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

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.