EDITORIALS
Breast Cancer Prevention Using Calcium and Vitamin D:
A Bright Future?
Corey Speers, Powel Brown
Despite aggressive treatment and screening efforts, breast cancer
remains the second leading cause of cancer-related deaths among
women in the United States (1). Because of the large number of
women dying from this disease and the toxicity of breast cancer
treatments, recent efforts have focused on identifying effective can-
cer preventive agents. These efforts have led to the development of
antiestrogen agents, such as tamoxifen and raloxifene, which pre-
vent approximately 50% of invasive breast cancers in women who
are at high risk for breast cancer. However, the use of these agents
for breast cancer prevention has been limited by their toxicity.
A large amount of evidence exists to indicate that vitamin D
may be a particularly promising cancer preventive agent. Vitamin
D is a fat-soluble vitamin that is essential for bone formation and
calcium homeostasis. The potential link between vitamin D levels
and reduced cancer incidence was suggested by results from epide-
miological studies by Garland et al., Giovannucci, and others (2–5)
and by recent data suggesting a strong association between low
vitamin D levels and increased colon cancer risk (6). Several case–
control and cohort studies support an inverse relationship between
vitamin D intake and breast cancer incidence (7–11); however,
other studies show either no association or an association with
increased breast cancer risk (10,12–14). In addition, recent studies
found that vitamin D deficiency was linked to poor outcomes in
patients with early breast cancer (15).
It is against this backdrop that Chlebowski et al. (16) report the
results of a randomized controlled clinical trial evaluating the
breast cancer preventive effect of vitamin D and calcium supple-
mentation. This study, which was compiled from the calcium plus
vitamin D (CaD) arm of the Women’s Health Initiative (WHI),
randomly assigned 36 282 postmenopausal women to receive daily
doses of either 1000 mg calcium with 400 IU vitamin D3 supple-
mentation or placebo and were followed up for an average of 7
years. To maximize participation and size, the WHI trial had over-
lapping groups, including a dietary modification (DM) group, a
hormone therapy (HT) group, and a CaD group, which was added
in the second year of the study. As a result, 69% of women in the
calcium with vitamin D trial were also part of the DM group, 54%
were part of the HT group, and 14% had participated in both the
DM and the HT trials (17). Furthermore, in this trial, personal use
of calcium and vitamin D was permitted in both the supplementa-
tion and the placebo groups.
Chlebowski et al. should be congratulated for successfully com-
pleting such a large and sophisticated trial. The well-designed and
well-executed randomized, double-blinded, placebo-controlled
trial with a nested case–control study is unrivaled in its scope and
complexity. This current study tested the hypothesis that 1000 mg/
day calcium plus 400 IU vitamin D3 supplementation would reduce
1562 Editorials | JNCI
the risk of breast cancer among postmenopausal women. Breast
cancer incidence was a prospectively planned secondary endpoint
in the WHI study. This trial had a large number of racially diverse
women who maintained relatively good adherence to the study
protocol. Despite the meticulous design, careful control, and ade-
quate adherence, Chlebowski et al. report that calcium and vitamin
D supplementation did not reduce the incidence of breast cancer.
Previous groups (17,18) have reported the results of the other
components of the WHI study. In these studies, there was a small
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but statistically significant increase in hip bone density, suggesting
the possibility of a clinically relevant effect of CaD supplementa-
tion. Analysis of this WHI data also demonstrated that there was
no decrease in hip bone fractures or colorectal cancer incidence,
which were the other primary and secondary endpoints of the trial
(17,18). These results, along with the results presented in this issue
(16), suggest that women who received the CaD in this trial did not
experience the predicted benefits of calcium and vitamin D supple-
mentation—a reduction in bone fractures, colon cancer, and breast
cancer.
Should these negative results discourage the use of calcium and
vitamin D in future breast cancer prevention studies? Not neces-
sarily. Although Chlebowski et al. (16) did not find a statistically
significant association between calcium and vitamin D supplemen-
tation and reduced incidence of breast cancer, there could be sev-
eral important confounders at play. The first confounder is that of
variable baseline vitamin D levels. The authors measured the base-
line level of plasma 25-hydroxyvitamin D and compared this level
with self-reported vitamin D intake. There was a large overlap of
baseline self-reported vitamin D intake across the plasma 25-
hydroxyvitamin D quintiles, suggesting that factors besides intake
(such as sunlight exposure, body mass index, metabolism, physical
activity, and genetic factors) have a stronger influence on plasma
25-hydroxyvitamin D than just intake quantity alone.
