectal, breast, prostate, or lung cancer. The criteria for excluding studies were as follows: non-eligible publication types, such as review articles, editorials, comments, guidelines, or case reports. No exclusion criteria were applied based on language or journal publication date. The titles, abstracts, and full texts were independently reviewed by 2 reviewers (E.U.-G. and A.C.-L.), and disagreements were solved by consensus or involving a third researcher.

9The following data was extracted from the original reports: (1) first author and year of publication; (2) tumour site; (3) no. of cases; (4) no. of non-cases; (5) mean follow-up; and (6) main results. The Mendeley software was used for data management.

10The Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews (Table S2) was used to evaluate the risk of bias for cohort studies as in previous cancer and diet reviews. The assessed methodological criteria included 11 items, each of them with four possible answers: “yes” (criterion met), “no” (criterion not met), “unclear”, and “not applicable” (N/A). A study was considered as “high quality” when the quality score was at least 0.75 (i.e., 75%), whereas studies were considered as “low quality” when the quality score was lower than 0.75. In addition, a score for each criterion was calculated, by dividing the number of positively scored by the total number of included studies, to provide an overview of how well the current literature scores on each criterion.

11Data extraction and quality assessment were independently performed by two researchers, and inconsistencies were solved by consensus or involving a third researcher.

12Due to the overlap of participants among studies, a quantitative meta-analysis was not undertaken. Therefore, the evidence was summarized qualitatively for each of the included cancer types (colorectal, breast, lung, and prostate cancer). The results are shown by type of cancer and grouped according to exposure type following the “Third Expert Report of Diet, Nutrition, Physical Activity and Cancer: a Global Perspective, from World Cancer Research Fund”.

13All 110 studies that entered the review (see Figure 1) were high quality studies according to the assessment tool for Systematic Reviews from The Joanna Briggs Institute. Table S3 shows the percentage of studies meeting the quality criteria and provides detailed information on the quality score of each study.

14When the studies were analysed by individual domains, 100% of the studies measured the exposure and the outcomes in a valid and reliable manner, identified the potential confounders and took them into account within the study design or in the data analysis, the participants were free of the outcomes of interest at the start of the study, the follow up was completed by a large percentage of participants, and the statistical analysis used was appropriate. It should be taken into account that, among the studies that had two groups, 44.7% had similar groups that were recruited from the same population, and 100% of those studies measured the exposures similarly in order to assign people to the exposed or unexposed groups. Most of the studies presented an appropriate length of time for follow up (93.6%). In no study was it necessary to apply strategies to address incomplete follow up.

15We identified 43 studies on colorectal cancer (Table 1), with a mean follow-up of 9.2 ± 4.0 years.

16Wholegrains, vegetables and fruit: A higher consumption of fruits and vegetables combined was related to a lower risk of colorectal cancer: HR 0.86 (0.75–1.00), but no consistent associations were observed for separate consumption of fruits and vegetables. Similar findings were observed for the association between fibre consumption and colorectal cancer: HR 0.58 (0.41–0.85), HR 0.79 (0.63–0.99), and HR 0.87 (0.79–0.96) per 10 g/day increase in fibre. A protective effect was also observed between intake of nuts/seeds and the risk of colon cancer in women: HR 0.69 (0.50–0.95), with no associations in men.

17Meat, fish, dairy products, and preservation/processing of foods: Two studies showed a protective effect of fish intake on colorectal cancer: HR 0.88 (0.80–0.96) comparing the highest vs. lowest quintile, and HR 0.69 (0.54–0.88) comparing >80 g/day vs. <10 g/day of intake. The opposite was found with regards to meat consumption as an increase of red and processed meat consumption associated with a higher risk of colorectal cancer: HR 1.55 (1.19–2.02) per 100-g increase. Pre-diagnostic red meat, processed meat or fibre intakes were not associated with colorectal cancer mortality; however, a marginal trend of processed meat was detected. With regards to calcium, dietary calcium intake was associated with a lower colorectal cancer risk: IRR 0.69 (0.50–0.96), and HR 0.95 (0.91–0.99) per 200 mg/day. There was also an association between milk consumption and colorectal cancer risk: HR 0.93 (0.89–0.98) per 200 g/day. Finally, yogurt intake was associated with a lower risk of colorectal cancer: HR 0.65 (0.48–0.89), and HR 0.65 (0.48–0.89).

