These results are consistent with a diminishing utility of one-time serum 25(OH)D measurements for determining the effect of vitamin D in reducing the risk of cancer as the follow-up time increases.
The finding that a single reading is not an accurate measure of the effect of a particular cancer risk-modifying factor is not limited to vitamin D. For example, a study of dietary risk factors for pancreatic cancer in the United States found the following:
The positive association for available carbohydrate intake was observed during the first four years of follow-up [HR(<2 years) = 2.60, 95% CI: 1.34, 5.06; HR(2–<4 years) = 1.94, 95% CI: 1.06, 3.55)] but not subsequently (HR = 0.86, 95% CI: 0.52, 1.44); the opposite pattern was observed for total fat and saturated fat intake. Rather than being causal, the short-term increase in pancreatic cancer risk associated with high available carbohydrate and low fat intake may be capturing dietary changes associated with subclinical disease.16
These results also help clear up some of the confusion regarding the role of vitamin D in reducing the risk of cancer. Both breast and colorectal cancer have strong support from ecological studies,7,8,17
which this analysis supports. A recent study in France found a contribution of vitamin D from a combination of both oral intake and solar UVB irradiance.18
Tumor growth rates for breast cancer come from two papers. An early paper suggested a power law (exponential) growth rate for breast cancer with an exponent of 0.5.19
In that paper, the tumor volume is near 0 mL until 20 years and then increases to 2,200 mL by year 25. A more recent paper, based on mammography screening, estimated that tumors increase from 1.5 cm diameter to 4.0 cm in 1.5 years.20
Backtracking from 2 cm to 2 mm, we find that such growth would take about 1.7 years according to the Hart et al. value. Thus, there appears to be about a 1- to-2-year window to go from start of angiogenesis to detection of breast cancer. Further support for this finding is that breast cancer diagnoses have peaks in spring and fall, with the authors suggesting that vitamin D in summer and melatonin in winter reduce the breast tumor growth rate in those seasons.21
Prostate cancer, however, has mixed results with respect to solar UVB irradiance. In 1990, Schwartz and Hulke22
originally suggested that prostate cancer was vitamin D sensitive; Hanchette and Schwartz23
extended this finding. Recent work, however, noted that the geographical variation of prostate cancer mortality rates in the United States24
is highly correlated with ethnic background as found in the Atlas of Greatest Ancestry by County
Another study hypothesized that apolipoprotein E ε4 (ApoE4) might be a risk factor,15
in part because cholesterol is an important risk factor for high-grade prostate cancer.26
In a study in Japan, prostate cancer was the only type of cancer for which cholesterol was a risk factor.27
ApoE4 produces more cholesterol in the liver28
and insulin in the pancreas to facilitate storage of excess food as fat.29
Thus, current or recent hunter-gatherer populations have a higher prevalence of ApoE4 to protect them from starvation between feasts. A recent multicountry ecological study found that risk of prostate cancer was directly correlated with ApoE4 and inversely with fraction of energy supply derived from cereals and grains.15
On the other hand, several papers indicate a reduced risk of prostate cancer with respect to solar UVB irradiance. Two studies reported a reduced risk of prostate cancer incidence with respect to early-life and/or entire-life UVB irradiance.30,31
Other studies have reported similar findings for prostate cancer on the basis of diagnosis of nonmelanoma skin cancer.32–34
Breast, colon and prostate cancer apparently have different rates of growth from initiation to detection, with breast cancer the most likely to be diagnosed early in life and prostate cancer most likely to be diagnosed late in life. The mortality rate data for the United States in 2004 and the UK in 2005 were plotted versus age.35
The average exponent of the power-law fit to the data is 4.0 for breast cancer, 6.1 for colon cancer and 11.7 for prostate cancer. Larger exponents are associated with faster increases with respect to age.
The recent Vitamin D Pooling Project (VDPP) found no evidence of a beneficial role of vitamin D in reducing the risk of seven rarer cancers: endometrial, esophageal, gastric, kidney, NHL, ovarian and pancreatic.36
The median follow-up time for the 10 studies included in the VDPP ranged from 2.1 to 10.8 years, with a median value of 4–5 years. As seen from the analysis presented here, that is one problem with the VDPP study. A second problem is that the 95% CIs for the highest serum 25(OH)D quantile range are all greater than 0.5 because of the few cases in the studies. Thus, detecting a small effect would be extremely difficult.37
In the IOM report, the following statement summarized the committee's finding regarding colorectal cancer:1
Taken in aggregate, epidemiological studies examining associations between vitamin D status and colorectal cancer incidence generally support an inverse association, although the shape of the dose-response relationship curve over a wide range of vitamin D intake remains very speculative. The biological plausibility is supported by data from cell culture and rodents, with additional support from surrogate biomarker studies in humans. There remains a paucity of prospective randomized intervention studies, and those available have not shown a significant relationship at this time. Thus, the data are insufficient for the committee to utilize colon cancer as an outcome for establishment of vitamin D DRIs. The data for an effect of dietary calcium on colorectal cancer risk are also highly suggestive of a protective effect, but there are not sufficient data available on dose-response relationships to utilize colorectal cancer as a health outcome for DRI development.
Thus, the reliance on NCCS and exclusion of CCS ecological studies by the IOM's committee on dietary requirements for calcium and vitamin D seem to be important reasons why the committee failed to find health benefits of vitamin D for colorectal and other cancers. There being only one RCT that found a beneficial effect of vitamin D in reducing the risk of cancer38
is due to two important factors: that most RCTs on cancer to date used a vitamin D dosage of 400 IU/d39,40
and that funding for RCTs involving vitamin D has been limited until recently.
Another limitation of NCCS and CCS is that they are not sensitive to early-life cancer risk-modifying factors. A classical example is the effect of diet on cancer risk. In 1975, Armstrong and Doll41
published their classical ecological multicountry study showing that “dietary variables were strongly correlated with several types of cancer, particularly meat consumption with cancer of the colon and fat consumption with cancers of the breast and corpus uteri.” For many years thereafter, NCCS could not verify that finding.42,43
Eventually it was realized that ecological studies integrate dietary intake over the entire lifetime and that the effects of high-fat diets on risk of cancer might be related to early life rather than late life. When younger women were enrolled in the cohort studies, findings indicated that meat and animal fat were risk factors for breast cancer.44
Other studies associated soy consumption in adolescence with reduced risk of breast cancer.45
This review has several implications regarding how to determine the effect of vitamin D status on risk of cancer:
- In NCCS, having multiple serum draws would be helpful, perhaps every 2 years and in different seasons, so that the variability of serum 25(OH)D can be assessed.
- CCS should be used rather than NCCS. Although concern exists that disease state can affect serum 25(OH)D level, we need a way to ascertain whether any change in vitamin D intake, body mass index and lifestyle occurred over the past year or so that would affect UVB irradiance and vitamin D production.
- In vitamin D RCTs, measuring serum 25(OH)D levels is important; individual response to oral vitamin D intake varies considerably.46 Part of the reason is the inverse relation between serum 25(OH)D and body weight.47
- Any study that measures 25(OH)D should use a reliable assay as well as NIST standards.48–50
- Such reviews should take into account viewpoints of experts on the topic, fully consider all valid epidemiological approaches, resolve discrepancies between different types of studies, conduct the review in an open fashion and respond to peer review. The IOM review1 did not follow these guidelines, which severely undercuts its credibility and validity.