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Indicators of Lifetime Estrogen Exposure: Effect on Breast Cancer Incidence and Interaction With Raloxifene Therapy in the Multiple Outcomes of Raloxifene Evaluation Study Participants

From the Osteoporosis Research Program, Women’s College Hospital, Toronto, Ontario, Canada; Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC; Lilly Research Laboratories, Indianapolis, IN; Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA; and Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, CA.

Address reprint requests to Marc E. Lippman, MD, Department of Internal Medicine, 3101 Taubman Center, University of Michigan Health System, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0368; email: lippmanm{at}umich.edu

PURPOSE: To test the hypothesis that risk factors related to lifetime estrogen exposure predict breast cancer incidence and to test if any subgroups experience enhanced benefit from raloxifene.

PATIENTS AND METHODS: Postmenopausal women with osteoporosis (N = 7,705), enrolled onto the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, were randomly assigned to receive placebo, raloxifene 60 mg/d, or raloxifene 120 mg/d for 4 years. Breast cancer risk was analyzed by the following baseline characteristics indicative of estrogen exposure: previous hormone replacement therapy, prevalent vertebral fractures, family history of breast cancer, estradiol level, bone mineral density (BMD), body mass index, and age at menopause. Therapy-by-subgroup interactions were assessed using a logistic regression model.

RESULTS: Overall, women with the highest one-third estradiol levels ( 12 pmol/L) had a 2.07-fold increased invasive breast cancer risk compared with women with lower levels. Raloxifene significantly reduced breast cancer risk in both the low- and high-estrogen subgroups for all risk factors examined (P < .05 for each comparison). The women with the highest BMD and those with a family history of breast cancer experienced a significantly greater therapy benefit with raloxifene, compared with the two thirds of patients with lower BMD or those without a family history, respectively; the subgroup-by-therapy interactions were significant (P = .005 and P = .015, respectively).

CONCLUSION: The MORE trial confirms that increased lifetime estrogen exposure increases breast cancer risk. Raloxifene therapy reduces breast cancer risk in postmenopausal osteoporotic women regardless of lifetime estrogen exposure, but the reduction is greater in those with higher lifetime exposure to estrogen.

Supported by Eli Lilly and Company, Indianapolis, IN.

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