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]
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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)