In this nested case-control study, which included 724 incidence prostate cancer cases and 879 controls, we observed no overall association between prediagnostic selenium concentrations and prostate cancer. However, greater serum selenium concentrations were associated with lower risks of this disease in men who reported a high vitamin E intake, in multivitamin users, and in smokers.
The strongest support for a chemopreventive effect of selenium in human prostate carcinogenesis comes from the Nutritional Prevention of Cancer Trial, a randomized study to evaluate selenium supplementation (200 μg/d) and skin cancer prevention, which found, as secondary endpoints, reduced risks of total cancer mortality (50%) and prostate cancer incidence (52% reduced risk; average intervention period 6.4 y, with 64 prostate cancer cases) (1
). In a second trial (SU.VI.MAX), no overall association was found with selenium supplementation; however, among men with a normal baseline PSA (< 3 ng/mL), the risk of prostate cancer was 48% lower in the group of selenium-treated men than in the group of placebo-treated men (47
). The result of this study cannot be attributed directly to selenium (dose: 100 μg/d), because 5 other antioxidative vitamins and minerals were given simultaneously as a multivitamin supplement.
), but not all (53
), case-control studies nested in prospective cohorts also showed inverse associations between serum selenium and prostate cancer risk, with several reporting stronger associations for advanced prostate cancer (most studies defined advanced cancer as stage III and IV disease)(48
). Of 3 retrospectively designed population-based case-control studies (55
), only one (56
) found a non-significant inverse association between serum selenium and prostate cancer.
Because the enzyme activity of some selenoenzymes, such as the glutathione peroxidases, tend to plateau at high serum selenium concentrations (58
), selenium supplementation may be most effective in populations with low selenium exposure. The Nutritional Prevention of Cancer Trial, which was conducted specifically in areas with low selenium intake, supported this hypothesis showing the strongest inverse associations with prostate cancer in men with low baseline serum selenium concentrations (1st tertile: < 106 ng/mL, and 2nd tertile: 106–121 ng/mL) and no association in men with high baseline concentrations (3rd tertile: > 121 ng/mL) (4
). However, the inverse selenium-prostate cancer associations observed in epidemiologic studies do not appear to be limited to settings with low mean serum selenium concentrations ( and ), and, from our study, the strongest inverse associations were noted in areas with high soil selenium content. Furthermore, it is unknown how these circulating concentrations translate to the prostate, which also expresses selenoenzymes not found in the circulating system, eg, selenoprotein 15 (60
). In addition, selenium may also prevent prostate cancer directly through active selenium metabolites, in particular methylated forms; however, such effects, as shown in experimental studies, are achieved only at supranutritive doses (16
FIGURE 1 Clinical trial and observational studies on selenium and the risk of prostate cancer listed by mean or median selenium concentrations. ORs and 95% CIs were obtained in a comparison of the highest with the lowest quantile of selenium. , randomized (more ...)
FIGURE 2 Observational studies on selenium and risk of advanced prostate cancer (1) listed by mean or median selenium concentrations. ORs and 95% CIs were obtained in a comparison of the highest with the lowest quantile of seleniuim. ▲, nested case-control (more ...)
Our results suggest a synergistic relation between selenium and vitamin E, showing little evidence that one antioxidative nutrient can replace the other in prostate cancer prevention. Our finding is consistent with 2 observational studies (12
) and a nutritional intervention trial conducted in Linxian China (5
), although not all observational studies (49
) found such interactions. However, our study lacks specificity on this point because most vitamin E supplementation was in the form of multivitamins, making it difficult to separate the effects of vitamin E from those of other multivitamin constituents. Because the Selenium and Vitamin E Cancer Prevention Trial, one of the largest ongoing intervention trials, makes a multivitamin without vitamin E and selenium, available to trial participants who prefer to continue using multivitamin while participating in the trial, this trial will be able to further explore interaction between selenium, vitamin E, and multivitamins. The trial is expected to be completed in 2013 (7
We also observed a strong inverse association between serum selenium and prostate cancer risk in smokers. Although smoking itself was not associated with prostate cancer risk in the present study (data not shown) and several other studies (63
), it is noteworthy that another antioxidant, vitamin E, is associated with reduced risk of this disease primarily in smokers, as seen in this cohort (64
) and most other studies (65
). Additional exploration of a 3-way interaction between vitamin E, smoking, and selenium was beyond the scope of the present study, because the numbers of cases and controls in these subgroups were small. Effect modification of the selenium-prostate cancer association by smoking was found in 3 observational studies (49
), but not in another (51
) and not in an investigation of prostate cancer risk in smokers and asbestos workers (53
). Smoking results in increased exposure to radical oxidative species (35
), and selenium inhibits the damaging effect of oxidative species on DNA and other biomolecules. The protective role of selenium in smokers could also be enhanced by the presence of oxidative-response elements in the promoter regions of genes encoding for selenoenzymes, such as GPX1
), and their increased transcription related to exposure to oxidative stressors (72
Given an increasing nationwide distribution of foods, we were somewhat surprised to observe statistically significant differences in serum selenium concentrations by regional soil selenium content. However, this difference was not accounted for by regional differences in dietary pattern [eg, differences in the level of consumption of foods high in selenium, such as grains, eggs, meat, and fish (75
)], because adjustment for these and other foods did not significantly change the results (data not shown).
A limitation of our study was the relatively short follow-up, to a maximum of 8 y. To avoid potential effects of disease on selenium concentrations, we only included cases diagnosed ≥ 1 y after blood draw; excluding cases diagnosed within the first 2 y showed similar results (data not shown). We only measured selenium at a single point in time, and multiple measurements ideally over the entire period of cancer development would have reduced the possibility of attenuated risk estimates due to random error. Stratified analysis by antioxidative nutrients was based on questionnaire data, which may introduce measurement error. Correlations of serum selenium with BMI and intakes of alcohol, red meat, vitamin E, β-carotene, lycopene, and energy suggest that combined lifestyle factors may contribute to prostate cancer prevention and that observational studies such as ours only incompletely control for unmeasured confounding. Clinical trials with selenium as an intervention could address this.
The present study was large ( and ), and the men studied had a broad range of serum selenium concentrations [almost as wide as the intervention effect in the Nutritional Prevention of Cancer Trial, in which mean serum selenium concentrations rose from 114 ng/mL at baseline to 190 ng/mL at the end of the intervention (1
)]. By restricting our analysis to men randomly assigned to the screening arm of the trial, disease detection bias was limited. Compliance with the PLCO protocol for prostate cancer screening was very high and similar across quartiles of selenium. Our large sample size ensured sufficient power to observe ORs of ≤ 0.68 in comparisons of the 4th with the 1st quartile, similar to the summary OR of a recent meta-analysis (OR: 0.72) (76
) and within the range of expected associations ().
In conclusion, overall we observed no inverse association between prediagnostic serum selenium concentrations and the risk of prostate cancer in this large cohort, which was followed up by standardized screening procedures. However, higher serum selenium may be associated with lower prostate cancer risk in men who report a high intake of vitamin E, in multivitamin users, and in smokers.