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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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Ding Spaghetti Plot and pooled dose-response relationship between circulating 25(OH)D Levels and breast cancer risk, stratified by menopausal status (A, premenopausal, and B, postmenopausal women). The solid dark gray line represents the central pooled dose-response estimate, and the surrounding black lines represent 95% confidence interval bands. Each light gray “spaghetti noodle” represents a relative risk series from the same study; data points are represented by circles, with the relative size of each circle reflecting the analytic weight of each RR estimate.Note: Quantitative RR for Figure 2: Postmenopausal p value for nonlinear dose effect modification:  • at 27 ng/mL: p for nonlinear slope change = 0.02  • at 35 ng/mL: p for nonlinear slope change = 0.05 Point-specific RRs compared to 27 ng/mL (reference) among postmenopausal women:  • 35 ng/mL: RR = 0.81 (95% CI, 0.69–0.96), p = 0.01  • 40 ng/mL: RR = 0.83 (95% CI, 0.71–0.97), p = 0.02 Dose-response nonlinear slope RRs per 5 ng/mL increase in circulating 25(OH)D in postmenopausal women:  • <27 ng/mL range: RR per 5 ng/mL increase = 1.01 (95% CI, 0.98–1.04)  • 27–34 ng/mL range: RR per 5 ng/mL increase = 0.88 (95% CI, 0.79–0.97)  • 35–40 ng/mL range: RR per 5 ng/mL increase = 1.03 (95% CI, 0.94–1.12)
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Figure 2: Ding Spaghetti Plot and pooled dose-response relationship between circulating 25(OH)D Levels and breast cancer risk, stratified by menopausal status (A, premenopausal, and B, postmenopausal women). The solid dark gray line represents the central pooled dose-response estimate, and the surrounding black lines represent 95% confidence interval bands. Each light gray “spaghetti noodle” represents a relative risk series from the same study; data points are represented by circles, with the relative size of each circle reflecting the analytic weight of each RR estimate.Note: Quantitative RR for Figure 2: Postmenopausal p value for nonlinear dose effect modification:  • at 27 ng/mL: p for nonlinear slope change = 0.02  • at 35 ng/mL: p for nonlinear slope change = 0.05 Point-specific RRs compared to 27 ng/mL (reference) among postmenopausal women:  • 35 ng/mL: RR = 0.81 (95% CI, 0.69–0.96), p = 0.01  • 40 ng/mL: RR = 0.83 (95% CI, 0.71–0.97), p = 0.02 Dose-response nonlinear slope RRs per 5 ng/mL increase in circulating 25(OH)D in postmenopausal women:  • <27 ng/mL range: RR per 5 ng/mL increase = 1.01 (95% CI, 0.98–1.04)  • 27–34 ng/mL range: RR per 5 ng/mL increase = 0.88 (95% CI, 0.79–0.97)  • 35–40 ng/mL range: RR per 5 ng/mL increase = 1.03 (95% CI, 0.94–1.12)

Mentions: A novel meta-analytic visual representation method was developed by Eric L. Ding to aid in detecting nonlinear relationships between circulating 25(OH)D levels and breast cancer risk among postmenopausal women (Figure 2). The Ding Spaghetti Plot consists of connected study-series line plots of individual study RRs, where each “spaghetti noodle” represents a RR series from the same study; and data points are represented by circles, in which the relative size of each circle reflects the analytic weight of each RR estimate (although weighting does not affect the shape of the connected line plots). Thus, RRs with smaller standard errors (that is, relatively larger sample sizes) are represented by larger data points. The aggregate graphical visual representation, via the Ding Spaghetti Plot of all studies’ dose-response “noodle” plots together, allows investigators to visually identify potential nonlinear associations and different dose-response curves from multiple data series across various studies. The centrally averaged pooled dose-response curve, highlighted as the main “noodle” in the Spaghetti Plot, represents the aggregate slope between knot-points. It is accompanied by upper and lower 95% CI bands that represent the uncertainty of the central pooled dose response curve.


