Elsevier

European Journal of Cancer

Volume 46, Issue 12, August 2010, Pages 2196-2205
European Journal of Cancer

Meta-analysis: Serum vitamin D and breast cancer risk

https://doi.org/10.1016/j.ejca.2010.03.037Get rights and content

Abstract

We reviewed and summarised observational epidemiological studies regarding the association between serum vitamin D (measured as 25(OH)D levels) and the risk of breast cancer (BC). Relevant studies published until September 2009 were identified by systematically electronic searching Ovid Medline, EMBASE and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardised manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, BC incidence/BC mortality according to serum 25-hydroxyvitamin D (25(OH)D) and the respective ratios, and covariates adjusted for in the analysis. All existing observational epidemiological studies that reported at least one serum 25(OH)D level in subjects in any time period before or after a diagnosis of breast cancer were included in our review. Individual and summary risk ratios (RRs) for an increase of serum 25(OH)D by 20 ng/ml were calculated using meta-analysis methods. Only 25(OH)D was considered. Overall, 10 articles were included. Specific results for BC incidence were reported in nine articles and for BC mortality in one article. In meta-analyses, summary RRs (95% confidence interval (CI)) for an increase of 25(OH)D by 20 ng/ml were 0.59 (0.48–0.73), 0.92 (0.82–1.04) and 0.73 (0.60–0.88) with P values of <0.001, 0.164 and 0.001 for case-control studies, nested case-control studies and both study designs combined, respectively. No indication for publication bias was found, but there was large heterogeneity between studies. In conclusion, while case-control studies with measurement of 25(OH)D after diagnosis suggest an inverse association, a statistically significant inverse association remained unconfirmed in prospective studies with measurement of 25(OH)D years before diagnosis. Further studies are needed to clarify the potential role and the relevant exposure time regarding vitamin D and breast cancer risk.

Introduction

Although vitamin D is obtained from diet and dietary supplements, the main source for vitamin D is its production in the skin under the influence of solar ultraviolet B (UV-B) radiation. In 1980, Garland and Garland1 hypothesised that lower levels of vitamin D resulting from much weaker UV-B radiation at higher latitudes may account for the striking geographical pattern of cancer mortality. Partly stimulated by this article, further research in this area has been conducted in observational studies over the past 20 years.2, 3, 4

A number of ecological studies found vitamin D status to increase with decreasing latitude and to parallel the south to north gradient in the incidence of female breast cancer (BC),5, 6, 7, 8, 9 however, results were not consistent, and even inverse associations have being reported from Europe.10, 11 Most epidemiologic studies addressing the association between vitamin D and BC have assessed dietary vitamin D intake, and results have also been inconsistent.12, 13, 14, 15, 16, 17, 18, 19, 20 In recent years, several studies have addressed the association of BC risk and serum 25(OH)D levels representing an integrated measure for vitamin D from diet, dietary supplements and skin production, which has a relatively long half-life in the circulatory system of about 2–3 weeks. By contrast, serum levels of 1,25(OH)2, the active metabolite of vitamin D has only a short half-life and its physiological control depends on many factors other than UV exposure or diet, such as calcium balance and the parathyroid hormone. Hence, only serum 25(OH)D is considered to be a useful marker reflecting the ‘vitamin D status’.21

Combining two studies identified by searching the Medline database for 1966–2006, Garland and colleagues22 performed a pooled analysis regarding the association between serum 25(OH)D and BC risk. They found a 50% lower risk of BC associated with a serum 25(OH)D level ⩾52 ng/ml, compared to ⩽13 ng/ml. Since then, a rapidly increasing number of studies have addressed the association of 25(OH)D with BC risk. Therefore, we aimed to provide an up-to-date systematic review and meta-analyses of observational epidemiological studies investigating the association between serum 25(OH)D levels and BC risk by using methods for comprehensive trend estimation from summarised dose–response data.23

Section snippets

Identification of studies and study selection

A literature search was conducted to identify longitudinal studies, nested case-control studies or case-control studies assessing the association between serum levels of 25(OH)D and BC incidence or mortality. We searched Ovid (Ovid Technologies Inc., New York, 1950 – 18th September 2009), EMBASE (Elsevier, Amsterdam, the Netherlands, 1980 – 24th September 2009) and ISI Web of Knowledge (Thomson Scientific Technical Support, New York, 1945 – 24th September 2009) databases for relevant articles

Identification of studies

A flow diagram of the search process is given in Fig. 1. Total searches yielded 4264 entries. Following removal of 1208 duplicates, 3056 titles and abstracts were assessed and 122 articles appeared to be potentially relevant for inclusion into the review. One hundred and ten articles were excluded for the following reasons: no original articles but editorials, comments, reviews (N = 84), only vitamin D intake reported (N = 13), associations of 25(OH)D with BC not reported/not derivable from

Discussion

Our review and meta-analysis summarising the results of nine studies on the association between serum 25(OH)D and incident BC show ambiguous evidence: while case-control studies with measurement of serum 25(OH)D levels after diagnosis support the hypothesis that serum 25(OH)D levels are inversely associated with BC risk, a statistically significant inverse association remained unconfirmed in nested case-control studies, with measurement of serum 25(OH)D levels from blood taken at baseline of

Conclusions

Despite its limitations, our review and meta-analysis provide the most comprehensive and updated summary of epidemiological evidence to date on the association between serum 25(OH)D and BC risk. While case-control studies with measurement of serum 25(OH)D levels after diagnosis seem to support the hypothesis that serum 25(OH)D levels are inversely associated with BC risk, a statistically significant inverse association remained unconfirmed in nested case-control studies, with measurement of

Conflict of interest statement

None declared.

Acknowledgement

The work of Lu Yin was supported by a scholarship from the German Research Foundation (Deutsche Forschungsgemeinschaft) within the framework of a PhD program (Graduiertenkolleg 793).

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