18Diet patterns: Adherence to the Mediterranean diet, the Italian Mediterranean Index, and the Modified Mediterranean diet score (mMDS) were found to protect against colorectal cancer with HR 0.54 (0.36–0.81), HR 0.50 (0.35–0.71), and HR 0.89 (0.80–0.99), respectively. In contrast, higher scores (lower nutritional quality diet) in the Food Standards Agency nutrient profiling system dietary index (FSA-NPS DI), and higher values in the Dietary inflammatory index (DII) were associated with a higher risk of colorectal cancer: HR 1.11 (1.01–1.22), and HR 1.15 (1.04–1.27), respectively.

19Alcoholic and non-alcoholic drinks: Alcohol consumption was a risk factor for colorectal cancer in six studies. Of note, a HR of 1.74 (1.08–2.80) was found among participants drinking >3 drinks/day versus those drinking <1 drink/day. Alcohol consumption (per 15-g/d increment) was associated with a higher risk of colorectal cancer: HR 1.05 (1.03–1.07) and HR 1.08 (1.04–1.12). More specifically, the risk of colorectal cancer was higher when drinking beer (HR 1.38, 1.08–1.77) than wine (HR 0.61–1.21). Finally, total soft drink consumption was a risk factor for colorectal cancer mortality (≥1 glass per day vs. <1 glass per month): HR 1.25 (1.07–1.47).

20Other dietary exposures: Several vitamins have been associated with colorectal cancer risk. A protective effect between levels of 25-(OH)D (vitamin D) and colorectal cancer risk was found in several publications. The cancer risk associated with 10% higher level of circulating 25-(OH)D were: HR 0.97 (0.95 to 0.99) for colorectal; HR 0.95 (0.93 to 0.98) for colon; HR 1.00 (0.97 to 1.03) for rectum. Higher plasma concentrations of vitamins B2 and B6 were associated with a lower colorectal cancer risk: RR 0.71 (0.56–0.91), and RR 0.68 (0.53–0.87), respectively. A lower colon cancer risk was associated with a higher plasma retinol concentration and dietary b-carotene: IRR 0.63 (0.46–0.87), and OR 0.69 (0.52–0.94), respectively. Dietary vitamin C and dietary vitamin E also protected against distal colon cancer (highest vs. lowest quartile): OR 0.60 (0.39–0.93), and OR 0.65 (0.42–0.99), respectively. Finally, associations with colorectal cancer were also found for other variables such as plasma total alkyl-resorcinols, plasma methionine, plasma choline, fatty acids, glycaemic index, and concentration of zinc, among others.

21The number of included studies on breast cancer was 41 (Table 2), with a mean follow-up (years) of 10.0 ± 3.0.

22Wholegrains, vegetables and fruit: Low consumption of fruit and vegetables combined was associated with a higher risk of breast cancer: HR of 1.76 (1.10–2.82). The isolated intake of vegetables was also associated with a lower risk (highest vs. lowest quintile): HR 0.87(0.80–0.94), and HR 0.65 (0.53–0.81). According to subtypes of vegetables, protective effects were found (highest vs. lowest quintile): HR 0.70 (0.57–0.86) for leafy vegetables; HR 0.75 (0.60–0.94) for fruiting vegetables; and HR 0.82 (0.66–1.01) for raw tomatoes. Conversely, a study did not show associations between vegetable or fruit intake and breast cancer risk. Higher intakes of total dietary fibre and fibre from vegetables were also associated with a lower risk of breast cancer: HR 0.95 (0.89–1.01), and HR 0.90 (0.84–0.96), respectively; but not with fibre from fruit, cereals, or legumes.

