Editorial
Postmenopausal Estrogen Replacement and Breast Cancer
N Engl J Med 1989; 321:319-320August 3, 1989DOI: 10.1056/NEJM198908033210510
- Article
AN epidemiologic study in this issue of the Journal 1 could change the way we think about postmenopausal hormone replacement. In the report, 23,244 Swedish women identified from prescription records for the noncontraceptive use of estrogen were followed for an average of six years, and their risk of breast cancer was compared with that of other women from the same geographic area. Cases of breast cancer in the population were identified from a cancer registry. In the combined analysis of all women following all hormone-replacement regimens, estrogen use was not associated with an increased risk of breast cancer. Nevertheless, at least nine years' use of estradiol, the most commonly used noncontraceptive estrogen in Sweden, carried nearly double the risk of breast cancer. No increase in risk was found with conjugated estrogens or other estrogens, even when they were used for many years, but the number of women treated with such estrogens was relatively small and provided little power to detect differences after prolonged use.
Evidence that estrogen increases the risk of breast cancer has been surprisingly difficult to obtain. Clinical and epidemiologic studies and studies in animals strongly suggest that endogenous estrogen plays a part in causing breast cancer.2 If so, exogenous estrogen should be a potent promoter of breast cancer. Although more than 20 case–control and prospective studies of the relation of breast cancer and noncontraceptive estrogen use have failed to demonstrate the expected association,2 relatively few women in these studies used estrogen for extended periods. Studies of the use of diethylstilbestrol and oral contraceptives suggest that a long exposure or latency may be necessary to show any association between hormone use and breast cancer.3 , 4 In the Swedish study, only six years of follow-up was needed to demonstrate an increased risk of breast cancer with the postmenopausal use of estradiol. It should be noted, however, that half the women in the subgroup that provided detailed data on the duration of hormone use had taken estrogen for many years before their base-line prescription status was defined. The duration of estrogen exposure in these women before the diagnosis of breast cancer was probably seriously underestimated; a short latency cannot be attributed to estradiol on the basis of these data. Other recent studies of the use of noncontraceptive estrogen5 6 7 suggest a slightly increased risk of breast cancer after 15 to 20 years' use.
The most provocative finding of the Swedish study is the fourfold increase in the risk of breast cancer in women after more than four years' use of estrogen plus a progestin. Readers should note that the 95 percent confidence intervals (0.9 to 22.4) for this association are very wide and include 1 and that the association was found after multiple subgroup comparisons for which, apparently, no statistical correction was made. Nevertheless, these results support the hypothesis of Key and Pike8 that estrogen plus progestin would be more carcinogenic than estrogen alone. They are also compatible with a large population-based case–control study from Denmark,9 which found sequential therapy with estrogen and progestin to be possibly associated with an increased risk of breast cancer (relative risk, 1.36; 95 percent confidence interval, 0.98 to 1.87), but no increased risk with estrogen use overall.
In contrast, other studies suggest that an estrogen–progestin regimen reduces the risk of breast cancer. In a very large and widely quoted case series, women who received both estrogen and progestin had a significantly reduced risk of breast cancer as compared with women not receiving hormone treatment.10 This association, in the opposite direction and statistically stronger than the results reported here, may have been confounded by bias in treatment selection, however. If physicians were less likely to prescribe estrogen (alone or in combination) to women with a family history of breast cancer (or other risk factors for breast cancer), these results might follow. Randomized clinical trials are designed to avoid such known and unknown biases. In the only randomized placebo-controlled trial of extended hormone replacement and breast-cancer risk, 168 institutionalized women received daily placebo or conjugated estrogen (2.5 mg) and cyclic medroxyprogesterone (10 mg). After 10 years there was no breast cancer in the women treated with hormone as compared with a 5 percent incidence in the women given placebo (P = 0.05).11
The addition of a progestin to estrogen is widely recommended for long-term use on the grounds that this combination is necessary to prevent endometrial hyperplasia and uterine cancer. Although unopposed estrogen (primarily conjugated estrogen) has been used in the United States for more than 20 years, the combination of progestin and estrogen in postmenopausal women was not used widely until the 1980s. Concern has been expressed that adding a progestin may negate the strongly suspected (and quantitatively much greater) benefit of unopposed estrogen in cardiovascular disease.12 Now a possibly increased risk of breast cancer in women receiving postmenopausal hormone replacement must be considered in the risk–benefit equation of such treatment, particularly in view of the fact that uterine cancer is less common and less lethal than breast cancer.
