In 1997 the Oxford Collaborative Group on Hormonal Factors in Breast Cancer reanalysed data from 51 of the 52 published observational studies of hormone replacement therapy and breast cancer, which included more than 16 000 women, and reported that breast cancer risk increased after 5 years of hormone therapy. The 2.3% increased risk for each year of added use was the same as the increased risk for each year of delayed menopause, providing supporting evidence that oestrogen promotes breast cancer.
Subsequently, other large observational studies (each with >1000 breast cancer cases) also reported an increased risk of breast cancer in women who used hormone replacement therapy for more than 4 or 5 years, most notably in women taking oestrogen with a progestogen.
Despite the strong epidemiological evidence and biological plausibility that oestrogen promotes breast cancer, until the Women’s Health Initiative, no clinical trial had sufficient size and duration to test this hypothesis. The Women’s Health Initiative found a 26% increased risk of breast cancer, first apparent after 4 years of combined treatment (Writing Group for the Women’s Health Initiative Investigators 2002). The increased risk was highest in women who had used hormone replacement therapy before the trial. The other Women’s Health Initiative comparison, of unopposed oestrogen versus placebo, has not been stopped, suggesting no excess in breast cancer to date.
Other clinical trial evidence that combined hormone replacement therapy may be more harmful than unopposed oestrogen comes from the PEPI trial, where about one-third of women taking oestrogen plus a progestin versus 15% of women taking unopposed oestrogen had increased breast density on routine mammogram. Increased breast density is a risk factor for breast cancer in postmenopausal women, increasing during the first year of hormone therapy, but reversible within one year of stopping it.
Indirect evidence that oestrogen increases breast cancer risk comes from studies of the selective oestrogen receptor modulators tamoxifen and raloxifene; each has been shown to reduce the risk of breast cancer in a large clinical trial. In an interesting sidelight to the Italian Tamoxifen Trial, overall breast cancer rates were very low except in women taking hormone replacement therapy: 8 of 390 women taking hormone replacement therapy plus placebo developed breast cancer compared to 1 of 362 women taking hormone replacement therapy and tamoxifen.
Although breast cancer is a justifiable concern, excess risk is small for an individual woman, and the risk appears to be reversible, with no excess risk 5 years after stopping oestrogen. The Women’s Health Initiative calculated absolute excess risks per 10 000 person-years attributable to oestrogen plus progestin were eight more invasive breast cancers (Writing Group for the Women’s Health Initiative Investigators 2002). In observational studies, breast cancer occurring in women taking oestrogen was usually in situ, node negative, oestrogen-receptor positive, and had a better prognosis than non-hormone replacement therapy-associated breast cancer. This improved prognosis may reflect more frequent mammograms with earlier diagnosis and treatment in women taking hormone replacement therapy, and was not reported in Women’s Health Initiative.