Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations ≥60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort

Abstract

Background: While numerous epidemiologic studies have found an association between higher serum 25-hydroxyvitamin D [25(OH)D] concentrations and lower breast cancer risk, few have assessed this association for concentrations >40 ng/ml.

Objective: To investigate the relationship between 25(OH)D concentration and breast cancer risk across a broad range of 25(OH)D concentrations among women aged 55 years and older.

Methods: Analyses used pooled data from two randomized clinical trials (N = 1129, N = 2196) and a prospective cohort (N = 1713) to examine a broad range of 25(OH)D concentrations. The outcome was diagnosis of breast cancer during the observation periods (median: 4.0 years). Three analyses were conducted: 1) Incidence rates were compared according to 25(OH)D concentration from <20 to ≥60 ng/ml (<50 to ≥150 nmol/L), 2) Kaplan-Meier plots were developed and 3) multivariate Cox regression was used to examine the association between 25(OH)D and breast cancer risk using multiple 25(OH)D measurements.

Results: Within the pooled cohort (N = 5038), 77 women were diagnosed with breast cancer (age-adjusted incidence: 512 cases per 100,000 person-years). Results were similar for the three analyses. First, comparing incidence rates, there was an 82% lower incidence rate of breast cancer for women with 25(OH)D concentrations ≥60 vs <20 ng/ml (Rate Ratio = 0.18, P = 0.006). Second, Kaplan-Meier curves for concentrations of <20, 20-39, 40-59 and ≥60 ng/ml were significantly different (P = 0.02), with the highest proportion breast cancer-free in the ≥60 ng/ml group (99.3%) and the lowest proportion breast cancer-free in the <20 ng/ml group (96.8%). The proportion with breast cancer was 78% lower for ≥60 vs <20 ng/ml (P = 0.02). Third, multivariate Cox regression revealed that women with 25(OH)D concentrations ≥60 ng/ml had an 80% lower risk of breast cancer than women with concentrations <20 ng/ml (HR = 0.20, P = 0.03), adjusting for age, BMI, smoking status, calcium supplement intake, and study of origin.

Conclusions: Higher 25(OH)D concentrations were associated with a dose-response decrease in breast cancer risk with concentrations ≥60 ng/ml being most protective.

Fig 1. Frequency distribution and breast cancer incidence rates by 25(OH)D concentration, pooled cohort (N = 5038).

The bars represent the number of participants by groupings of 10 ng/ml (left y-axis), white dots represent the 25(OH)D concentration for each breast cancer case, black dots represent breast cancer incidence rates per 100,000 person-years for each 25(OH)D group (plotted at the median value for each group: 16, 25, 32, 39, 47, 57, and 70 ng/ml) (right y-axis). Vertical error bars represent the 95% confidence intervals.

Fig 2. Kaplan-Meier plot comparing the proportion of breast cancer-free participants by 25(OH)D concentration, pooled cohort (N = 5038).

Participants were allowed to move between strata of 25(OH)D according to changes in 25(OH)D concentration over the course of the observation periods. Four-year cumulative breast cancer-free proportion was 99.3% among participants with 25(OH)D concentrations ≥60 ng/ml compared to 96.8% for those with 25(OH)D concentrations <20 ng/ml (the proportion with breast cancer was 78% lower for ≥60 ng/ml vs <20 ng/ml, P = 0.02).

Fig 3. Association between serum 25(OH)D (as a continuous variable) and risk of breast cancer adjusted for age, BMI, smoking status, calcium supplement intake, and study of origin in the range of ≤100 ng/ml, pooled cohort (N = 5308).

Solid black line represents the estimated hazard ratio for the Cox regression model with restricted cubic splines with three knots; dashed lines represent the 95% confidence interval of the estimate.