23Meat, fish, dairy products, and preservation/processing of foods: There were no associations with the intake of fish, meat intake, and calcium intake. An association was only shown between high risk of breast cancer and low consumption of fatty fish: HR 1.80 (1.17–2.78).

24Diet patterns: The relationship between breast cancer and dietary profiles was also studied. The Mediterranean diet was found to protect against breast cancer (highest vs. lowest score): HR 0.94 (0.88–1.00). In contrast, a higher score in the FSA-NPS DI was associated with a higher risk of postmenopausal breast cancer (highest vs. lowest quintile): HR 1.08 (1.00–1.16).

25Alcoholic and non-alcoholic drinks: The risk of breast cancer increases with alcohol intake: HR 1.05 (1.03–1.07), HR 1.04 (1.03–1.06), HR 1.74 (1.14–2.68) and TE 1.17(1.01–1.35), among others. Particularly, in the consumption of beer/cider and wine (for 1 SD increment), the risk of breast cancer was HR 1.05 (1.03–1.06) and HR 1.04 (1.02–1.06), respectively. Other drinks showed protective effects on breast cancer. Caffeinated coffee intake was associated with lower risk of postmenopausal breast cancer (highest vs. lowest consumption): HR 0.90 (0.82–0.98). For every 100 ml increase in caffeinated coffee intake, the risk of ER-PR- breast cancer was lower: HR 0.96 (0.93–1.00). Tea intake and total, sugar-sweetened, and artificially sweetened soft drink consumption were not associated with breast cancer.

26Other dietary exposures: Diet rich in β-carotene, riboflavin, thiamine, folate, fibre, iron, calcium, magnesium, potassium, phosphorus, vitamins C and vitamin B6 was associated with a lower risk of breast cancer: HR 0.89 (0.83–0.95). A-carotene and b-carotene had protective effects on oestrogen-receptor–negative breast tumours risk (highest vs. lowest quintile): OR 0.61 (0.39–0.98), and OR 0.41 (0.26–0.65), respectively. Regarding the relationship between breast cancer and fatty acids, the risk of breast cancer increased with increasing dietary total industrial trans fatty acids intake and levels of total trans-MUFAs: HR 1.14 (1.06–1.23), and OR 1.75 (1.08–2.83), respectively. Specifically with the levels of trans-palmitoleic acid, elaidic acid, and conjugated linoleic acid: OR 2.24 (1.30–3.86), HR 1.14 (1.06–1.23), and HR 1.11 (1.03–1.20), respectively. Palmitoleic acid was associated: OR 1.37 (1.14–1.64), and HR 1.08 (1.01–1.16). In addition, a higher dietary glycaemic load was associated with a higher risk factor of breast cancer: HR 1.36 (1.02–1.82), and RR 1.45 (1.06–1.99).

27A total of 11 studies on lung cancer were included (Table 3), with a mean follow-up (years) of 8.7 ± 4.5.

28Wholegrains, vegetables and fruit: The combination of eating fruits and vegetables was associated with a lower lung cancer risk (per 100 g/day increase of intake): HR of 0.94 (0.89–0.99). Fruit consumption also protects against lung cancer risk (highest vs. lowest quintile): HR 0.75 (0.49–0.96), and HR 0.60 (0.46–0.78). Lung cancer risk decreased with higher vegetable consumption (per 100 g/day increase) in one study: HR 0.92 (0.85–0.99). Conversely, two studies did not show associations between vegetable consumption and lung cancer.

29Meat, fish, dairy products, and preservation/processing of foods: There were no consistent associations between meat and fish consumption and the risk of lung cancer.

30Diet patterns: Higher scores in the FSA-NPS DI were associated with a higher lung cancer risk (highest vs. lowest quintile): HR 1.26 (1.06–1.51).

