So although adequate intakes of micronutrients do not guarantee protection against cancer, studies do show that people who consume insufficient quantities in the long term have a considerably higher risk of developing some types of cancer. As antioxidants and enzymatic co-factors, vitamins and other micronutrients are involved in many physiological processes which serve to maintain cell structures and functions, including the repair and maintenance of DNA. Inefficient or even faulty repairs to DNA due to a lack of nutrients leads to genome instability, which in turn can lead to an increased risk of developing cancer. Moreover, micronutrients are essential for the regulation of intercellular communication, inhibition of certain cancer-promoting substances and strengthening the immune system. The extent to which an adequate nutrient intake offers protection is dependent on many other factors, including lifestyle and the type of cancer.
Fruit and vegetables
The results of numerous case-control studies show that a diet rich in fruit and vegetables can lower the risk of developing a number of different types of cancer, especially cancers of the digestive system (esophagus, stomach, bowel) and lung cancer (1, 2). The results of some of these studies provided the basis for the "five-a-day" programs of the American National Cancer Institute and many national nutrition societies aimed at increasing fruit and vegetable consumption in the population to a minimum of five portions a day. In contrast to the results of the case-control studies, many more recent prospective cohort studies have found little or no connection between overall fruit and vegetable consumption and the risk of developing various types of cancer (3–23). However, some of the studies did provide evidence that a high intake of certain classes of fruit and vegetables could be associated with a reduced risk of some types of cancer. Thus a higher intake of fruits was linked to a modest but significant reduction in the risk of lung cancer (8) and bladder cancer (24). In men greater consumption of vegetables from the cabbage family was associated with a significant fall in the risk of bladder cancer (25) and prostate cancer (26) and increased consumption of tomato products was associated with a reduction in the risk of prostate cancer (27).
While investigations with cell cultures and animal studies produced evidence that natural and synthetic retinoids can reduce the incidence of skin, breast, liver, bowel and prostate cancer (28), the results of human studies into a possible connection between consumption of preformed vitamin A (retinol) and cancer were less clear. The majority of the epidemiological studies found no significant associations between retinol intake and the risk of breast cancer in women (29–32), although a large prospective study revealed that with increased total vitamin A intake amounts the risk of breast cancer in premenopausal women with a family history of breast cancer decreased (33). The blood concentration of retinol reflects the intake both of preformed vitamin A and of provitamin A carotenoids such as beta-carotene. Although one case-control study showed that with increasing serum retinol concentrations the risk of breast cancer fell (34), this finding could not be confirmed by two prospective studies (35, 36).
Of ten prospective studies only one found a statistically significant association between increased retinol concentrations in serum and reduced risk of lung cancer (37). The results of two studies indicate that a high-dose intake of vitamin A and beta-carotene should be avoided by people at high risk of developing lung cancer (38, 39). Hence a significantly more frequent incidence of lung cancer was observed in heavy smokers and people exposed to asbestos who ingested 10 to 15 times the recommended doses of beta-carotene over a period of years (see also Expert Opinion). This was not observed in other studies (40, 41). In 2012 the European Food Safety Authority (EFSA) stated that epidemiological studies had come to the conclusion that no increased incidence of lung cancer was to be found among heavy smokers who consumed beta-carotene as a food supplement in doses between 6 and 15 mg per day for a period of five to seven years (42). Nor would an intake of less than 15 mg beta-carotene daily from fortified foods or food supplements give rise to concern about health risks in the general population, including heavy smokers. Clearly, smoking itself is the biggest risk factor for the incidence of lung cancer and an unhealthy lifestyle cannot be compensated for by consuming micronutrients.
Generally, a relationship between dietary factors and cancers is first observed in epidemiological studies and then research is conducted into possible connections at the cellular level. In the case of vitamin B3 (niacin) results from in-vitro experiments that linked niacin to DNA repair processes stimulated interest in human studies (43). In a large case-control study, increased consumption of niacin, together with antioxidant nutrients, was linked to a lower incidence of mouth, throat and esophageal cancer: an intake of 6.2 mg niacin a day was associated with an approximately 40 percent drop in cases of cancer of the mouth and throat, while daily intake of 5.2 mg niacin was linked to a similar reduction in cases of esophageal cancer (44,45).
