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.

Citation: McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF, Gorham ED, et al. (2018) 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. PLoS ONE 13(6): e0199265. doi:10.1371/journal.pone.0199265

Editor: Ramesh Narayanan, University of Tennessee Health Science Center, UNITED STATES

Received: January 16, 2018; Accepted: June 1, 2018; Published: June 15, 2018

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: The data is available through the Zenodo repository and can be accessed at

Funding: The 2007 Lappe RCT was funded by the National Institute of Aging. The 2017 Lappe RCT was funded by the National Cancer Institute and Creighton University internal funding. GrassrootsHealth is a nonprofit entity; this project was funded by self-sponsorship by the participants and donations from Bio-Tech Pharmacal, Pure North S’Energy Foundation, and the Vitamin D Society. These funds provided the resources for the study design and data collection for the GRH study and the analysis and interpretations of this pooled analysis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Bio-Tech Pharmacal was a commercial source of funding. It did not have any relationship with GrassrootsHealth, UC San Diego, MUSC, Inova Schar, or Creighton University with regard to employment, patents, projects in development, or products marketed. Representatives of this source did not review the manuscript or play any role in design, analysis, or writing of the manuscript and had no control over any decision to publish it. This does not alter our adherence to PLOS ONE policies on sharing data and materials.