Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies
Part 4. The Million Women Study
- 1Visiting Professor of Epidemiology, Department of Epidemiology, University of Cape Town, Cape Town, South Africa
- 2Emeritus Professor of Epidemiology, Department of Epidemiology, University of Surrey, Guildford, UK
- 3Consultant Physician and Reader in Metabolic Medicine, National Heart and Lung Institute, Imperial College, London and Royal Brompton Hospital, London, UK
- 4Emeritus Director, Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton, and Consultant Endocrinologist, Jean Hailes Medical Centre for Women, Clayton, Victoria, Australia
- 5Professor of Clinical Pharmacology and Experimental Endocrinology, Department of Endocrinology, University Women's Hospital, Tubingen, Germany
- Correspondence to Professor Samuel Shapiro, Department of Public Health and Family Medicine, University of Cape Town Medical School, Anzio Road, Observatory, Cape Town, South Africa;
- Received 28 September 2011
- Accepted 2 November 2011
- Published Online First 16 January 2012
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.
Competing interests Samuel Shapiro, John Stevenson, Henry Burger, and Alfred Mueck presently consult, and in the past have consulted, with manufacturers of products discussed in this article. Richard Farmer has consulted with manufacturers in the past.
Provenance and peer review Not commissioned; externally peer reviewed.