Prior to the current study, to our knowledge, the association between circulating 25(OH)D and total cancer mortality had been examined in three study populations,(8
) with mixed results. In an earlier NHANES III study of circulating vitamin D, total cancer mortality was not associated with baseline 25(OH)D in the entire population, men, women, or ethnic/racial subpopulations.(8
) Similarly, a population-based, presumably Caucasian, Norwegian study of circulating 25(OH)D found no significant association with total cancer mortality in smokers and in non-smokers, but specific risks were not reported by gender.(9
) A substantially smaller German study of Caucasian patients referred for coronary angiography, with only 95 cancer deaths, found a major reduction in fatal cancer risk in those with the highest circulating vitamin D levels, but the medical characteristics of the study population limit the generalizability of the findings.(10
) The current NHANES III study has substantially more cancer cases than earlier studies, and permits examination by gender, and racial/ethnic groups, and some specific cancer sites.
Here we observed no association between serum 25(OH)D and overall cancer mortality in the total population, in men or in women with both season/latitude groups combined.(8
) However, there was some suggestion that the association may differ between the sexes. For example, in men, our results suggested that serum 25(OH)D > 80 nmol/L may increase risk of overall cancer mortality. Specifically, the RR was significant in the two highest categories (>80–100 and >= 100 nmol/L) when season/latitude groups were combined, and there was a significant adverse trend in the summer/higher latitude group when season/latitude was analyzed separately. However in women, results suggested either no association (season/latitude groups combined and winter/lower latitude group) or that there was an inverse relationship (summer/higher latitude group).
The divergent findings for overall mortality may stem from sex differences observed for some of the cancer site-specific analyses. An adverse trend was seen for lung cancer mortality in men, but not in women. Epidemiologic data on lung cancer and 25(OH)D is limited, but another prospective study(18
) that examined serum 25(OH)D and lung cancer incidence in Finland found a significant interaction between 25(OH)D and sex, with an inverse association in women. The Finnish study did not find elevated lung cancer risks in men, but the number of male cases was small (n=97) and only 25 had 25OHD values > 52 nmol/L, so presumably there were few cases above the 100 nmol/L cut-point where substantially elevated risks were seen in the NHANES III study. The authors of the Finnish study speculate that sex-dependent hormones may affect lung cancer etiology,(18
) and presumably could interact with 25(OH)D status. Sex hormones may also play a role in lung cancer prognosis, and thus mortality.(35
) In addition, men and women differ in the histological distribution of lung cancers;(35
) but because our case information derived from death certificates, we could not assess whether histology contributed to the sex pattern of our results. Although adjusting for pack-years in more detail did not materially reduce the strength of the associations in men, it is possible that residual confounding by smoking contributed to the finding, particularly smoking outdoors. In addition, uncontrolled socioeconomic or occupational exposures may have contributed to the results, such as, for example, work environments that combine UV exposure and potential lung carcinogens (e.g., shipbuilding, construction, and painting).(36
Also noteworthy were the elevated risks for mortality of other digestive cancers (pancreatic, esophageal, stomach and liver cancer) seen in men, but not in women. Three studies have reported an elevated risk of pancreatic cancer related to higher 25(OH)D status, including, a prospective study in Finnish male smokers,(37
) the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial study for those living in northern latitudes in the U.S. (although not in the full PLCO study) (38
), and the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP).(39
) Although neither the PLCO nor the VDPP found an interaction by sex, the association was greater and statistically significant in the highest category in VDPP (≥100 vs 50–<75 nmol/L) in men compared to women (RR=2.33 (95% =1.24–4.36) vs. 1.46 (0.47–4.61)). Another prospective study in China found higher levels of serum 25(OH)D related to esophageal squamous cell carcinoma incidence in men, but not in women.(40
) There was no association with gastric cancer incidence in either sex in that study.(40
) But in the VDPP, circulating 25(OH)D was associated with significantly increased risk of upper gastrointestinal cancer incidence in never smokers and in Asians.(41
) Thus, the limited epidemiologic data on these cancers suggests elevated risks for some cancer sites in this category, particularly for men in some studies. Nonetheless, the results in the present study may be viewed as suggestive in light of the small case numbers.
Results for some other cancer site-specific analyses did not appear to differ by sex, however. For example, the association with colorectal cancer mortality was inverse in both men and in women, although it was not statistically significant when sexes were combined (P-trend=0.09) or when analyzed separately by sex. Nonetheless, the generally falling risks with rising 25(OH)D levels is consistent with the earlier finding,(8
) as well as a large number of epidemiological studies on colorectal cancer incidence.(42
Neither the earlier or present study found a significant trend in breast cancer risk related to 25(OH)D, although both suggest declining risks with increased levels. With 53 breast cancer deaths, however, the case numbers continue to be small for detecting an association. To date the evidence for an inverse prospective breast cancer relationship with one-time measures of circulating 25(OH)D, as in this account, is not strong,(42
): one study suggested an inverse association in some subpopulations,(45
) whereas others found no association.(46
) These studies, however, involve breast cancer incident cases rather than deaths, and thus may relate to breast cancers that may differ in histology or stage from breast cancer deaths.
