Limits...
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.

Show MeSH

Related in: MedlinePlus

Forest plot of linear dose-response of circulating 25(OH)D and breast cancer risk, stratified by menopausal status, listed by first author and date of study. (P for menopause effect modification = 0.05.) Note: Bertone-Johnson et al contributed 3 study sets as determined by batch (except in situ was pooled for the 3 batches due to few cases).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4553988&req=5

Figure 3: Forest plot of linear dose-response of circulating 25(OH)D and breast cancer risk, stratified by menopausal status, listed by first author and date of study. (P for menopause effect modification = 0.05.) Note: Bertone-Johnson et al contributed 3 study sets as determined by batch (except in situ was pooled for the 3 batches due to few cases).

Mentions: In our primary analysis, analyzing 25(OH)D levels to carefully assess a dose-response, results indicated a significant inverse, nonlinear association between circulating 25(OH)D and breast cancer risk among postmenopausal women, with apparent thresholds of 27 ng/mL (67 nmol/L) and 35 ng/mL (see Figure 2 and 3). Notably, while no dose-response relationship was observed among the lowest range of 25(OH)D levels <27 ng/mL (RR slope = 1.01 per 5 ng/mL; 95% CI, 0.98–1.04), higher 25(OH)D levels were associated with a reduced risk of breast cancer between 27 ng/mL and 35 ng/mL (RR slope = 0.88 per 5 ng/mL; 95% CI, 0.79–0.97), with a p for nonlinear risk change of 0.02 at 27 ng/mL. Furthermore, the reduction in risk somewhat flattened (p = 0.05 for nonlinear risk change) at highest levels ≥35 ng/mL (RR slope = 1.03 per 5 ng/mL; 95% CI, 0.94–1.12), yet remained at lower risk compared to 27 ng/mL. The nonlinear results were robust and relatively insensitive to changes in knot location. The point-specific RRs among postmenopausal women compared to a reference risk level of 27 ng/mL were RR = 0.81 (95% CI, 0.69–0.96) at 35 ng/mL, and RR = 0.83 (95% CI, 0.71–0.97) at 40 ng/mL. Moreover, effect modification by menopause was also confirmed in these spline models (p = 0.05), with no association in premenopausal women.


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)

Forest plot of linear dose-response of circulating 25(OH)D and breast cancer risk, stratified by menopausal status, listed by first author and date of study. (P for menopause effect modification = 0.05.) Note: Bertone-Johnson et al contributed 3 study sets as determined by batch (except in situ was pooled for the 3 batches due to few cases).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Forest plot of linear dose-response of circulating 25(OH)D and breast cancer risk, stratified by menopausal status, listed by first author and date of study. (P for menopause effect modification = 0.05.) Note: Bertone-Johnson et al contributed 3 study sets as determined by batch (except in situ was pooled for the 3 batches due to few cases).
Mentions: In our primary analysis, analyzing 25(OH)D levels to carefully assess a dose-response, results indicated a significant inverse, nonlinear association between circulating 25(OH)D and breast cancer risk among postmenopausal women, with apparent thresholds of 27 ng/mL (67 nmol/L) and 35 ng/mL (see Figure 2 and 3). Notably, while no dose-response relationship was observed among the lowest range of 25(OH)D levels <27 ng/mL (RR slope = 1.01 per 5 ng/mL; 95% CI, 0.98–1.04), higher 25(OH)D levels were associated with a reduced risk of breast cancer between 27 ng/mL and 35 ng/mL (RR slope = 0.88 per 5 ng/mL; 95% CI, 0.79–0.97), with a p for nonlinear risk change of 0.02 at 27 ng/mL. Furthermore, the reduction in risk somewhat flattened (p = 0.05 for nonlinear risk change) at highest levels ≥35 ng/mL (RR slope = 1.03 per 5 ng/mL; 95% CI, 0.94–1.12), yet remained at lower risk compared to 27 ng/mL. The nonlinear results were robust and relatively insensitive to changes in knot location. The point-specific RRs among postmenopausal women compared to a reference risk level of 27 ng/mL were RR = 0.81 (95% CI, 0.69–0.96) at 35 ng/mL, and RR = 0.83 (95% CI, 0.71–0.97) at 40 ng/mL. Moreover, effect modification by menopause was also confirmed in these spline models (p = 0.05), with no association in premenopausal women.

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