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Vitamin D and breast cancer: Stop torturing the data!

O’Brien and colleagues’ post hoc analysis of a short series of 6857 women from the Sister Study cohort, which concluded that “findings add to the evidence that vitamin D protects against breast cancer and highlight a possible path for intervention in 2 racial/ethnic groups,” deserves robust comment. First, post hoc analysis is only about hypothesis generation, and the study does not conform to reporting guidelines. Preregistration is one of the many quality requirements of the Strengthening the Reporting of Observational Studies in Epidemiology guidelines, whose endorsement is recalled in the journal’s instructions for authors. Could O’Brien and colleagues indicate if they preregistered their analysis (e.g., the Open Science Framework) to avoid phacking (a potential issue for serial analyses, even more so as a PubMed search hit 186 previous publications from the Sister Study cohort) and pharking (hypothesizing after the results are known)? Second, the statistical adjustment for confounding factors is questionable. For example, it is a catch 22 for smoking: (1) Smokers have lower 25hydroxyvitamin D (25(OH)D) concentrations, and (2) 25(OH)D is associated with a higher risk of tobaccorelated cancers. Furthermore, the categorization into three subgroups (current, former, and never smokers) is not adequate because amount and duration matter. Lastly, insulin resistance and Type 2 diabetes, which also affect the vitamin D status, were not tested. Third, the confidence intervals for the hazard ratios include 1 and, therefore, are not significant (see Tables 2– 4 in O’Brien et al.) Furthermore, hazard ratios are rarely appropriate and are frequently misinterpreted: Their direction can be used to explain the direction of the relative risk, but the magnitude is not related to the relative risk, which, being much higher and more impressive than its absolute counterpart, is not appropriate for clinical decisions. Notably, an adequately sized series (231,203 women in the UK Biobank cohort) also failed to provide evidence for an association between vitamin D and ductal carcinoma in situ, and a Mendelian randomization analysis comprising 15,748 breast cancer cases did not support a causal effect of 25(OH)D concentrations. Lastly, the 2018 negative randomized control trial analyzing the incidence of cancer following vitamin D supplementation with a daily dose of 2000 IU of vitamin D3 in more than 25,000 participants should have ended the torture of old data with poor methodology. Low vitamin D seems to be a witness of a poor health condition associated with cancer risk and not a cause per se.