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Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies
  1. Samuel Shapiro1,
  2. Richard D T Farmer2,
  3. Helen Seaman2,3,
  4. John C Stevenson4 and
  5. Alfred O Mueck5
  1. 1Department of Epidemiology, University of Cape Town, Cape Town, South Africa
  2. 2Department of Epidemiology, University of Surrey, Guildford, UK
  3. 3Freelance Medical Writer, Aldershot, UK
  4. 4National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, UK
  5. 5Department of Endocrinology, University Women's Hospital of Tuebingen, Tuebingen, Germany
  1. 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; samshap{at}

Part 1. The Collaborative Reanalysis


Background Concern that hormone replacement therapy (HRT) may cause breast cancer has existed since the time it was introduced, and based on evidence in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that causality is now established.

Objective To evaluate the evidence for causality in the three studies.

Methods Using generally accepted causal criteria, in this paper the authors begin with an evaluation of the CR. Analogous evaluations of the WHI and MWS will follow.

Results The findings in the CR did not adequately satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, dose/duration-response, internal consistency, external consistency or biological plausibility.

Conclusion HRT may or may not increase the risk of breast cancer, but the CR did not establish that it does.

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  • Competing interests Samuel Shapiro, John Stevenson and Alfred Mueck presently consult, and in the past have consulted, with manufacturers of products discussed in this article. Richard Farmer has consulted with some manufacturers in the past.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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