31Alcoholic and non-alcoholic drinks: Neither ethanol intake at recruitment nor mean lifetime ethanol intake was associated with lung cancer.

32Other dietary exposures: A lower risk for lung cancer was observed for elevated serum levels of B6 and for serum methionine (fourth vs. first quartile): OR 0.44 (0.33–0.60), and OR 0.52 (0.39–0.69), respectively. Above-median levels of both were associated with a lower lung cancer risk overall: OR 0.41 (0.31–0.54), as well as separately among never, former and current smokers: OR 0.36 (0.18–0.72), OR 0.51 (0.34–0.76), and OR 0.42 (0.27–0.65), respectively. Finally, vitamin C concentration, vitamin K2 intake and haem iron intake (highest vs. lowest categories) were associated with the risk of lung cancer: HR 0.57 (0.41–0.81), HR 0.38 (0.20–0.71), and HR 1.16 (1.02–1.32), respectively.

33Twenty-five studies on prostate cancer were selected (Table 4), with a mean follow-up (years) of 9.4 ± 3.8.

34Wholegrains, vegetables and fruit: No associations between fruits and vegetables consumption and prostate cancer risk were observed in one study. However, these results were later disconfirmed in another study that showed protective associations with the consumption of fruits (highest vs. lowest quintile): HR 0.91 (0.83–0.99). Overall, there was no association between dietary fibre intake (total, cereal, fruit or vegetable fibre) and prostate cancer risk.

35Meat, fish, dairy products, and preservation/processing of foods: There were no associations between prostate cancer and the intake of dairy products, fish, fat from red meat, and dietary fat. However, there was an association between the risk of high-grade prostate cancer and the intakes of total, monounsaturated, and polyunsaturated fats. For each 10% increase in the observed intake of total fat, the risk of high-grade prostate cancer decreased: HR 0.83 (0.72–0.95). Each 5% increase in monounsaturated and polyunsaturated fat intake was associated with a lower risk of high-grade prostate cancer: HR 0.82 (0.70–0.97) and HR 0.77 (0.62–0.97), respectively. Higher fat intake from dairy products was also associated with lower risk of localized prostate cancer: HR 0.92 (0.86–0.99) and HR 0.90 (0.82–0.99), for the observed and calibrated intakes, respectively. In contrast, yoghurt intake, total dietary calcium intake, calcium intake and protein intake from dairy products were associated with an increased risk of prostate cancer (highest vs. lowest quintile): HR 1.17 (1.04–1.31), HR 1.17 (1.00–1.35), HR 1.18 (1.03–1.36), and HR 1.22 (1.07–1.41), respectively.

36Diet patterns: One study found a borderline association between a higher score in the FSA-NPS DI and a higher risk of prostate cancer (highest versus lowest quintile): HR 1.07 (0.98–1.17).

37Alcoholic and non-alcoholic drinks: Neither alcohol consumption at baseline nor average lifetime alcohol consumption was associated with risk for prostate cancer. No evidence of association for consumption of total, caffeinated or decaffeinated coffee or tea and risk of total prostate cancer or cancer by stage, grade or fatality (highest vs. lowest consumers). Neither total, sugar-sweetened, and artificially sweetened soft drink consumption was associated with risk of death from prostate cancer.

38Other dietary exposures: There was a protective effect between menaquinone intake and prostate cancer: HR 0.37 (0.16–0.88) for advanced prostate cancer, HR 0.65 (0.44–0.97) for prostate cancer incidence, OR 1.38 (1.03–1.86) for serum undercarboxylated osteocalcin (ucOC)/intact osteocalcin (iOC) ratio in advanced-stage prostate cancer, and OR 1.21 (1.00–1.46) for serum ucOC/iOC ratio in high-grade prostate cancer. Fatty acids were a risk factor for prostate cancer: HR 1.08 (1.01–1.15) for butyric acid intake, HR 1.05 (1.00–1.11) for eicosenoic acid intake, HR 1.07 (1.00–1.14) for eicosapentaenoic acid intake, and OR 1.27 (1.01–1.60) for plasma phytanic acid concentration. Finally, the serum concentration of insulin-like growth factor I was also a risk factor for prostate cancer.