It is also of interest that there was an inverse association with 25(OH)D for women in the summer/higher latitude group, although there was no overall cancer relationship in women for both seasonal/latitude groups combined. One can speculate about factors contributing to the disparate associations by seasonal/latitude group. If, for example, peak values of 25(OH)D are particularly relevant to risk, measures in the “summer” would be most informative. It is also possible that low levels measured in higher latitudes in the “summer” constitute a particularly stable reference category given the low likelihood that those with insufficient levels in the “summer” increase their 25(OH)D status in colder months.
There has been substantial scientific interest in whether low 25(OH)D contributes to the elevated cancer and other disease risks characterizing African-Americans (3
), but to date, there have been few prospective studies of measured, circulating 25(OH)D and cancer risk in African-Americans to address this hypothesis.(49
) The present analysis, although based on relatively small numbers, helps fill this gap. We found no statistically significant trend in cancer mortality risk related to 25(OH)D levels in non-Hispanic black men or women. Total cancer mortality risks were, in fact, lowest in non-Hispanic black men and women with 25(OH)D levels in the lowest category, <37.5 nmol/L. Moreover, the fact that the risk of total cancer mortality for non-Hispanic blacks compared to that of non-Hispanic whites was not reduced by adjusting for serum 25(OH)D levels also fails to support the hypothesis that low 25(OH)D levels in African-Americans contribute to racial cancer disparities. Thus, our results caution against assuming a beneficial relationship, and points to the possibility that risks might rise with elevated levels of 25(OH)D.
The strengths of the present study include that 25(OH)D was based on measured, circulating 25(OH)D in a population that is representative of the civilian, U.S. population. As a diverse population, we could explore relationships with 25(OH)D and cancer mortality in non-Hispanic blacks as well as Mexican-Americans, unlike most cohort studies. Because of the extensive collection of information on participants in NHANES III, a wide range of covariates was available.
Limitations of the study principally include the small numbers of cases for subgroup analyses and the collection of data in a manner in which geographic region is confounded by season. It is, however, reassuring that we did see the generally expected gradient for mean 25(OH)D level by month, although the gradient might be sharper had latitude not played a role in the timing of collections. The study also relied on a single measure of 25(OH)D as a surrogate for long-term exposure. We note that a recent study of long-term variation in circulating 25(OH)D showed relatively stable measures over several years, although blood collections for any given individual occurred in the same month each year, and thus did not address potential variability across seasons.(50
) These limitations diminish the opportunity to detect associations; they do not, as far as we can determine, contribute to biases that would inflate potential associations. However, it is possible that the numerous comparisons undertaken in the analyses may have contributed to some significant findings due merely to chance.
The mean follow-up of the study, 13.4 years, is relatively lengthy, but is not clearly a limitation. The overall relationship between 25(OH)D and total cancer mortality in the two genders for the two periods (1988–2000; 2001–2006) was not substantially different, with some attenuation in risk in men in the later period. Serum assays of 25(OH)D for all cohort members were undertaken during the baseline survey or shortly thereafter, which reduces the risk of samples degrading differentially over time. Finally, because there is no consensus on the etiological relevant time for 25(OH)D’s potentially cancer preventive effects, the optimal follow-up period is unknown.
The fact that we did observe statistically significant adverse associations in men is noteworthy given the interest in undertaking intervention trials that employ high levels of vitamin D supplements in healthy persons.(42
) Supplements of 2000 IU or more, which have been advocated by some groups(42
) (and discussed for intervention trials), could markedly raise 25(OH)D blood levels.(51
) Substantial increases in 25(OH)D may pose increased harms if, as these data suggest, some increases in 25(OH)D relate to increased risks for particular outcomes.
In sum, we found no overall relationship between 25(OH)D and cancer mortality risk in the general population, nor in the ethnic/racial groups, including non-Hispanic blacks. We did observe an inverse association with colorectal cancer mortality in the general population which, although not statistically significant, is consistent with findings in the prior study, and with the mainstay of the epidemiologic literature. Some of our results suggested that the relationship between 25(OH)D and overall cancer mortality and at some selected sites may vary by sex. For example, an adverse trend between increasing serum 25(OH)D and overall cancer mortality, and death due to lung cancer and some digestive cancers was seen in men. On the other hand, we found a significant trend toward falling risk of overall cancer mortality with increasing 25(OH)D levels in women in one season/latitude group. More work is needed to explore possible divergent associations with vitamin D by sex, and, identify biological mechanisms that might contribute to such differences. These results suggest that the relationships between 25(OH)D and cancer may be more complex than has been thought, and advise caution before encouraging vitamin D supplementation to further the goal of preventing cancer, particularly in men.