Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin
Introduction
Combined estrogen plus progestin (E + P) use increased incident breast cancers diagnosed at a more advanced stage compared with placebo use in an average of 5.6 years of follow-up in the Women's Health Initiative (WHI) randomized trial [1], [2]. The diverging incidence rates over time between treatment arms and a trend toward greater effects in women reporting prior menopausal hormone use suggest a role for cumulative hormone exposure. Observational studies, while generally reporting an association between cumulative exposure to combined hormone and breast cancer risk, demonstrate considerable variability in both the magnitude of the effect and the threshold duration of exposure needed [3], [4], [5], [6], [7], [8].
Following publication of the WHI results, the U.S. Food and Drug Administration (FDA) changed the labeling of all estrogen and combined estrogen plus progestin products and recommended using the lowest dose for the shortest duration consistent with treatment objectives [9]. Subsequently, menopausal hormone therapy (HT) use has decreased [10]. However, the high prevalence of vasomotor symptoms at menopause and the limited alternative therapies for such symptoms warrants further exploration of risks and benefits of HT for subgroups of women to further refine the elements of the risks and benefits that may have an impact on therapeutic decision making. To address this issue, more detailed analyses were conducted of overall hormone use, emphasizing cumulative hormone exposure as related to breast cancer risk in the WHI trial of estrogen plus progestin.
Section snippets
Study population, randomization and intervention
Postmenopausal women aged 50–79 years (N = 16,608) with an intact uterus were recruited largely by mass mailing at 40 U.S. clinical centers into this randomized, double-blind, placebo-controlled trial of E + P. Women for whom HT was contraindicated, who were unlikely to be adherent to the assigned regimen or who had a medical condition associated with less than 3-year survival were excluded. HT use at initial screening for eligibility required a 3-month wash out period before baseline testing. All
Hormone use and breast cancer risk factors
Prior HT use selected for a population of women with several characteristics associated with lower breast cancer risk compared to those of never users. Although the differences were small, women with prior hormone use were significantly younger, more often white, had more education, had lower body mass index (BMI) and were more physically active and more likely to have moderate or severe vasomotor symptoms (Table 1). Prior HT users had somewhat fewer pregnancies but were younger at the first
Discussion
The main objective of these analyses was to determine whether the observed differences in E + P effects on breast cancer risk between prior hormone users and never users [1], [2] could be explained by potential confounders of prior hormone use, and if not, to determine whether the observed effect modification supported the hypothesis of increasing risk with longer durations of exposure.
When the influence of total duration of exposure on breast cancer risk incorporates both pre- and
Acknowledgements
The WHI program is funded by the National Heart, Lung and Blood Institute, U.S. Department of Health and Human Services. Wyeth provided study medications (estrogen plus progestin and matching placebo tablets). The authors wish to thank Lieling We for assistance with statistical analyses.
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