Hormones and breast cancer: Evidence and implications for consideration of risks and benefits of hormone replacement therapy

The role of estrogen replacement therapy (ERT) in the etiology of breast cancer continues to be debated. The implications for counseling women about a causal relation between hormones and breast cancer with regard to long-term use of postmenopausal hormones remain controversial. The literature on hormones and breast cancer, including articles on cell proliferation, endogenous hormone levels, epidemiologic studies, and the risk of breast cancer, is reviewed. A cause of cancer is defined as a factor that increases the probability that cancer will develop in an individual. A causal relation between female hormones and breast cancer is based on duration of use, dose-response, biologic plausibility, temporality, strength of association, and coherence. The magnitude of the increase in risk of breast cancer caused by using hormone replacement therapy (HRT) is comparable to that seen in delayed menopause. The positive relation between endogenous hormone levels and risk of breast cancer supports a biologic mechanism for this relationship. The increase in risk of breast cancer with increasing duration of use, which does not vary substantially across studies, offers further evidence for a causal relation. The reduction in total mortality with short-term use of hormones, although strongest among women with risk factors for cardiovascular disease, adds complexity to the risk-benefit tradeoff associated with the use of hormones for longer durations. All evidence supports a causal relation between both endogenous estrogens and the use of postmenopausal estrogens and progestins and breast cancer incidence in postmenopausal women. Among postmenopausal women, prior use of oral contraceptives is not related to risk of breast cancer. Strategies for relief of menopausal symptoms and long-term prevention of osteoporosis and heart disease that do not cause breast cancer are urgently needed.