39Colorectal cancer: Several EPIC studies have found protective effects against colorectal cancer risk of the following diet-related factors: consumption of fish, dietary fibre, fruits and vegetables, nuts/seeds, dietary calcium, milk, yogurt, circulating vitamin D concentration, plasma concentrations of vitamins B2 and B6, plasma retinol concentration, dietary b-carotene, dietary vitamin C, and dietary vitamin E. On the contrary, alcohol and red and processed meat consumption were associated with a significant increase in colorectal cancer risk. Adherence to a traditional Mediterranean diet was strongly associated with a reduction of colorectal cancer risk, whereas higher FSA-NPS DI scores, i.e., lower nutritional quality of the diet, and higher DII scores, i.e., a more pro-inflammatory diet, were particularly associated with higher risks of cancer of the colon-rectum. However, the associations for the DII scores were more evident in men and not significant in women. These sex-differences can be due to hormonal influences because oestrogen plays a key protective role in the pathogenesis of colorectal cancer in women. Therefore, diet and hormonal components can affect colorectal cancer risk differently in women than in men.

40The EPIC study findings are in line with the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) latest report that concluded that there is strong evidence to support that consuming foods containing dairy products, dietary fibre, and dietary calcium decreases the risk of colorectal cancer while consuming alcohol and red and processed meat increases it. According to this report, there is also limited evidence supporting that the intake of fish, carotene, vitamin C, and vitamin D might decrease colorectal cancer risk; however, a recent mendelian randomisation study on vitamin D and risk of seven cancers concluded that there is limited evidence of a linear causal relationship between circulating vitamin D concentration and colorectal cancer risk. Further, ingested red and processed meat is classified following the International Agency for Research on Cancer (IARC) as a probable human carcinogen (group 2A) and carcinogen to humans (group 1), respectively. A current review of 45 meta-analyses also found convincing and biologically plausible evidence for the association between lower risk of colorectal cancer and higher dietary fibre intake, higher dietary calcium and yogurt intake, and lower alcohol and red meat intake. The EPIC study findings appear to be in agreement with the latest systematic review from the WCRF and AICR and a recent umbrella review of meta-analyses of prospective observational studies. Hence, they largely support existing cancer prevention recommendations that advise increased fibre and dairy products intake and limited red meat and alcohol intake to reduce colorectal cancer risk.

41Breast cancer: The EPIC results showed that intake of vegetables, fruits and vegetables, total dietary fibre, fibre from vegetables, and fatty fish protect against breast cancer, whereas no associations were found for fruit or fibre derived from fruit, cereals, or legumes. However, one study did not find associations between fruit or vegetable intake and breast cancer risk. Since these results were obtained during the first years of EPIC, the relatively short follow-up might not best reflect the true association. Later, significant associations were found in longer follow-up studies. Lower breast cancer risk was associated with adherence to a Mediterranean diet whereas diets with lower nutritional quality were associated with a higher risk of postmenopausal breast cancer. Overall, stronger associations were found for progesterone-receptor–negative and oestrogen-receptor–negative cancer types for vegetable intake, fibre from vegetables, and Mediterranean diet. Conversely, alcohol intake clearly and strongly increased the risk of breast cancer regardless of the menopausal status. A diet rich in β-carotene, riboflavin, thiamine, folate, fibre, iron, calcium, magnesium, potassium, phosphorus, vitamins C and vitamin B6 protects against breast cancer. In addition, high saturated fatty acids intake, and high dietary glycaemic load were all significantly associated with a higher risk of breast cancer.

