Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease

JNCI: Journal of the National Cancer Institute, Oct 2001

The recognition of selective estrogen receptor modulation in the laboratory has resulted in the development of two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, for clinical application in healthy women. SERMs are antiestrogenic in the breast but estrogen-like in the bones and reduce circulating cholesterol levels. SERMs also have different degrees of estrogenicity in the uterus. Tamoxifen is used specifically to reduce the incidence of breast cancer in premenopausal and postmenopausal women at risk for the disease. In contrast, raloxifene is used specifically to reduce the risk of osteoporosis in postmenopausal women at high risk for osteoporosis. The study of tamoxifen and raloxifene (STAR) trial is currently comparing the ability of these SERMs to reduce breast cancer incidence in high-risk postmenopausal women. There is intense interest in understanding the molecular mechanism(s) of action of SERMs at target sites in a woman's body. An understanding of the targeted actions of this novel drug group will potentially result in the introduction of new multifunctional medicines with applications as preventive agents or treatments of breast cancer and endometrial cancer, coronary heart disease, and osteoporosis.

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Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease

Journal of the National Cancer Institute Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease V. Craig Jordan 0 1 Susan Gapstur 0 1 Monica Morrow 0 1 0 Affiliations of authors: V. C. Jordan (Robert H. Lurie Comprehensive Cancer Center), S. Gapstur (Department of Preventive Medicine), M. Morrow (Department of Surgery), Northwestern University Medical School , Chicago , IL. hensive Cancer Center , 710 North Fairbanks Court, Olson Pavilion 8258, Chicago, IL 60611 , USA 1 Oxford University Press The recognition of selective estrogen receptor modulation in the laboratory has resulted in the development of two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, for clinical application in healthy women. SERMs are antiestrogenic in the breast but estrogen-like in the bones and reduce circulating cholesterol levels. SERMs also have different degrees of estrogenicity in the uterus. Tamoxifen is used specifically to reduce the incidence of breast cancer in premenopausal and postmenopausal women at risk for the disease. In contrast, raloxifene is used specifically to reduce the risk of osteoporosis in postmenopausal women at high risk for osteoporosis. The study of tamoxifen and raloxifene (STAR) trial is currently comparing the ability of these SERMs to reduce breast cancer incidence in high-risk postmenopausal women. There is intense interest in understanding the molecular mechanism(s) of action of SERMs at target sites in a woman's body. An understanding of the targeted actions of this novel drug group will potentially result in the introduction of new multifunctional medicines with applications as preventive agents or treatments of breast cancer and endometrial cancer, coronary heart disease, and osteoporosis. [J Natl Cancer Inst 2001;93:1449-57] - It is well established that estrogens and progestins play an important role in breast cell proliferation and in the promotional stage of hormone-responsive tumors. In postmenopausal women, exposure to endogenous steroid hormones, particularly estrogen, has been associated with an increase in the risk of breast cancer ( 1 ). The association between postmenopausal hormone replacement therapy (HRT) and breast cancer risk is more controversial. The results of more than 60 epidemiologic studies of this association are inconsistent, and these inconsistencies have been attributed to issues related to small sample sizes and differences in statistical methodology. To address these problems, the Collaborative Group on Hormonal Factors in Breast Cancer ( 2 ) combined original data from 51 studies and reported a 14% higher risk of breast cancer for women who had ever used compared with those who had never used HRT. Among the current or recent users of HRTfor 5 or more years, the risk of breast cancer was 2.3% higher per year of use compared with nonusers (P<.05); in contrast, among women who had not used hormones for more than 5 years, there was no evidence of an association of duration of HRTuse with breast cancer risk. Because HRTuse must be long-term to prevent osteoporotic fracture, evidence of an association between duration of use and breast cancer risk has particular clinical importance. Recent studies ( 3,4 ) have suggested that combined estrogen replacement therapy (ERT) and progestin may confer a higher risk of breast cancer than ERTalone. In one case?control study (3), unopposed estrogen increased breast cancer risk by 6% (P .18) per 5 years of use. In contrast, per 5 years of use of estrogen plus progestin, the risk of breast cancer was increased by 24% (P .005). These epidemiologic findings are supported by studies in macaque monkeys, in which combined therapy induced greater breast cell proliferation than unopposed estrogen ( 5 ). Other indirect evidence that HRTuse affects the risk of breast cancer comes from studies of mammographic breast density, an independent risk factor for breast cancer ( 6 ). Data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial ( 7 ) were used to examine the associations of breast density with use of conjugated equine estrogen (CEE), CEE plus either cyclic medroxyprogesterone acetate (MPA) for 12 days per month or daily MPA, or CEE plus micronized progesterone for 12 days per month. After 36 months, density increases were found in 2% of the women in the placebo group, in 8% of the women in the unopposed estrogen group, and in more than 18% of the women in each of the other three combined HRTgroups. Most of these increases occurred in the women within 12 months of initiating HRT. Although HRTmay increase the risk of breast cancer, studies ( 8?10 ) have found a lower breast cancer mortality or improved survival among HRTusers compared with nonusers. These findings have been attributed to an increased use of breast cancer screening in women on HRT. In an analysis of data from the Iowa Women?s Health Study, Gapstur e (...truncated)


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Jordan, V. Craig, Gapstur, Susan, Morrow, Monica. Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease, JNCI: Journal of the National Cancer Institute, 2001, pp. 1449-1457, Volume 93, Issue 19, DOI: 10.1093/jnci/93.19.1449