Research Article: 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

Date Published: June 15, 2018

Publisher: Public Library of Science

Author(s): Sharon L. McDonnell, Carole A. Baggerly, Christine B. French, Leo L. Baggerly, Cedric F. Garland, Edward D. Gorham, Bruce W. Hollis, Donald L. Trump, Joan M. Lappe, Ramesh Narayanan.


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.

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.

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

Partial Text

Breast cancer is the most common non-skin cancer in women [1]. More than 252,000 new cases of female breast cancer and 40,600 deaths were projected to occur in 2017 in the United States [1]. While more early detection and improvements in treatment have reduced the mortality rate, there has been no reduction in the incidence of breast cancer in the past 20 years [2]. Identifying and implementing effective primary prevention strategies could reduce breast cancer incidence rates.

Women in the 2007 Lappe et al. cohort (hereafter termed 2007 Lappe cohort) participated in a four year, population-based, double-blind, placebo-controlled trial of vitamin D and calcium supplementation in a 9-county area in Eastern Nebraska. Participants were randomly assigned to: 1) calcium plus vitamin D3 (1400–1500 mg/day of calcium plus 1100 IU/day of vitamin D3), 2) calcium (calcium as mentioned previously plus vitamin D placebo), or 3) control (calcium and vitamin D placebos). This trial was registered at as NCT00352170.

Baseline demographic characteristics of the pooled and individual cohorts are shown in Table 1. The GrassrootsHealth cohort had a lower median age, BMI, and calcium supplement intake and a lower proportion of participants who were current smokers than either Lappe cohort. The 2007 Lappe cohort had the lowest baseline median serum 25(OH)D concentration (28 ng/ml) and the GrassrootsHealth cohort had the highest (43 ng/ml).

In this pooled cohort, 25(OH)D concentration was significantly inversely associated with breast cancer risk. All three analyses showed that women with 25(OH)D concentrations ≥60 ng/ml had significantly lower risk of breast cancer (~80%) compared to women with concentrations <20 ng/ml. There was a consistent decrease in breast cancer risk as 25(OH)D concentrations increased, with no evidence of increased risk in higher concentrations. Using a pooled cohort allowed for analysis across a wider range of serum 25(OH)D concentrations than any of the cohorts alone. While a novel approach, similar inclusion criteria were used for all three cohorts and analyses were adjusted for study of origin and breast cancer risk factors to account for differences in methodology and demographics.   Source:


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