Studies from the Women’s Health Initiative have reported an increased risk of breast cancer in estrogen and progestogen users. Among users of estrogen alone, an increased risk was not observed.Researchers conducted this study to evaluate the evidence for unopposed estrogen.In a related article, the authors apply generally accepted causal criteria to estrogen plus progestogen’s findings. Here, the authors use the standards for unopposed estrogen results, as reported in a clinical trial and combined data from the practice and an observational study.

The study concluded that after 7.1 years of follow-up, the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an ‘intention-to-treat’ analysis and 0.67 in an ‘as treated’ analysis; after 10.7 years, the risk reduction persisted. Time order was correctly specified; detection bias was minimal; in the ‘as treated’ study, confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of insufficient data; the findings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed.