Plasma Vitamin D Levels, Menopause, and Risk of Breast Cancer Dose-Response Meta-Analysis of Prospective Studies
ABSTRACT Previous evidence suggests that higher circulating 25-hydroxyvitamin D (25[OH]D) levels are variably associated with lower breast cancer risk; however, prospective studies and clinical trials have been inconsistent, particularly between older and younger women of differing menopausal status. We conducted a quantitative nonlinear dose-response meta-analysis of prospective studies evaluating the association between circulating 25(OH)D and breast cancer risk, stratified by menopause. A systematic search of MEDLINE and EMBASE included studies published through May 2011. We reviewed references from retrieved articles and contacted relevant investigators for additional data from prospective studies on circulating 25(OH)D levels and incident breast cancers. Prospective studies of circulating vitamin D and breast cancer risk were reviewed, and no language restrictions were imposed. Information on study population, menopausal status, 25(OH)D levels, and relative risk (RR) estimates were extracted using a standardized protocol.A total of 9 prospective studies were included, comprising 5206 cases and 6450 controls. Data were pooled using dose-response random-effects meta-regression models. Identifying nonlinear effects, spline models were optimized for thresholds. The relationship between circulating 25(OH)D and breast cancer risk differed by menopausal status (p = 0.05 for effect modification). While no association was found in premenopausal women, dose-response modeling revealed a nonlinear inverse association among postmenopausal women. Notably, a flat association was observed in the lowest range of 25(OH)D levels <27 ng/mL (RR = 1.01 per 5 ng/mL; 95% confidence interval [CI], 0.98-1.04). In contrast, postmenopausal breast cancer risk decreased with 25(OH)D levels 27-<35 ng/mL (p = 0.02 for nonlinear risk change), where a 5 ng/mL increase in 25(OH)D was associated with a 12% lower risk of breast cancer (RR = 0.88 per 5 ng/mL; 95% CI, 0.79-0.97), with suggestive flattening at higher doses >35 ng/mL. The significant inverse association did not appear to vary across strata of invasive/in-situ cases, body mass index adjustment, region, postmenopausal hormone use, or assay method.In summary, this dose-response meta-analysis of prospective studies of plasma 25(OH)D suggested a breast cancer risk differential by menopause, whereby a step-wise inverse association was observed beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL, in postmenopausal women. These findings help resolve prior inconsistent findings and may carry important clinical and public health implications.
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ABSTRACT: The traditionally recognized role of vitamin D consists in the regulation of bone metabolism and calcium-phosphorus homeostasis but recently a lot of in vitro and in vivo studies recognized several “noncalcemic” effects of vitamin D metabolites. Accumulating evidence suggests that the metabolic pathways of this vitamin may play a key role in the developing of gynaecological/obstetric diseases. VDR-mediated signalling pathways and vitamin D levels seem to (deeply) affect the risk of several gynaecological diseases, such as polycystic ovary syndrome (PCOS), endometriosis, and ovarian and even breast cancer. On the other hand, since also the maternal-fetal unit is under the influence of vitamin D, a breakdown in its homeostasis may underlie infertility, preeclampsia, and gestational diabetes mellitus (GDM). According to our literature review, the relationship between vitamin D and gynaecological/obstetric diseases must be replicated in future studies which could clarify the molecular machineries behind their development. We suggest that further investigation should take into account the different serum levels of this vitamin, the several actions which arise from the binding between it and its receptor (taking into account its possible polymorphism), and finally the interplay between vitamin D metabolism and other hormonal and metabolic pathways.01/2015; 2015:1-11. DOI:10.1155/2015/986281
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ABSTRACT: Low vitamin D levels have been associated with poor breast cancer outcomes in observational studies. We examined the association of vitamin D blood levels with relapse-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) in the MA.21 randomized clinical trial. Fasting blood was collected pre-chemotherapy in 934/2104 (44.4 %) of subjects; 25 hydroxy vitamin D was measured (radioimmunoassay, Diasorin) in one batch. Vitamin D was assessed as a transformed continuous factor, and categorically (quartiles and clinical classifications). Univariate and multivariate prognostic analyses (adjusted for treatment, stratification factors, and baseline imbalances) were performed using Cox models. Most patients were young (median 47.8 years), white (91.6 %) and premenopausal (69.4 %) with grade III (52 %), HER2 negative or missing (89.5 %), ER positive (61.9 %), T1-2 (89.4 %), N + (72.7 %) breast cancer. Compared to the full population, those with vitamin D levels were more likely to be white, PS 1 or 2, to have undergone mastectomy, and to have an ER + tumor. Mean vitamin D was 69.7 nmol/L (27.9 ng/ml) and did not vary by tumor subtype. The majority (80.5 %) had levels >50 nmol/L (20 ng/ml), considered adequate by Institute of Medicine. Continuous vitamin D was not multivariately associated with RFS, BCSS, or OS (p = 0.36, 0.26, 0.33, respectively); categorical vitamin D was also not associated with outcome. Vitamin D associations with RFS did not differ within ER/HER2 subgroups. There was no evidence that vitamin D blood level was associated with RFS, BCSS, and OS in MA.21; the majority of subjects had adequate vitamin D levels at study entry.Breast Cancer Research and Treatment 04/2015; 150(3):605-11. DOI:10.1007/s10549-015-3355-x · 4.20 Impact Factor
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ABSTRACT: Epidemiologic evidence for an association between plasma 25-hydroxyvitamin D [25(OH)D] and breast cancer is inconsistent. Data are especially limited for premenopausal women and for associations with mammographic density. To test the hypothesis that plasma concentration of 25(OH)D is associated with mammographic density, we conducted a cross-sectional study among 835 premenopausal women in the Nurses' Health Studies. We measured 25(OH)D in blood samples and used multivariable linear regression to quantify the association of average percent density by quartile of plasma 25(OH)D. In a nested case-control analysis including 493 breast cancer cases, we evaluated risk of breast cancer associated with vitamin D status within tertiles of mammographic density. Women in the top quartile of plasma 25(OH)D levels had an average percent breast density 5.2 percentage points higher than women in the bottom quartile (95 % confidence interval: 1.8, 8.7; P trend <0.01), after adjusting for predictors of 25(OH)D and established breast cancer risk factors. Plasma 25(OH)D concentration was significantly inversely associated with breast cancer risk among women with high mammographic density (P trend < 0.01) but not among women in lower tertiles of mammographic density (P-interaction < 0.01). These results do not support the hypothesis that vitamin D is inversely associated with percent mammographic density in premenopausal women. There was evidence that the association between premenopausal 25(OH)D and breast cancer risk varies by mammographic density, with an inverse association apparent only among women with high mammographic density.Breast Cancer Research and Treatment 12/2014; 149(2). DOI:10.1007/s10549-014-3247-5 · 4.20 Impact Factor