Considerable public and professional controversy has been generated over the possible link between hormone replacement therapy (HRT) and breast cancer. It has been suggested that unopposed estrogen replacement therapy (ERT) modestly increases a woman's risk of breast cancer. Combined HRT with both estrogen and progestin is thought to increase the risk more than ERT alone. These associations, however, remain controversial despite more than 50 epidemiologic studies and several meta-analyses that have been published during the past 25 years. Bush and colleagues examined all available evidence to study the risk of breast cancer in women who used ERT or HRT and the risk of death from breast cancer among these women.

The authors searched medical databases using the keywords estrogen, ERT, HRT, breast cancer, and breast neoplasm for relevant articles published between 1975 and 2000. They also examined the references of the originally identified articles and other sources. Forty-five publications relating to the association between ERT and risk of breast cancer, and 20 studies of HRT and breast cancer risk were identified. The authors found five studies concerning HRT and mortality from breast cancer and six studies on HRT and survival following breast cancer.

In 47 percent of the studies, the risk estimate of breast cancer in ERT users was between 0.9 and 1.1, indicating little or no effect. The risk estimate was less than 0.9 (protective) in 20 percent of studies and greater than 1.1 in 33 percent of studies. The results of the 20 studies on HRT and breast cancer risk were inconsistent. Only four studies achieved statistically significant results; two of these showed a higher risk, and two showed a protective effect of HRT. The study with the longest continuous use of hormones (up to 22 years) reported no increased risk of breast cancer. Despite the uncertainty about breast cancer incidence in hormone users, mortality and survival after diagnosis were improved in women who used hormones.

The authors conclude that the current literature does not support an association between ERT or HRT and breast cancer incidence. Although an association is biologically plausible, the authors do not believe that additional studies will reveal an association, even with long-term use. Conversely, hormone therapy appears to be associated with reduced mortality from breast cancer. This could be caused by detection of tumors at a lower grade or enhanced screening of women during hormone therapy.