Selenium, Genetic Variation, and Prostate Cancer Risk: Epidemiology Reflects Back on Selenium and Vitamin E Cancer Prevention Trial

The randomized, controlled Selenium and Vitamin E Cancer Prevention Trial (SELECT) found that selenium supplementation did not decrease the risk of prostate cancer, which contradicted a secondary finding from the Nutritional Prevention of Cancer (NPC) Study. In the wake of SELECT, we expect that many groups will report results from epidemiologic studies on selenium and prostate cancer, some of which may illuminate reasons for SELECT’s null results. One such effort is reported in this issue of Journal of Clinical Oncology by Chan et al, who conducted a cross-sectional epidemiologic study of plasma selenium, an SOD2 variant, and aggressive prostate cancer in men diagnosed with clinically localized or locally advanced prostate cancer and who provided a blood specimen. They observed an unexpected positive association between plasma selenium and aggressive disease. As expected, an SOD2 variant, a substitution of alanine for valine at amino acid 16 in the antioxidant enzyme manganese superoxide dismutase, was not statistically significantly associated with aggressive disease, although the relative risks (RRs) for one or two alanine alleles were above 1.0. Two patterns emerged in the analysis of the joint association of plasma selenium and SOD2: men with low selenium and two alanine alleles had a higher risk of aggressive disease (compared with low selenium and none or one alanine alleles); high selenium seemingly protected men with two alanine alleles; and men with high selenium and none or one alanine allele had a higher risk of aggressive disease (compared with low selenium and none or one alanine allele). In light of these findings, Chan et al commented that their data “indicate caution against broad use of selenium supplementation for men with prostate cancer” and that “complete interpretation of results from SELECT may depend on assessment of SOD2 genotype in trial participants.” Before discussing the broader context (related observational studies, the NPC study, and SELECT) and implications of this study, we will discuss a design feature that complicates drawing etiologic inferences—and thus implications for selenium supplementation— from the Chan et al study. They estimated the prevalence of aggressive disease in a cohort of men with prostate cancer, making the denominator for risk calculation men with prostate cancer. Etiologic research on aggressive prostate cancer typically estimates risk of aggressive disease in a cohort of men who do not have a diagnosis of prostate cancer at baseline, making at-risk men without prostate cancer the denominator. Table 1 illustrates several hypothetical scenarios (a subset of all possible scenarios) that could explain the higher risk of aggressive prostate cancer found by Chan et al in men with higher plasma selenium. Columns 4 to 6 involve a typical cohort of at-risk men. The cohort of cancer patients (aggressive and nonaggressive) involved in column 7 is derived from the at-risk cohort and reflects the design of Chan et al. Although all are hypothetical, the data and assumptions in Table 1 are consistent with the epidemiologic literature on nutrients and genetic variants and are not out of line with the data of Chan et al (the same can be said of the hypothetical data and assumptions in Table 2, which is discussed below). Scenario D is a plausible scenario in which the increased RR of aggressive disease (1.25) in a design similar to that of the study by Chan et al would be misleading because the true RR of aggressive disease is 0.75, as illustrated by the more informative typical cohort design. Scenarios A to D are all plausible but unknowable because of this study’s design. Differences in implication make it absolutely critical to discern the correct scenario behind the Chan et al results. The implication of hypothetical scenarios A and C—caution against taking a selenium supplement—is diametrically opposed to that of B and D—a recommendation for taking a selenium supplement. The typical cohort design for etiologic research, using at-risk individuals, enables correct implications that are not derivable from a design using cancer patients at baseline. The design of the study by Chan et al is frequently used in clinical studies of potential biomarker associations or correlations with cancer aggressiveness, where inferences are unambiguous (barring other sources of error). This design also sometimes is used for etiologic research, but investigators should be alert to the etiologic ambiguity it raises for interpreting a positive or inverse association between an exposure and aggressive disease. Previously published studies in at-risk men may help in drawing inferences from the Chan et al findings on the main effects of selenium and SOD2 and their joint effects, which are even more challenging to interpret with a cohort of only cancer patients. Regarding associations between circulating selenium and overall prostate cancer, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 22 AUGUST 1 2009