Elsevier

Clinical Nutrition ESPEN

Volume 30, April 2019, Pages 170-184
Clinical Nutrition ESPEN

Original article
Vitamin D and breast cancer: A systematic review and meta-analysis of observational studies

https://doi.org/10.1016/j.clnesp.2018.12.085Get rights and content

Summary

Context

Breast cancer (BC) is the most common malignancy among women in the US. Vitamin D status and intakes are thought to be inversely associated with BC occurrence.

Objectives

In our systematic review and meta-analysis, we evaluated evidence linking serum 25(OH)D (both in serum and diet) with breast cancer (BC) occurrence.

Data sources and extraction

Only observational studies from databases such as PubMed and Cochrane (January 1st 2000 through March 15th, 2018) were included using PRISMA guidelines. Publication bias and consistency upon replication were assessed, while harmonizing risk ratios (RR, 95% CI) of BC, per fixed increment of 5 exposures [10 ng/mL of 25(OH)D; 100 IU/d for total/dietary vitamin D intakes; vitamin D deficiency; supplement use). RRs were pooled using random effect models.

Data analysis

Pooled findings from 22 studies suggested a net direct association between 25(OH)D deficiency and BC, with RRpooled = 1.91, 95% CI: 1.51–2.41, P < 0.001). Total vitamin D intake (RRpooled = 0.99, 95% CI: 0.97–1.00, P = 0.022, per 100 IU/d) and supplemental vitamin D (RRpooled = 0.97, 95% CI:0.95–1.00, P = 0.026) were inversely associated with BC. No evidence of publication bias was found; all 5 exposures of interest were consistent upon replication.

Conclusions

25(OH)D deficiency was directly related to BC while total vitamin D and supplemental vitamin D intakes had an inverse relationship with this outcome. Randomized clinical trials are warranted pending further evidence from primary meta-analyses of observational studies.

Introduction

Breast cancer (BC) is the most prevalent malignancy among US women [1]. Vitamin D is a steroid hormone known to influence multiple organ functions in our body, including the heart, the skeletal system, the lungs, the intestines and the mammary glands. Its effect on mammary gland development is mediated through the actions of the vitamin D receptor (VDR). While vitamin D is present in fatty fish, cod liver oil, egg yolk, some mushrooms and meats etc., vitamin D deficiency has become a pandemic over the last few decades [2]. Recent epidemiologic studies have reported links between vitamin D deficiency and key adverse health outcomes, namely cardiovascular and cancer-related morbidity and mortality [3]. It is known to have multiple anti-proliferative, pro-apoptotic, and pro-differentiating actions on different malignant cells, mediated by VDR [4], [5] Over 90% of vitamin D is produced endogenously in the skin, subsequently undergoing two hydroxylation reactions to form the active hormonal form 1,25-dihydroxyvitamin D [1,25(OH)2D]. The half-life of 1,25(OH)2D is about 6 h, while [25(OH)D] has a half-life almost 1000 times higher than the active form [6]. It has been, therefore, more commonly used in previous studies as a vitamin D status biomarker. However, epidemiologic evidence for a relationship between plasma 25(OH)D and BC incidence and/or prevalence is limited [7]. Several longitudinal studies on serum 25(OH)D and multiple cancer risks have concluded that 25(OH)D concentrations are inversely associated with colorectal cancer incidence [8], [9], [10], [11], [12] but not with prostate cancer or BC incidence [10], [13], [14], [15]. In relation to BC, vitamin D has mixed results when separated by menopausal status. However, a cross-sectional study of postmenopausal women in Brazil showed that low serum 25 (OH)2 vitamin D level is a risk factor for ER negative tumors [16]. Furthermore, there is a definitive lack of randomized clinical trials (RCTs) with vitamin D supplementation and risk of cancer. In short, the relationship between vitamin D status and cancer risk remains incompletely understood [17].

Following the MOOSE guidelines [18], we hypothesized that vitamin D is inversely associated with BC occurrence in pre-and post-menopausal women. Our present systematic review and meta-analysis aimed at pooling, interpreting and evaluating research evidence for the past ∼18 years that links serum vitamin D and vitamin D from both food and supplements using BC as outcome. Finally, this study discusses potential biological mechanisms behind those putative associations.

Section snippets

Search strategy

A systematic review of the literature on BC was conducted using primarily PubMed and Cochrane library as a secondary search. Using PubMed search engine, focus was on serum and dietary vitamin D as specific exposures. A systematic hand search combined the keywords “vitamin D” and “BC” prior to sorting and literature search was restricted to human studies published in English between January 1st 2000 and March 15th 2018. Synonymous keywords were not included in the search to avoid heterogeneity

Study selection, characteristics and quality score

Out of 3826 un-duplicated titles and abstracts between 2000 and 2018, 22 original publications were selected for the systematic review and meta-analyses. Those selected studies were published between 2005 and 2017 (Mean ± SD: 2010.7 ± 3.7), with 14 being US studies, 1 Canadian, 4 European and 3 from Asia (Table 2). Moreover, most studies had a case-control or nested case-control design (n = 19), with only 3 being prospective cohort studies. Twelve studies comprised adult women of varying age

Discussion

This study is to our knowledge, the most up to date among very few meta-analyses conducted to synthesize the literature on vitamin D exposure and BC occurrence. Pooled findings indicated that there was a net direct association between 25(OH)D deficiency and BC occurrence, with a pooled RR = 1.91, 95% CI: 1.51–2.41, p < 0.001). A weaker inverse association was also observed for total vitamin D intake from foods and supplements (RR = 0.99, 95% CI: 0.97–1.00, P = 0.022, per 100 IU/d) and BC. A

Conclusions

Previous meta-analyses have demonstrated important evidence of reverse causation in studies of circulating vitamin D and BC. Only retrospective case-control studies have shown an inverse association between circulating 25(OH)D and breast cancer risk, whereas prospectively conducted studies have found no association. Our review and meta-analysis indicated that serum 25(OH)D deficiency, as well as total and supplemental vitamin D intake, were associated with BC occurrence in the general

Author contributions

SH: Conceptualization; literature search and review; plan of analysis; write-up of manuscript; revision of manuscript.

MAB: Literature review, plan of analysis, data management, statistical analysis, write-up of parts of the manuscript, revision of the manuscript.

HAB: Literature review; write-up of parts of manuscript; revision of manuscript.

XC: Literature review; write-up of parts of the manuscript; revision of the manuscript.

ABZ: Plan of analysis, write-up of parts of the manuscript; revision

Acknowledgments

All authors read and approved the final manuscript. The authors would like to thank Gregory A. Dore and Ola S. Rostant (NIA/NIH/IRP) for their internal review of the manuscript. There is no conflict of interest. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging (NIA/IRP).

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