The Association of a Breast Cancer Diagnosis With Serum 25-Hydroxyvitamin D Concentration Over Time

Katie M. O'Brien; Dale P. Sandler; Melissa House; Jack A. Taylor; Clarice R. Weinberg


Am J Epidemiol. 2019;188(4):637-645. 

In This Article

Abstract and Introduction


Prospective and retrospective studies of vitamin D levels and breast cancer have produced discrepant results. This may be due to variations in serum 25-hydroxyvitamin D (25(OH)D) concentrations over time, including systematic changes after breast cancer diagnosis. We measured total serum 25(OH)D levels in participants from the Sister Study, a US cohort study of sisters of breast cancer patients, who provided samples at baseline (2003–2009) and 4–10 years later (2013–2015). This included 827 women with an intervening breast cancer and 771 women without one. Although 25(OH)D levels were modestly correlated over time (R = 0.42), 25(OH)D concentrations increased in both groups, with larger increases among cases (averaging 31.6 ng/mL at baseline and 43.5 ng/mL at follow-up) than among controls (32.3 ng/mL at baseline, 40.4 ng/mL at follow-up). Consequently, the estimated association between 25(OH)D and breast cancer depended on whether baseline measurements (per 10-ng/mL increase, odds ratio = 0.87, 95% confidence interval: 0.78, 0.98) or measurements from the second blood draw (per 10-ng/mL increase, odds ratio = 1.17, 95% confidence interval: 1.08, 1.26) were used. Concentrations were related to regular use (≥4 times/week) of vitamin D supplements, which became more common over time; increases in regular use were greater in cases (from 56% to 84%) than in controls (from 56% to 77%). Our results do not explain previously observed differences between retrospective and prospective studies, but they do demonstrate how reverse causation and temporal trends in exposure can distort inference.


Vitamin D has known anticarcinogenic properties,[1] but previous clinical trials and observational studies have not established a clear association between vitamin D and breast cancer risk.[2–4] Observational studies of the association between breast cancer and levels of the vitamin D biomarker 25-hydroxyvitamin D (25(OH)D) have produced mixed results. Although many retrospective case-control studies that measured 25(OH)D after the cases had been diagnosed found evidence suggesting that 25(OH)D is inversely associated with breast cancer,[5–9] results from prospective cohort studies have been less consistent. In most, prediagnostic 25(OH)D concentrations were either not associated with or only weakly inversely associated with breast cancer.[2,10–25]

In our recent prospective study of serum 25(OH)D and breast cancer risk,[26] we found that high concentrations of 25(OH)D were associated with decreased risk of breast cancer over the subsequent 5 years. We had restricted the follow-up interval because 25(OH)D levels vary over time[27–29] and recent exposure could be most relevant to risk, with attenuation of effect estimates over the course of prolonged follow-up periods. We further hypothesized that the protective association observed in retrospective case-control studies could also be due, in part, to reverse causation, with recently diagnosed cases experiencing lifestyle changes or treatment effects that reduced their 25(OH)D concentrations. However, because we only had measurements taken at a single time point prior to cases' diagnoses, we could not estimate effects of either time or breast cancer on 25(OH)D levels.

We undertook this new study to address those remaining gaps. Specifically, we aimed to assess serum 25(OH)D concentrations in samples collected several years after baseline to study changes over time. If changes did occur, we wanted to understand what factors influenced these changes, with particular attention to an intervening breast cancer diagnosis.