Because of the important role that vitamin B9 (folate) plays in DNA and RNA synthesis it is possible that DNA repair and the expression of genes that are important in this context are influenced by folate intake. In observational studies low blood folate concentrations could be linked to a rise in the incidence of cancer of the cervix, colon and rectum, as well as lung, esophagus, brain, pancreas and breast cancer. A connection was found between low levels of folate and high alcohol intake and an increased risk of bowel cancer (46–48). Alcohol interferes with the uptake and metabolism of folic acid (49). In a prospective study with more than 45,000 male health professionals, consuming more than two alcoholic beverages a day was found to double the risk of developing bowel cancer (50). The combination of high alcohol consumption and low folate intake resulted in an even greater risk of developing colon cancer. In contrast, no increased risk of bowel cancer was observed in people who ingested 650 micrograms or more of folic acid per day, even with a high alcohol intake (50). In some studies it was shown that for people with a particular variant (C677T) of a folate metabolizing gene (MTHFR) the risk of developing bowel cancer was reduced by appropriate folate adminis-tration (51, 52). On the whole, the role of folate for the possible prevention of colorectal cancer is a good example of the complex interactions between genetics and nutrition. Intervention studies with folic acid in humans were conducted primarily for prevention of cervical and colorectal cancer. While the results for cervical cancer were inconsistent (53), the outcomes of randomized controlled studies on bowel cancer were promising (54, 55).
A study with patients who had a previous history of colorectal polyps (adenomas) linked supplementation with 1 mg folic acid per day (more than double the recommended amount) with a statistical trend towards increased incidence of advanced bowel lesions and with an increased risk of the occurrence of colorectal adenoma (56). This link was also reported in the follow-up observations (57) (see also Expert Opinion). However, other studies found no evidence to support this (58, 59). A meta-analysis of seven randomized controlled studies found that supplementary intake of folic acid (800 micrograms to 40 mg per day for up to seven years) did not increase the risk for the incidence of cancer or the disease-related mortality rate (60).
Studies that have investigated the extent to which folate consumption influences the risk of breast cancer have produced inconsistent results (61). The results of two prospective studies indicate that increased folic acid consumption can reduce the risk of breast cancer in women who regularly consume alcohol (62–64); moderate alcohol consumption has been linked to an increased risk of breast cancer in women in several studies. One very large prospective study with more than 88,000 nurses observed that folic acid intake and breast cancer in women who consumed less than one alcoholic beverage per day were not linked (64). In women who consumed at least one alcoholic beverage a day, taking at least 600 micrograms of folic acid resulted in a breast cancer risk that was approximately half as high as in women who ingested less than
300 micrograms of folic acid daily.
Folate is needed for synthesis of DNA and there are indications that reduced availability of folate is associ-ated with the formation of DNA strands that are more prone to damage. A deficiency of both folate and vitamin B12 (cyanocobalamin) leads to a reduced ability to perform methylation reactions to stabilize DNA. Hence vitamin B12 deficiency can lead to a rise in the rate of DNA damage and deviant DNA methylation patterns, both of which are important risk factors for cancer. A number of recent studies with young adults and older men have shown that high homocysteine levels and lower levels of vitamin B12 in the bloodstream are associated with an increase in the presence of a biomarker for chromosome breaks in white blood cells. In a randomized controlled study the concentration of the same biomarker could be reduced in young adults by administration of 700 micrograms of folic acid and 7 micrograms of vitamin B12 for two months (65).
One case-control study showed that the risk of breast cancer for women with the lowest serum concentra-tions of vitamin B12 was more than double that of the women with the highest levels (66). Another case-control study resulted in a risk reduction of up to 68 percent in women with high vitamin B12 levels, and that the link was more obvious in postmenopausal women than in women who had not yet reached menopause (67). However, it is unclear whether the low serum levels of vitamin B12 are the cause or effect of breast cancer. Some studies that linked increased intake of folate with a reduced risk of breast cancer reported that vitamin B12 could influence this link (68, 69).
While numerous case-control studies indicate that increased consumption of vitamin C is associated with a lower incidence of cancer of the oral cavity, the throat and the larynx, esophagus, stomach, colon and rec-tum and also lung cancer, prospective studies regularly produced inconsistent results. In general observa-tional studies in which participant groups with the lowest intake of vitamin C consumed more than 86 mg daily reported no differences in respect of cancer risk. Studies in which subjects ingested at least 80 to
110 mg vitamin C daily showed some evidence of reduced cancer risks, compared to participants with a considerably lower intake (70). One study that observed 870 men over a period of 25 years showed that those who consumed more than 83 mg vitamin C a day showed an up to 64 percent lower risk of lung cancer, compared to those who consumed less than 63 mg a day (71). However, after purging the results of any possible preventive effects from other dietary factors, a meta-analysis of eight prospective studies showed that vitamin C is not connected to lung cancer (72).
