Contents - IARC

Vitamin D and Cancer
Chapter 1 – Summary overview of the report
Ecological studies, mainly conducted in the USA, have shown an increasing risk of several
cancers and other chronic conditions with increasing latitude of residence, suggesting that these
diseases might be related to vitamin D status. This “vitamin D hypothesis” was first reinforced by
evidence that vitamin D can inhibit cell proliferation and promote apoptosis in vitro, and secondly, by
the discovery that several tissues could locally produce the physiologically active form of vitamin D,
1α,25-dihydroxyvitamin D, which has anti carcinogenic properties.
IARC has established a Working Group (WG) of international experts to investigate whether or
not a causal relationship exists between vitamin D status and cancer risk. The WG has systematically
reviewed the epidemiological literature on vitamin D and cancer and has performed a meta-analysis
on observational studies of serum 25-hydroxyvitamin D levels (the best available biomarker of an
individual’s vitamin D status) and the risk of colorectal, breast and prostate cancers and of colorectal
adenomas.
Much of the data suggesting a link between vitamin D status and cancer have been derived from
ecological studies that assessed the correlation between latitude and cancer mortality. However,
causal inference from ecological studies is notoriously perilous as, among other things, these studies
cannot adequately control for confounding by exposure to various cancer risk factors which also vary
with latitude (e.g. dietary habits or melatonin synthesis). Studies from the USA show a weak
association between latitude and vitamin D status and that other factor such as outdoor activities and
obesity are better predictive factors of vitamin D status. In Europe, the opposite has been found, with a
south to north increase in serum 25-hydroxyvitamin D that parallels a similar gradient in the incidence
of colorectal, breast and prostate cancers.
In people of the same age and skin complexion, there is considerable inter individual variation in
serum 25-hydroxyviatmin D even with similar levels of sun exposure.
Many physiological mechanisms have evolved through history to avoid accumulation of vitamin
D in the body. The higher existing serum 25-hydroxyvitamin D levels are, the less effective additional
exposure to sources of UVB radiation and vitamin D supplements will be in raising them further.
This report outlines a meta-analysis on observational studies. The results show evidence for an
increased risk of colorectal cancer and colorectal adenoma with low serum 25-hydroxyvitamin D
levels. Overall, the evidence for breast cancer is limited, and there is no evidence for prostate cancer.
Two double-blind placebo controlled randomised trials (the Women’s Health Initiative trial (WHI) in the
USA and one smaller trial in the UK) showed that supplementation with vitamin D (10 µg per day in
the WHI trial, and 21 µg per day in the UK trial) had no effect on colorectal or breast cancer incidence.
There are many reasons to explain the apparent contradiction between observational studies and
randomised trials on colorectal cancer incidence, including the use of too low doses of vitamin D, or in
the WHI trial, an interaction with hormone therapy. Some laboratory and epidemiological data suggest
that vitamin D could be more influential on cancer progression and thus cancer mortality, rather than
cancer incidence.
New observational studies are unlikely to disentangle the complex relationships between vitamin
D and known cancer risk factors. Also, studies on vitamin D and cancer should not be isolated from
associations with other health conditions, particularly cardiovascular disease. A published metaanalysis
on randomised trials found that the intake of ordinary doses of vitamin D supplements (10 to
20 µg, i.e. 400 to 800 IU per day) reduces all cause mortality in subjects 50 years old and over, many
of whom had low vitamin D status at the trials inception. Patients with chronic kidney disease who
were treated with vitamin D supplements also have reduced mortality. A recent analysis of the Third
National Health and Nutrition Examination Survey (NHANES III) cohort data from the USA showed
increased mortality in subjects with low vitamin D status. None of these studies could identify a specific
cause of death responsible for the differences in overall mortality.
Currently, the key question is to understand whether low vitamin D status causes an increased
risk of cancer, other chronic health conditions and death, or is simply a consequence of poor health
status. If the first hypothesis is true, then supplementation with vitamin D is likely to prevent some
diseases and improve health status. If the second hypothesis is true, then supplementation is less
likely to prevent diseases or improve health status. Failure of the two aforementioned randomised
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