VOLUME

27

NUMBER

22

AUGUST

2009

JOURNAL OF CLINICAL ONCOLOGY

Selenium, Genetic Variation, and Prostate Cancer

Risk: Epidemiology Reflects Back on Selenium and
Vitamin E Cancer Prevention Trial
Elizabeth A. Platz, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; James Buchanan Brady
Urological Institute; and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD
Scott M. Lippman, Divisions of Cancer Medicine and Cancer Prevention and Population Sciences, The University of Texas
M. D. Anderson Cancer Center, Houston, TX

The randomized, controlled Selenium and Vitamin E Cancer

Prevention Trial (SELECT)1 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.2 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 SELECTs
null results.
One such effort is reported in this issue of Journal of Clinical
Oncology by Chan et al,3 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 al3
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
inferencesand thus implications for selenium supplementation
from the Chan et al study.3 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 studys 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
supplementis diametrically opposed to that of B and Da 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 al3 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, Vol 27, No 22 (August 1), 2009: pp 3569-3572

DOI: 10.1200/JCO.2009.22.2117; published online ahead of print at www.jco.org on June 15, 2009

2009 by American Society of Clinical Oncology

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Table 1. Hypothetical Scenarios Involving an At-Risk Cohort of Men That May Explain the Apparent Positive Association Made by Chan et al3 Between Higher
Circulating Selenium Level and Aggressive Prostate Cancer
Hypothetical True Direction of
Association Between
Selenium and Prostate
Cancer
Scenario

Aggressive

Typical Cohort Design for Etiologic Research: Denominator Is At-Risk Men Without Prostate
Cancer at Baseline
RR of Total Prostate
Cancer

RR of Aggressive Prostate
Cancer

RR of Nonaggressive
Prostate Cancer

RR of Aggressive
Prostate Cancer

(53.3 60/1,000)/
(40 60/1,000) 1.13
(40 45/1,000)/
(40 60/1,000) 0.85
(53.3 45/1,000)/
(40 60/1,000) 1.00
(30 30/1,000)/
(40 60/1,000) 0.60

(53.3/1,000)/(40/1,000) 1.33

(60/1,000)/(60/1,000) 1.00

(40/1,000)/(40/1,000) 1.00

(45/1,000)/(60/1,000) 0.75

(53.3/1,000)/(40/1,000) 1.33

(45/1,000)/(60/1,000) 0.75

(30/1,000)/(40/1,000) 0.75

(30/1,000)/(60/1,000) 0.50

(53.3/53.3 60)/
(40/40 60) 1.18
(40/40 45)/
(40/40 60) 1.18
(53.3/53.3 45)/
(40/40 60) 1.36
(30/30 30)/
(40/40 60) 1.25

Nonaggressive

Null

Null

22

Chan et al3 Design:

Denominator Is Men
With Prostate Cancer

Abbreviation: RR, relative risk.

1 and 2 signify an increase or decrease in risk of 1.33 or 0.75 (these RRs are equidistant from the null on the natural logarithm scale), respectively in the
high-selenium group. 22 signifies a decrease in risk of 0.5 in the high-selenium group.
The cohort in these columns consists of 2,000 at-risk men, half of whom are in the high-selenium group. In the low-selenium group, 100 men develop prostate
cancer, 40% of which is aggressive disease.
The cohort in this column consists of the prostate cancer cases that are diagnosed in the cohort in .
Denominator is all prostate cancer cases in the high-selenium group.
Denominator is all prostate cancer cases in the low-selenium group.

most large studies found no association,4-7 whether the study involved

populations with low or high selenium exposure or with or without
routine prostate-specific antigen (PSA) screening (one small study did
find an inverse association8). Regarding associations between selenium levels and aggressive disease, a study of selenium content in
toenails9 and some other studies4,6 reported inverse, albeit nonlinear,
associations and other studies reported no association.5,6 Regarding
associations between selenium and nonaggressive disease,4-6 only the
Physicians Health Study (PHS)4 found an association, which was an
inverse association with nonaggressive disease diagnosed before but
not since the PSA era began. If selenium is not associated with nonaggressive disease in the PSA era, then the Chan et al finding of a positive
association for aggressive disease likely is not explained by scenario B,
C, or D in Table 1 (suggesting prevention of nonaggressive disease).
The worrisome scenario A showing an increased risk of aggressive
disease with selenium, however, contradicts the findings of some large
studies.4,6,9 Again, we cannot be certain which scenario is correct

