Abstract and Introduction
Abstract
Background Based principally on findings in three studies, the collaborative reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P. The authors have previously reviewed the findings in the CR and WHI (Parts 1–3).
Objective To evaluate the evidence for causality in the MWS.
Methods Using generally accepted causal criteria, in this article (Part 4) the authors evaluate the findings in the MWS for E+P and for ET.
Results Despite the massive size of the MWS the findings for E+P and for ET did not adequately satisfy the criteria of time order, information bias, detection bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. Had detection bias resulted in the identification in women aged 50–55 years of 0.3 additional cases of breast cancer in ET users per 1000 per year, or 1.2 in E+P users, it would have nullified the apparent risks reported.
Conclusion HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.
Introduction
In Parts 1–3 of this series of articles we have applied generally accepted epidemiological principles of causality to studies of the risk of breast cancer in users of hormone replacement therapy (HRT), as reported from the collaborative reanalysis (CR) (Part 1, and the Women's Health Initiative (WHI) (Parts 2 and 3). In Part 1 we concluded that the CR findings for HRT [both unopposed estrogen therapy (ET) and estrogen plus progestogen (E+P)] did not establish causality. In Part 2 we concluded that the WHI findings for E+P did not establish causality. By contrast, in Part 3 we concluded that valid WHI findings suggested that ET does not increase the risk of breast cancer, and may even decrease it; the latter possibility, however, was statistically borderline.
In 2003, a year after the WHI findings for E+P were published, the Million Women Study (MWS) investigators reported an increased risk of breast cancer in HRT users, and based on the combined evidence from the CR, the WHI and the MWS it is now widely believed that E+P is an established and major cause of the disease. The MWS investigators (but not the WHI investigators) claim that ET also increases the risk, although to a lesser degree than does E+P.
Here, in Part 4 we apply causal principles to the evidence from the MWS. In the MWS the estimated levels of risk associated with the use of HRT were greater than in the CR or the WHI, and in view of the impact the study had on regulatory authorities, and on the public perception of safety, it is especially important to evaluate its validity.