Although most of the large prospective studies revealed no connection between breast cancer and vitamin C, two studies did show a risk reduction in some participant subgroups. In the Nurses’ Health Study premeno-pausal women with a family history of breast cancer who had consumed an average of 205 mg vitamin C per day in their diet had an up to 63 percent lower risk of breast cancer than those who had consumed 70 mg per day on average (73). In a Swedish study, overweight women who consumed an average of 110 mg vitamin C daily were 39 percent less likely to develop cancer compared to overweight women who only consumed 31 mg per day on average (74).
A number of observational studies produced evidence that an increased intake of vitamin C could be associated with a reduced risk of stomach cancer, and laboratory trials showed that vitamin C inhibits the production of carcinogenic compounds in the stomach (75, 76). Although two intervention studies could not prove that food supplementation with vitamin C can effect a reduction in the risk of stomach cancer (77), more recent research proposes that vitamin C supplementation could be a useful complement to the stan-dard H. pylori eradication treatment in the course of reducing the risk of stomach cancer (78, 79). Another randomized controlled study, the Physicians’ Health Study II, with more than 14,000 older men, was also unable to find evidence of a significant link between dietary supplementation with vitamin C (500 mg/day) for an average of eight years and the overall incidence of cancer or specific forms of cancer, including bowel, lung and prostate cancer (80). Some experts criticize that neither blood levels of vitamin C nor markers for oxidative stress and inflammation were determined, either at the start of or during the study. The possibility cannot therefore be excluded that study participants with high oxidative stress or inflammation had benefited from the vitamin C administration.
Two characteristics of cancer cells are a lack of differentiation (specialization) and rapid growth or reproduc-tion (proliferation). Many malignant tumors have been identified (in breast, lung, skin, colon and bone) which contain vitamin D receptors. Studies on cell cultures have shown that biologically active forms of vitamin D, such as 25-hydroxy-vitamin D (25(OH)D) and its analogs, can induce differentiation or can inhibit proliferation in cancerous and non-cancerous cell types (81). Results from some, but not all, epidemiological studies indicate that vitamin D could protect against several types of cancer.
The geographic distribution of mortality rates due to bowel cancer is similar to the historic distribution of rickets cases (82), which leads us to assume that reduced sunlight and an insufficient vitamin D status could contribute to an increased risk of bowel cancer. However, as a rule this could not be confirmed by cohort studies (83–86). Some more recent studies did, however, produce evidence that increased intake of vitamin D and higher serum 25(OH)D levels could contribute to a fall in bowel cancer risk. Hence a five-year study with more than 120,000 participants showed that the risk of bowel cancer for the men with the highest vitamin D intakes was around 29 percent lower than that of participants with the lowest intakes (87). No such association could be found for women. Moreover, it could be shown that an increased serum 25(OH)D concentration, which reflects the scale of physiological, sunlight-induced vitamin D synthesis and vitamin D intake in the diet, appears to be linked to a reduced risk for the incidence of colorectal adenoma (88) and for proliferation of epithelial cells in the colon (89), two indicators for bowel cancer risk. In one case-control study from the Nurses’ Health Study cohort, higher levels of plasma 25(OH)D were linked to a reduction in the incidence of colorectal cancer (90). A large-scale randomized controlled study with over 36,000 post-menopausal women showed that a combination of vitamin D (400 IU/day) and calcium (1,000 mg/day) did not reduce the incidence of colorectal cancer (91). It was discussed whether the dose of vitamin D used in the study was possibly too low to have a measurable effect on the incidence of the cancer (92). In favor of such a conclusion is the result of a dose-effect analysis which assumes that an oral intake of 1,000 IU of vitamin D daily could lower the risk of colon cancer by 50 percent (93).