because of the etiologic ambiguity resulting from the Chan et al

study design.
Large studies with a risk-estimation denominator of at-risk men
suggest that the SOD2 alanine allele is positively associated with prostate cancer,10-12 although so weakly in some studies that the authors
concluded no association.13,14 In studies finding a moderate association, it was present for aggressive and nonaggressive disease10,12 but
possibly was stronger for the former. The Chan et al3 results are
consistent with these results10,12; if the alanine allele is more strongly
positively associated with aggressive than nonaggressive disease in a
typical, at-risk cohort design, then the RR of aggressive disease would
be above 1.0 when using the Chan et al design (Table 2, in which the
hypothetical scenario is constructed as are those in Table 1).
The PHS and another cohort study with an at-risk denominator for risk estimation11,13 found a joint association for two alanine
alleles plus low selenium with a higher prostate cancer risk (compared
with none or one alanine alleles and low selenium), which was more

Table 2. Hypothetical Scenario Involving an At-Risk Cohort of Men That May Explain the Apparent Positive Association Made by Chan et al3 Between the
Alanine Allele of SOD2 and Aggressive Prostate Cancer
Hypothetical True Direction of
Association Between the Alanine
Allele and Prostate Cancer
Aggressive
11

Nonaggressive
1

Typical Cohort Design: Denominator Is Men Without Prostate Cancer at Baseline

Chan et al3 Design:

Denominator Is Men
With Prostate Cancer

RR of Total Prostate
Cancer

RR of Aggressive Prostate
Cancer

RR of Nonaggressive
Prostate Cancer

RR of Aggressive
Prostate Cancer

(80 79.8/1,000)/
(40 60/1,000) 1.60

(80/1,000)/(40/1,000) 2.00

(79.8/1,000)/(60/1,000) 1.33

(80/80 79.8)/
(40/40 60) 1.25

Abbreviation: RR, relative risk.

1signifies an increase in risk of 1.33 in the group with 2 alanine alleles. 11 signifies an increase in risk of 2.0 in the group with 2 alanine alleles.
The cohort in these columns consists of 2,000 at-risk men, sampled so that half have two alanine alleles and half have zero alanine alleles. In the group with zero
alanine alleles, 100 men develop prostate cancer, 40% of which is aggressive disease.
The cohort in this column consists of the prostate cancer cases that are diagnosed in the cohort in .
Denominator is all prostate cancer cases in the two alanine-allele group.
Denominator is all prostate cancer cases in the zero alanine-allele group.

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2009 by American Society of Clinical Oncology

