Combined hormone therapy and breast cancer: a single-edged sword.

THE WOMEN’S HEALTH INITIATIVE (WHI) TRIAL OF EStrogen plus progestin hormone therapy represents a major landmark in medical research. The study demonstrates that alteration of a woman’s basic hormonal physiology over decades in the interest of long-term disease prevention is fraught with hazard. The WHI investigators terminated the trial after an assessment of the overall risk-benefit ratio of this combined hormone therapy regimen failed to demonstrate a benefit. A statistically significant 26% increase in breast cancer incidence contributed to the overall negative effect of estrogen plus progestin. In the past, women and their physicians had been reassured that although combined hormone therapy increases breast cancer risk, this increase is observed in cancers of a favorable type, is associated with long duration of use, and does not result in increased mortality. In this issue of THE JOURNAL, the study by Chlebowski and colleagues provides more detailed information on breast cancer outcomes with estrogen plus progestin. With a mean (SD) follow-up of 5.6 years (1.3) (compared with 5.2 years [1.3] in the initial article), 349 invasive and 84 in situ breast cancers were available for this analysis. A 24% increase in breast cancer risk was observed in the estrogen plus progestin group, but this increased risk was not evident until the third year of the study. This risk estimate is remarkably close to estimates derived from well-conducted observational research, such as the study by Li and colleagues, which is also reported in this issue. What is new here, apart from the strong confirmation that the association between combined hormone therapy and breast cancer is causal, and probably not due to unappreciated differences between combined hormone therapy users and nonusers? The expanded report from the WHI trial is significant because it strongly suggests that the breast cancers related to estrogen plus progestin use are not “good” ones, that they occur earlier than expected based on some previous studies, that there are no easily identified subgroups at higher risk, and that, to top it off, women using estrogen plus progestin experience a much higher rate of mammographic abnormalities leading to anxiety and further costly workups. The use of combined menopausal hormone therapy has been documented to decrease both the sensitivity and the specificity of mammography, because of an increase in radiographic breast density. Changes in breast density in response to combined therapy appear to occur during a relatively short interval. In the Postmenopausal Estrogen/ Progestin Interventions trial, the 16% to 26% of women taking estrogen plus progestin who experienced an increase in breast density did so within 12 months of initiating treatment. The finding by Chlebowski et al that significantly more women had an abnormal mammogram after 1 year is consistent with the results of case-control studies and is biologically plausible, given the well-documented effects of estrogen and progestin on the proliferation of normal breast epithelium. It is tempting to speculate that the findings of a delayed time to diagnosis as well as an increase in abnormal mammograms are because of an increase in breast density, but density was not measured in the WHI trial. The ability of combined hormone therapy to decrease mammographic sensitivity creates an almost unique situation in which an agent increases the risk of developing a disease while simultaneously delaying its detection. Thus, the incidence curves presented in the report by Chlebowski et al show a striking crossover. The incidence of breast cancer diagnosis is actually lower in the estrogen plus progestin group for the first 2 years, after which the slope of the incidence curve for estrogen plus progestin begins to increase, leading to a crossover in cumulative breast cancer occurrence at year 4 and continuing divergence in risk at the end of follow-up. Given these nonproportional hazards over time, the summary risk ratio of 1.24 from the proportional hazards model is probably conservative. The authors, having anticipated this problem, also provide a weighted analysis that down-weights the importance of the early years of follow-up. A simplified but conservative analysis based on an a priori analysis plan is justifiable, particularly in an initial study.