Although breast-cancer-related mortality rates show a similar geographical distribution to those of bowel cancer (82, 94), there are only limited indications for a connection between vitamin D status and breast cancer risk. One prospective study with women who took part in the first National Health and Nutrition Examination Survey (NHANES I) showed that measures to increase the amount of exposure to sunlight and vitamin D consumption were associated with a reduced risk of developing breast cancer 20 years later (95). In one 16-year study with more than 88,000 women, higher intakes of vitamin D were associated with a considerably lower breast cancer risk in premenopausal women, but not in postmenopausal women (96). A combined dose-effect analysis of two case-control studies in which women with breast cancer had significant-ly lower plasma 25(OH)D levels than the control group (97, 98) showed that women with a 25(OH)D level of 52 ng/mL (130 nmol/L) had a 50 percent lower risk of developing breast cancer than women with 25(OH)D levels below 13 ng/mL (32.5 nmol/L) (99). It was calculated that in order to achieve a serum vitamin D concentration of 52 ng/mL, around 4,000 IU of vitamin D3 must be consumed daily, or 2,000 IU of vitamin D3 daily plus very moderate exposure to sunshine (99).
Epidemiological studies provided evidence that there could be a link between the risk factors for prostate cancer and conditions that can lead to reduced levels of vitamin D (100). Thus the risk of prostate cancer and the risk of limited exposure to sunshine as well as a reduced ability to synthesize vitamin D increase with advancing age. The prevalence of prostate cancer in Afro-American men is greater than in white American men, while it is a known fact that the high melanin content of dark skin reduces the effectiveness of physio-logical, sunlight-induced vitamin D synthesis. However, as a rule, observational studies were not able to demonstrate a significant association between serum 25(OH)D levels and the risk of developing prostate cancer (101–104). While one prospective study showed that low serum 25(OH)D levels could be linked to an earlier onset and more aggressive progression of prostate cancer (100), another study established an asso-ciation between a greater risk of prostate cancer and serum 25(OH)D concentrations of under 19 nmol/L or over 80 nmol/L (105). More investigations are necessary to clarify the relationship between vitamin D status and the risk of prostate cancer.
It is assumed that many kinds of cancer are triggered by oxidative damage to DNA from free radicals. The ability of vitamin E (alpha-tocopherol) to neutralize free radicals has made it the object of a number of studies on the prevention of cancer. Large observational studies could not, however, detect significant associations between vitamin E intake and the incidence of lung or breast cancer (106). One study with a cohort of over 77,000 men and women reported that using food supplements with vitamin E over a period of 10 years could increase the risk of lung cancer in smokers (107). Most clinical studies up to now have shown that supplementation with vitamin E has no effect on the risk of various types of cancer. One randomized controlled study with over 39,000 participating women came to the conclusion that supplementation with
600 IU (400 mg) RRR-alpha-tocopherol every other day for 10 years had no effect on the prevalence of cancer overall (including breast, lung and bowel cancer) or on the number of deaths due to cancer (108). Further, a meta-analysis of 12 randomized controlled studies showed that supplementation with vitamin E did not influence the incidence of cancer, cancer mortality or overall mortality (109).
Of particular interest was a possible preventive effect of vitamin E supplements in the genesis of prostate cancer. An intervention study to investigate the preventive effects of supplementation with alpha-tocopherol on the development of lung cancer showed that there was a 34 percent reduction in the prevalence of prostate cancer in smokers who consumed 50 mg of synthetic alpha-tocopherol (corresponding to 25 mg RRR-alpha-tocopherol) daily (110). A meta-analysis that combined the results of this study with three other clinical studies found an association between the use of vitamin E supplements and a 15 percent reduction in the risk of prostate cancer (107). In contrast, two following large randomized studies found either no benefit or a possible negative influence on the risk of prostate cancer in healthy men who specifically consumed vitamin E. In the Physicians’ Health Study II, in which over 14,000 healthy men aged 50 years and over took 400 IU synthetic vitamin E (corresponding to 180 mg RRR-alpha-tocopherol) every other day for eight years, supplementation with vitamin E showed no influence on the risk of prostate cancer or all types of cancer (111). A large intervention study in which over 35,000 healthy men aged 50 years or over took dietary supplements containing alpha-tocopherol and selenium, alone or in combination, was stopped after a preliminary evaluation revealed no evidence of a benefit for the prevention of prostate cancer (112, 113). After an average of 5.5 years the participants who took 400 IU of vitamin E per day (which is about 20 times the recommended daily amount for vitamin E) showed a slightly higher risk of prostate cancer, which was not, however, statistically significant (114). A follow-up analysis after an average of seven years showed that men who had taken vitamin E had a statistically significant, 17 percent higher risk of prostate cancer than the placebo group (115). Because the study participants had no longer consumed dietary supplements with vitamin E after the preliminary evaluation, the increased risk of prostate cancer could not be unequivocally linked to vitamin E, especially since other, not investigated confounding factors could have been responsible for this rise (see also Expert Opinion 1 and 2).