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Editorial

pronounced for aggressive disease in the PHS.13 In contrast, men with

high selenium had a lower risk of prostate cancer irrespective of the
number of alanine alleles they carried.13 This pattern is not unique to
selenium, however. An increased risk of aggressive disease was associated with two alanine alleles and low lycopene in the Health Professionals Follow-up Study (HPFS)14 and with two alanine alleles and
low lycopene and low total antioxidants in the PHS.13 Regarding
effects on nonaggressive disease, there was no clear interaction between antioxidant status and SOD2 genotype in the PHS,13 and it can
be inferred that there was no interaction between lycopene and SOD2
genotype or that it possibly was inversely associated in the HPFS.14 The
increased risk of aggressive prostate cancer in men with two alanine
alleles and low selenium in the study by Chan et al3 is compatible with
the results from these at-risk denominator studies (paralleling the
argument depicted in Table 2). But again, the interaction with SOD2
may not be selenium specific.
The only finding in Chan et al3 that is not compatible with the
previous studies of the association between selenium and prostate
cancer reviewed here1,2,4-14 is the overall increased risk of aggressive
disease associated with higher circulating selenium, which was driven
by men with none or one alanine allele. Possible contributors to this
incompatible result were the Chan et al study design and methodologic limitations discussed by the authors (eg, lack of temporality and
a small sample size for evaluating joint effects). The study population,
however, had a selenium exposure (eg, distribution comparable to
that in US adult men15) and outcome (eg, PSA era) similar to those in
some of the other observational studies. Serum selenium in the Chan
et al study was higher than in the NPC study16 but lower than in
SELECT,1 and the distribution of stage/grade was likely intermediate
between the NPC study (which straddled the pre-PSA and PSA era)
and SELECT (PSA era, and virtually all patients had T1/T2 and Gleason 3 4 disease). In the NPC study, the inverse association for
selenium supplementation was present for both local and advanced
disease and was strongest in men with low circulating selenium.16 The
null SELECT result implies no association of selenium supplementation with nonaggressive disease. Baseline selenium level associations
with outcome have not been evaluated in SELECT,1 so it is unknown
whether supplementation in this trial may have decreased prostate
cancer risk in men with low baseline selenium, as in the NPC study,
and concurrently increased the risk of overall or aggressive disease in
men with high baseline selenium, as in the Chan et al study. That
selenium may have opposing effects at high versus low exposures is
plausible. In the NPC study, baseline plasma selenium and total cancer
(all sites) risk were directly associated in the selenium supplement arm
and possibly inversely associated in the placebo arm.17 Therefore,
what seems to be an anomalous prostate cancer result of Chan et al
warrants additional investigation.
The findings of Chan et al3 and others1,2,4-14 raise questions that
may lead to an increased understanding of selenium supplementation
in men at risk of prostate cancer. Did selenium supplementation in
SELECT reduce the risk of total or high-grade prostate cancer in men
with baseline circulating selenium levels as low as in the bottom tertile
of the NPC study? Did selenium supplementation in SELECT increase
the risk of total or high-grade disease in men with baseline circulating
selenium levels as high as in the top quintile of the Chan et al study? If
one combined across large observational studies to achieve adequate
sample size for phenotype and a wider range between low and high
selenium levels, would higher circulating selenium be associated with
www.jco.org

the risk of prostate cancer that is aggressive or nonaggressive as determined by stage alone, grade alone, both, and both plus PSA level? In
SELECT or combined large observational studies, is the selenium
effect on (or association with) prostate cancer risk beneficial, detrimental, or null in those groups of men with higher and lower exposure
to other antioxidants; higher and lower production or activity of
antioxidant enzymes including manganese superoxide dismutase,
perhaps as measured by genotype; higher and lower exposure to oxidant sources; and with variously combined exposures to selenium,
other antioxidants, antioxidant enzymes, and oxidant sources? Readers should note that the SOD2 interaction with circulating selenium in
relation to prostate cancer risk was present for low lycopene and total
antioxidants, not just selenium. Furthermore, manganese superoxide
dismutase encoded by SOD2 is only one of a large number of antioxidant enzymes. All of these interactions deserve in-depth study. A last
question, which probably cannot be resolved by data from epidemiologic studies, is whether lifelong, distant-past, or recent selenium level
is critical to supplement effects on prostate cancer risk.
None of the large observational studies or trials addressed the role
of selenium in preventing prostate cancer recurrence, nor did Chan et
al3 despite their caution against broad use of selenium supplementation for men with prostate cancer. Long-term follow-up of prostate
cancer patients characterized for selenium levels before, at, and after
diagnosis and treatment will be required to address recurrence. Adjusting for stage and grade at diagnosis will be necessary to determine
if selenium predicts recurrence independently of these two prognostic factors.
Placing the findings of Chan et al3 and SELECT in the context
of the existing literature does not clarify the role of selenium in
prostate cancer etiology. Nevertheless, we offer a couple of working
hypotheses. Selenium supplementation does not decrease risk except
possibly in selenium-deficient populations. Supplementation possibly
increases risk of prostate cancer, especially aggressive disease, in
selenium-replete men or men with a particular genotype for antioxidant enzymes. These hypotheses and the questions posed above suggest the need for personalized risk prediction. At present, we do not
know enough to determine how much selenium any man or woman
should receive from the diet or a supplement.
This lack of knowledge supports the common public health recommendation of moderation with respect to supplements for men
and women. Furthermore, we should encourage men and women to
eat a wide array of foods, maintain normal weight, be physically active,
not smoke, and drink in moderation if at all to prevent chronic
diseases in general. Unlike the prospect of personalized chemoprevention, this is not new or exciting advice, but it is common sense.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Elizabeth A. Platz, Scott M. Lippman

Data analysis and interpretation: Elizabeth A. Platz, Scott M. Lippman
Manuscript writing: Elizabeth A. Platz, Scott M. Lippman
Final approval of manuscript: Elizabeth A. Platz, Scott M. Lippman
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