Objective To determine the effect of different types and formulations of hormone replacement therapy (HRT) on the risk of breast cancer in postmenopausal women.

Design Population-based case–control study.

Setting UK, 1988–2004.

Participants Women 50–75 years between 1998 and 2004.

Main outcome measures Breast cancer incidence to estimate the rate ratio (RR) associated with use of various HRTs over a 30-year period.

Results We identified 6347 incident cases of breast cancer that were matched with 31 516 controls. Cases were on average 61 years at diagnosis and 22% had undergone a hysterectomy. The rate of breast cancer was increased with the use of opposed estrogens in oral form (adjusted RR 1.38; 95% CI 1.27–1.49) in contrast to patch form (RR 1.08; 95% CI 0.81–1.43). This rate was similarly elevated with both continuous (RR 1.29; 95% CI 1.07–1.56) and sequential (RR 1.33; 95% CI 1.21–1.46) forms of opposed estrogen. The rate of breast cancer was not increased among exclusive users of unopposed estrogens (RR 0.97; 95% CI 0.86–1.09) or of tibolone (RR 0.86; 95% CI 0.65–1.13). Users of tibolone who had switched from opposed estrogens, however, had an elevated rate (RR 1.29; 95% CI 1.09–1.52). The rate of breast cancer increased by 25% (95% CI 20–30%) with every ten prescriptions of orally administered opposed estrogen.

Conclusions The risk of breast cancer varies with the formulation and preparation of HRT. Opposed estrogens (progesterone–estrogen) in oral form are associated with an increased risk of breast cancer, which increases with use. Transdermal opposed estrogens, unopposed estrogens and tibolone do not increase this risk. However, this study is an observational study that carries risks of various biases, and thus the findings need to be interpreted with caution.

Introduction
Hormone replacement therapy (HRT) has been used extensively in postmenopausal women as a proven and effective therapy for climacteric symptoms and in osteoporosis treatment. Its widespread long-term use for indications such as primary prevention of cardiovascular disease or cognitive decline was called into question with the publication of several epidemiological studies, most notably the Million Women Study (MWS) and the Women’s Health Initiative (WHI), which reported several adverse effects among users of HRT, including breast cancer.

The magnitude of this risk, however, has been found to vary across studies. In particular, the breast cancer risk appears to vary with different HRT formulations (e.g. opposed versus unopposed estrogen), different modes of delivery (transdermal versus oral), the agent and the length of use. The addition of a progestin appears to increase the risk of breast cancer. However, it is unclear whether this risk varies with different classes of progestins. With respect to the mode of delivery, the transdermal form of delivery means that the user is exposed to continuous low doses of hormones with first pass clearance by the liver. This contrasts with oral absorption with an initial peak dose and subsequent clearance from the blood long before the next dose. This difference in hormone exposure may have effects on breast tissue and consequently breast cancer risk over a long duration of time. A new agent on the market, tibolone is a synthetic compound, classified as a selective tissue estrogenic activity regulator (STEAR) for which it has been suggested that its use may be associated with an increase in breast cancer.

Using the UKs General Practice Research Database (GPRD), we examined the risk of breast cancer in postmenopausal women associated with different formulations of HRT, different agents and different modes of delivery of HRT.

L Opatrny, Division of Internal Medicine, Department of Medicine, McGill University Health Center
  * S Dell’Aniello, McGill Pharmacoepidemiology Research Unit, Department of Epidemiology and Biostatistics
  * S Assouline, Division of Hematology-Oncology, Department of Medicine, SMBD Jewish General Hospital, McGill University, Montreal, Quebec, Canada
  * S Suissa McGill Pharmacoepidemiology Research Unit, Department of Epidemiology and Biostatistics, Dr S Suissa, Division of Clinical Epidemiology, Royal Victoria Hospital, 687 Pine avenue west, Ross 4.29, Montreal, Que’bec, Canada H3A 1A1. Email .(JavaScript must be enabled to view this email address)