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)

Ding Spaghetti Plot and pooled dose-response relationship between circulating 25(OH)D Levels and breast cancer risk, stratified by menopausal status (A, premenopausal, and B, postmenopausal women). The solid dark gray line represents the central pooled dose-response estimate, and the surrounding black lines represent 95% confidence interval bands. Each light gray “spaghetti noodle” represents a relative risk series from the same study; data points are represented by circles, with the relative size of each circle reflecting the analytic weight of each RR estimate.Note: Quantitative RR for Figure 2: Postmenopausal p value for nonlinear dose effect modification:  • at 27 ng/mL: p for nonlinear slope change = 0.02  • at 35 ng/mL: p for nonlinear slope change = 0.05 Point-specific RRs compared to 27 ng/mL (reference) among postmenopausal women:  • 35 ng/mL: RR = 0.81 (95% CI, 0.69–0.96), p = 0.01  • 40 ng/mL: RR = 0.83 (95% CI, 0.71–0.97), p = 0.02 Dose-response nonlinear slope RRs per 5 ng/mL increase in circulating 25(OH)D in postmenopausal women:  • <27 ng/mL range: RR per 5 ng/mL increase = 1.01 (95% CI, 0.98–1.04)  • 27–34 ng/mL range: RR per 5 ng/mL increase = 0.88 (95% CI, 0.79–0.97)  • 35–40 ng/mL range: RR per 5 ng/mL increase = 1.03 (95% CI, 0.94–1.12)
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Related In: Results  -  Collection

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Figure 2: Ding Spaghetti Plot and pooled dose-response relationship between circulating 25(OH)D Levels and breast cancer risk, stratified by menopausal status (A, premenopausal, and B, postmenopausal women). The solid dark gray line represents the central pooled dose-response estimate, and the surrounding black lines represent 95% confidence interval bands. Each light gray “spaghetti noodle” represents a relative risk series from the same study; data points are represented by circles, with the relative size of each circle reflecting the analytic weight of each RR estimate.Note: Quantitative RR for Figure 2: Postmenopausal p value for nonlinear dose effect modification:  • at 27 ng/mL: p for nonlinear slope change = 0.02  • at 35 ng/mL: p for nonlinear slope change = 0.05 Point-specific RRs compared to 27 ng/mL (reference) among postmenopausal women:  • 35 ng/mL: RR = 0.81 (95% CI, 0.69–0.96), p = 0.01  • 40 ng/mL: RR = 0.83 (95% CI, 0.71–0.97), p = 0.02 Dose-response nonlinear slope RRs per 5 ng/mL increase in circulating 25(OH)D in postmenopausal women:  • <27 ng/mL range: RR per 5 ng/mL increase = 1.01 (95% CI, 0.98–1.04)  • 27–34 ng/mL range: RR per 5 ng/mL increase = 0.88 (95% CI, 0.79–0.97)  • 35–40 ng/mL range: RR per 5 ng/mL increase = 1.03 (95% CI, 0.94–1.12)
Mentions: A novel meta-analytic visual representation method was developed by Eric L. Ding to aid in detecting nonlinear relationships between circulating 25(OH)D levels and breast cancer risk among postmenopausal women (Figure 2). The Ding Spaghetti Plot consists of connected study-series line plots of individual study RRs, where each “spaghetti noodle” represents a RR series from the same study; and data points are represented by circles, in which the relative size of each circle reflects the analytic weight of each RR estimate (although weighting does not affect the shape of the connected line plots). Thus, RRs with smaller standard errors (that is, relatively larger sample sizes) are represented by larger data points. The aggregate graphical visual representation, via the Ding Spaghetti Plot of all studies’ dose-response “noodle” plots together, allows investigators to visually identify potential nonlinear associations and different dose-response curves from multiple data series across various studies. The centrally averaged pooled dose-response curve, highlighted as the main “noodle” in the Spaghetti Plot, represents the aggregate slope between knot-points. It is accompanied by upper and lower 95% CI bands that represent the uncertainty of the central pooled dose response curve.

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