42The EPIC study findings are concordant with the WCRF/AICR third expert report that concluded that there is strong evidence that consuming alcoholic drinks increases the risk of breast cancer both in pre- and postmenopausal women. According to the report, there is also some evidence that the consumption of non-starchy vegetables may reduce the risk of oestrogen-receptor–negative breast cancer; the consumption of foods containing carotenoids the risk of breast cancer in general; and the consumption of dairy products and diets high in calcium the risk of premenopausal breast cancer. The evidence available for the risk of postmenopausal breast cancer is more limited but points in the same direction. As seen in the results from the WCRF and AICR and the EPIC study, the role of dietary factors in the development of breast cancer is not entirely resolved. Alcohol is the only established dietary risk factor, probably acting by increasing levels of endogenous oestrogen and other hormones associated with this cancer. Findings from a recent systematic review of dietary patterns and breast cancer risk suggest that patterns including vegetables, red and processed meats, and that limit saturated fat may reduce breast cancer risk. The association between saturated fat and breast cancer has been very controversial over the past years, with some studies such as EPIC supporting a positive relationship and others not finding enough evidence of a relationship. More studies are needed to confirm these results and to identify the biological pathways that may be the reason for the association.

43Lung cancer: The effect of diet on lung cancer has been investigated less in the EPIC study, with only 11 studies reported since 2004. Results from EPIC overall have shown that intake of fruit and vegetables protects against lung cancer. No consistent associations were found for meat and fish consumption. A lower nutritional quality of diet was associated with a higher lung cancer risk in men and women. On the other hand, a decreased risk of lung cancer was seen for high serum levels of B6 and methionine, even among former and current smokers. Along the same lines, dietary intake of vitamin C, vitamin K2 and haem iron were also associated with a lower risk of developing lung cancer.

44The EPIC results regarding vitamin C and fruit and vegetables intake are consistent with the epidemiological evidence moderately supporting a decrease in lung cancer risk. The WCRF and AICR report also concluded that food and fruits containing retinol, β-carotene or carotenoids probably decrease the risk of lung cancer, while there is strong evidence that taking high-dose β-carotene supplements increases the risk in current and former smokers. Vegetable intake might also have a protective role in current and former smokers, but more evidence is needed, as well as for red and processed meat, alcoholic drinks, and isoflavones intake. The latest WRCF/AICR report also highlights the robustly convincing role that drinking water containing arsenic has in increasing the risk of lung cancer. Unquestionably, more studies are warranted to explore these results, but since smoking is the main cause of lung cancer, the most effective measure of prevention among smokers remains to stop smoking.

45Prostate cancer: EPIC studies regarding prostate cancer and its relationship with diet have yielded controversial results. One study showed protective associations between consumption of fruits and prostate cancer, but no associations were observed with fruits or vegetables consumption in another study. This may be also due to the relatively short follow-up in this later study. High total dietary calcium, intake of yoghurt, and calcium and protein from dairy products were significant associated with a moderate increase in risk of prostate cancer. However, there was no evidence of association with the intake of dairy products. Results associated with diets rich in calcium are consistent with scientific evidence indicating that this association is likely. Some evidence from the WCRF/AICR report also relates higher intake of dairy products, low plasma vitamin E, and low plasma selenium concentrations with an increase in the risk of prostate cancer. No consistent associations were found in the EPIC study for diets with lower nutritional quality, fat from dairy products and fruit and vegetables combined consumption. Overall, in the EPIC study, there were no associations of intake of dietary fibre, vitamin D, fish, dietary fat, alcohol, coffee, tea, and soft drinks, with the risk of prostate cancer. However, a higher risk of prostate cancer was observed with higher intake of alcohol among the O6-Methylguanine-DNA methyltransferase (MGMT) gene Ile143Val polymorphism carriers of the variant genotype in comparison with the MGMT Ile143Ile common genotype with lower alcohol intake. Two mendelian randomisation studies on alcohol intake and the risk of prostate cancer yielded inconsistent results.

