Breast Cancer Trends: A Marriage Between Clinical Trial Evidence and Epidemiology

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Abstract
In this issue of the Journal, Glass et al. (1) report on the changes in screening mammography, menopausal hormone therapy, and breast cancer incidence between 1980 and 2006 in the Kaiser Permanente Northwest (KPNW) health plan. In particular, they report a drop in breast cancer incidence between 2000 and 2004. Similar drops have been reported in other population-based studies (2,3). Considering the various interventions and practices employed by plan participants, the authors conclude that the patterns of screening mammography and menopausal hormone therapy "parallel" breast cancer incidence. They stop short of saying that either screening mammography or decreased menopausal hor- mone therapy use caused the drop in incidence between 2000 and 2004. But the paralleling implicates the latter. In observational studies such as those of Glass et al. (1), the question of causation can be inferred but not directly proven. On the other hand, randomized trials are specifi cally designed to address causation. The relationship between and the importance of both randomization and epidemiology are well illustrated by the studies of menopausal hormone therapy. Investigators of early epi- demiologic studies drew a variety of conclusions about the impact of using menopausal hormone therapy on women's health. Fortunately, the limitations of these studies were recognized, and, despite some reservations, randomized studies ( 4 , 5 ) that could defi nitively address causation went forward and, with respect to some issues, proved the epidemiology studies to be wrong. But these randomized studies had the limitation that the inclusion cri- teria and highly specifi ed treatment plans left open the question as to whether the results can be broadly applied to the population as a whole ( 6 - 8 ). Such questions can be addressed only by epidemio- logic studies. So the two approaches nicely complement each other. Many randomized trials are based on logical hypotheses about disease processes and not epidemiology. Randomized trials of screening mammography were undertaken because of the intuitive and scientifi c appeal of early detection. These trials showed that screening causes an increase in breast cancer incidence, presumably because of capturing prevalent cases, early detection of cases (lead-time effects), and detection of cases that may have never become clinically relevant (overdiagnosis) ( 9 , 10 ). The increased incidence of breast cancer in the 1980s in the KPNW population as mammography was introduced provides evidence that the same phenomenon happens in clinical practice. Whether the increased breast cancer incidence in the 1990s and the decreased incidence between 2000 and 2004 are due to changes in use of hormone therapy is less clear. One reason is that the Women's Health Initiative (WHI) trials of menopausal hormone therapy drew different conclusions for unopposed estrogens and estrogens plus progestins. The former modestly decreased incidence