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Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies.

Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL - Medicine (Baltimore) (2013)

Bottom Line: Data were pooled using dose-response random-effects meta-regression models.Identifying nonlinear effects, spline models were optimized for thresholds.While no association was found in premenopausal women, dose-response modeling revealed a nonlinear inverse association among postmenopausal women.

View Article: PubMed Central - PubMed

Affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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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Related in: MedlinePlus

Summary of article selection process. *Studies belonging to multiple classifications were counted only once.
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Figure 1: Summary of article selection process. *Studies belonging to multiple classifications were counted only once.

Mentions: We conducted a comprehensive literature search of MEDLINE (National Library of Medicine, Bethesda, MD) and EMBASE (Elsevier, Amsterdam, The Netherlands) from 1966 through May 2011. We followed the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines for searching and reporting. Search terms included MESH, EmTree, title/abstract, and synonyms of breast cancer combined with vitamin D, 25-hydroxyvitamin D, or calcifediol. Additional studies were searched for via references of retrieved articles, direct author contact for unpublished data, and referral by experts in the field. Studies were excluded if they did not fulfill the following criteria: a) human studies, b) prospective cohort and nested case-control studies, c) measured circulating (serum/plasma) 25(OH)D at baseline, d) reported a relative risk (RR) or odds ratio and confidence interval (CI) per vitamin D category, e) reported outcome of breast cancer risk. No language restrictions were imposed. Incident breast cancer was analyzed as the outcome of interest due to varying screening and treatments by country. In the first round of screening abstracts (n = 974), 938 articles were excluded by search criteria (Figure 1). In a second round of screening full text articles (n = 36), 27 articles were excluded: not prospective (11 articles), circulating 25(OH)D not measured (6 articles), survival among cancer cohort (5 articles), duplicate studies (3 articles), and case report (2 articles). Our search criteria yielded 9 total prospective case control studies, comprising 5206 incident cases and 6450 controls (Table 1).


Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies.

Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL - Medicine (Baltimore) (2013)

Summary of article selection process. *Studies belonging to multiple classifications were counted only once.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4553988&req=5

Figure 1: Summary of article selection process. *Studies belonging to multiple classifications were counted only once.
Mentions: We conducted a comprehensive literature search of MEDLINE (National Library of Medicine, Bethesda, MD) and EMBASE (Elsevier, Amsterdam, The Netherlands) from 1966 through May 2011. We followed the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines for searching and reporting. Search terms included MESH, EmTree, title/abstract, and synonyms of breast cancer combined with vitamin D, 25-hydroxyvitamin D, or calcifediol. Additional studies were searched for via references of retrieved articles, direct author contact for unpublished data, and referral by experts in the field. Studies were excluded if they did not fulfill the following criteria: a) human studies, b) prospective cohort and nested case-control studies, c) measured circulating (serum/plasma) 25(OH)D at baseline, d) reported a relative risk (RR) or odds ratio and confidence interval (CI) per vitamin D category, e) reported outcome of breast cancer risk. No language restrictions were imposed. Incident breast cancer was analyzed as the outcome of interest due to varying screening and treatments by country. In the first round of screening abstracts (n = 974), 938 articles were excluded by search criteria (Figure 1). In a second round of screening full text articles (n = 36), 27 articles were excluded: not prospective (11 articles), circulating 25(OH)D not measured (6 articles), survival among cancer cohort (5 articles), duplicate studies (3 articles), and case report (2 articles). Our search criteria yielded 9 total prospective case control studies, comprising 5206 incident cases and 6450 controls (Table 1).

Bottom Line: Data were pooled using dose-response random-effects meta-regression models.Identifying nonlinear effects, spline models were optimized for thresholds.While no association was found in premenopausal women, dose-response modeling revealed a nonlinear inverse association among postmenopausal women.

View Article: PubMed Central - PubMed

Affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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.

Show MeSH
Related in: MedlinePlus