46Results from EPIC might underestimate the role that diet may play in prostate carcinogenesis. Prostate cancer aetiology remains largely unknown and increasing evidence is being gathered supporting the relevant role of dietary factors in the disease. According to a recent review, consumption of trans and saturated fatty acids, and food products such as processed meat contributes to prostate carcinogenesis through the alteration of prostate hormonal regulation, the induction of oxidative inflammation and stress, and the alteration of growth factor signalling and lipid metabolism. Conversely, a high consumption of fruits, vegetables, whole grain products, and fish seem to exert protective and/or therapeutic effects.

47Biological mechanisms believed to underlie the role of diet in carcinogenesis in general include cell-cycle regulation, growth factors (such as insulin and insulin-like growth factors), immunity, inflammation, and angiogenesis. Fruits and vegetables are a rich source of vitamin C and E, folate, and selenium, which are related to anti-tumorigenic effects in different cells. Potential mechanisms explaining the effects of red and processed meat on cancer risk include cooking at high temperatures, which results in mutagenic potential trough the formation of DNA adducts; some DNA-damaging mechanisms associated with high haem iron intake, and the high salt content of processed meat that may produce damage to the stomach resulting in inflammation or atrophy, among others. Finally, drinking alcohol can be carcinogenic to some cell types and genotoxic due to ethanol, can interfere in DNA repair mechanisms, and produce changes in hormone metabolism. The role of diet in the aetiology of cancer will continue to be investigated in EPIC, also using tumour molecular pathology and omics research, including metabolomics, genetics, and the microbiome.

48The EPIC study findings have contributed to the WRCF/AICR recommendations about cancer prevention. In comparison with the previous review, this updated article shows EPIC findings derived from longer follow-up studies that best reflect what is etiologically relevant. This review compiles novel and stronger evidence that confirms some weak associations described previously, such as the association of fruit and/or vegetables consumption with colorectal, breast, and prostate cancer, or dietary fibre intake with colorectal cancer. In the past years, more evidence has accumulated about dietary patterns (for example, Mediterranean diet, lower nutritional quality diet or inflammatory score of the diet), and other dietary exposures such as nutritional biomarkers (for example, several vitamins, carotenes, or fatty acids). New evidence has emerged regarding yogurt, milk, and soft drink consumption in relation to colorectal cancer risk; fatty fish and coffee intake and breast cancer risk; and yogurt and fat intakes with prostate cancer risk. Overall, this work adds ninety new published articles about colorectal, breast, lung, or prostate cancer. This reflects the remarkable increase in the available evidence from the EPIC study in the last ten years (n = 20 vs. n = 110).

49The EPIC study has been highly prolific and a major source of evidence regarding the aetiology of cancer and other chronic diseases. The most relevant strengths of the EPIC study are its very large sample size, its prospective nature, the availability of blood samples to explore biomarkers, and the very comprehensive dietary questionnaires, from diverse European populations with different predominant dietary patterns and a wide variation in cancer incidence. Nevertheless, the EPIC study also has limitations that could affect its results. Like in most observational studies, our results are in partly based on self-reported data that may be subject to misclassification or measurement error in dietary intake.

50The EPIC study has resulted in numerous high-quality publications about the role of diet in cancer prevention that help inform public health recommendations, policies, and strategies. Overall, fruit and vegetable consumption had a protective effect against colorectal, breast, and lung cancer, whereas only fruit had a protective effect against prostate cancer. A higher consumption of fish and lower consumption of red and processed meat were related with a lower risk of colorectal cancer; and higher consumption of fatty fish with lower risk of breast cancer. Calcium and yogurt intake were found to protect against colorectal and prostate cancer. Alcohol consumption increased the risk for colorectal and breast cancer. Finally, adherence to the Mediterranean diet emerged as a protective factor for colorectal and breast cancer.