A second potential confounder is the high level of calcium and
vitamin D self-supplementation (up to 1000 mg of calcium and
1000 IU of vitamin D) that was allowed during the study. This
“outside of study” supplementation led to 15% of placebo patients
“dropping in” to the active treatment component of the study.
Affiliations of authors: Department of Molecular and Cellular Biology (CS),
Lester and Sue Smith Breast Center and Department of Medicine (PB), Baylor
College of Medicine, Houston, TX.
Correspondence to: Powel H. Brown, MD, PhD, Lester and Sue Smith Breast
Center, Baylor College of Medicine, One Baylor Plaza, BCM 600, Houston, TX
77030 (e-mail: pbrown@breastcenter.tmc.edu).
DOI: 10.1093/jnci/djn390
© The Author 2008. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org.
Vol. 100, Issue 22 | November 19, 2008
Such “outside of study” supplementation, sometimes at levels more
than twice the trial dose, may have diminished the observed differ-
ence in breast cancer incidence between the placebo and CaD arms.
Another very important issue is the dose of vitamin D given in
this trial. Recent reports suggest that higher doses of vitamin D
(1000–2000 IU/day) may be required to prevent cancer (19). It is
possible that doses sufficient to prevent osteoporosis are not suffi-
cient to prevent cancer. The results of this trial suggest that a dose
of 400 IU of vitamin D could be insufficient to prevent breast
cancer (16) or colon cancer (17).
Another important aspect of this trial is the age of the study
population. The women in the WHI trial were postmenopausal
and aged 50–79 years. Previous epidemiological studies
(8,10,14,20) have not shown a clear association between vitamin
D intake and breast cancer in postmenopausal women (relative
risks [RRs] = 0.55 to 1.3); however, results from epidemiological
studies of premenopausal women (10,14) suggest that vitamin D
intake may prevent breast cancer in these women (RRs = 0.65 to
0.89). Furthermore, given long latency of breast cancer, many of the
postmenopausal women in the WHI trial may have already devel-
oped premalignant breast lesions or cryptic breast cancers at the
time of study enrollment. If vitamin D is effective as a cancer
preventive agent only before breast cells become cancerous, then
the vitamin D taken by women with existing, undetected breast
cancers would not prevent the progression of these cryptic can-
cers. Indeed, the results reported by Chlebowski et al. show that
140 women developed cancer within the first year of the trial;
these women may have had in situ noninvasive breast cancers or
small, undetected invasive breast cancers before the trial began. In
addition, 26% of women who developed breast cancer during the
trial were diagnosed with cancer within 2 years of trial initiation.
It is interesting that the cumulative hazard lines begin to separate
between the supplemented and placebo groups in the last 2 years
of the trial (although this difference is not statistically significant).
This result suggests that vitamin D plus calcium supplementation
is effective only at early stages of breast carcinogenesis. To inves-
tigate this hypothesis, it would be particularly useful to determine
whether these lines further separate with continued follow-up.
Should we then abandon further study of vitamin D as a breast
cancer prevention agent? Given the extensive preclinical data
showing a cancer preventative effect of vitamin D (21,22), to do so
may be premature. We should first attempt to answer several ques-
tions not answered by the current study. Could vitamin D have a
different cancer preventive effect on premenopausal vs postmeno-
pausal women? Should vitamin D be used earlier in the course of
breast carcinogenesis, ie, at a younger age? Did concomitant HT,
which may increase the risk of developing breast cancer, affect the
results of the study? Did DM with a low-fat, high fruit and vege-
table diet vs no DM affect the response to vitamin D and calcium?
Is 400 IU of supplemented vitamin D too low of a dose to prevent
breast and colon cancer?
These questions should drive the design of future vitamin D
cancer prevention trials. It is particularly important that future tri-
als evaluate higher doses of vitamin D. With such a high percent-
age of pre- and postmenopausal women taking vitamin D and
calcium supplements, future trials will likely need to compare
“standard dose” supplements with “high dose” supplements. In
jnci.oxfordjournals.org
addition, future trials may need to be carefully controlled for diet,
sunlight exposure, HT, and physical activity. Finally, such trials
may require earlier initiation and longer duration. Given the long
latency of breast cancer, longer follow-up times may be needed to
evaluate the effect of vitamin D on breast cancer incidence.
Because preclinical, epidemiological, and clinical trial results of
vitamin D supplementation are conflicting, additional studies will
be needed to determine whether vitamin D plus calcium will pre-
vent breast cancer. However, this article by Chlebowski et al.
offers an important first step in addressing this issue. Future clini-
cal trials should address the above questions to help determine
whether higher doses of vitamin D supplements will be cancer
preventive. The potential health benefits of vitamin D and calcium
may yet still have a bright future.
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