For the average North American woman, who will be postmenopausal for one third of her life, the benefits of estrogen seem strongly established. In addition to its unequivocal value for the relief of menopausal symptoms, the long-term use of postmenopausal estrogen can prevent osteoporosis and its debilitating or fatal consequences. The use of estrogen must also be considered in the light of a possible 50 percent reduction in the risk of cardiovascular disease and the possibility of a nearly doubled risk of breast cancer. In this decade the increased risk of endometrial cancer associated with estrogen use led to the frequent addition of a progestin to estrogen-replacement therapy, which further complicates the tallying of risks and benefits.
Prolonged hormone replacement is being used to prevent, not treat, disease. The unresolved issues of the relative risks and benefits demand our immediate attention. In the meantime, the paper by Bergkvist et al.1 serves to demonstrate that more attention needs to be focused on extended postmenopausal use of hormones. In my opinion, the data are not conclusive enough to warrant any immediate change in the way we approach hormone replacement, but they do show the need for additional research. Biologic and epidemiologic studies are needed to define the causes of breast cancer and to determine the safest form of estrogen replacement.
Elizabeth Barrett-Connor, M.D.
University of California, San Diego La Jolla, CA 92093- References
References
1
Bergkvist
Full Text | Web of Science | Medline2
Kelsey
Web of Science | Medline3
Greenberg
Full Text | Web of Science | Medline4
Kay
CrossRef | Web of Science | Medline5
Brinton
CrossRef | Web of Science | Medline6
Wingo
CrossRef | Web of Science | Medline7
La Vecchia
CrossRef | Web of Science | Medline8
Key
CrossRef | Medline9
Ewertz
CrossRef | Web of Science | Medline10
Gambrell
Web of Science | Medline11
Nachtigall
CrossRef | Web of Science | Medline12
Barrett-Connor
Web of Science | Medline
- Citing Articles (21)
Citing Articles
1
Avrum Z. Bluming, Carol Tavris. (2009) Hormone Replacement Therapy: Real Concerns and False Alarms. The Cancer Journal 15:2, 93-104
2
Robert Lindsay, Felicia Cosman. The Pharmacology of Estrogens in Osteoporosis. In: Principles of Bone Biology. Elsevier, 2008:1769-1775.
3
Cora E. Lewis, Janet Y. Groff, Carla J. Herman, Robert E. McKeown, Lynne S. Wilcox. (2000) Overview of Women's Decision Making Regarding Elective Hysterectomy, Oophorectomy, and Hormone Replacement Therapy. Journal of Women's Health & Gender-Based Medicine 9:supplement 2, 5-14
4
Peter W. F. Wilson. (1999) Metabolic risk factors for coronary heart disease: current and future prospects. Current Opinion in Cardiology 14:2, 176
5
DOMINIQUE DE ZIEGLER, RENATO FANCHIN, MARC MASSONNEAU, CHRISTINE BERGERON, RENÉ FRYDMAN, PHILIPPE BOUCHARD. (1994) Hormonal Control of Endometrial Receptivity.. Annals of the New York Academy of Sciences 734:1 The Human End, 209-220
6
Pascal Pujol, Susan G. Hilsenbeck, Gary C. Chamness, Richard M. Elledge. (1994) Rising levels of estrogen receptor in breast cancer over 2 decades. Cancer 74:5, 1601-1606
7
Elina Hemminki, Päivi Topo, Maili Malin, Ilka Kangas. (1993) Physicians' views on hormone therapy around and after menopause. Maturitas 16:3, 163-173
8
Douglas J. Marchant. (1993) Estrogen-replacement therapy after breast cancer risks versus benefits. Cancer 71:S6, 2169-2176
9
David Ingram. (1991) PREVENTING BREAST CANCER: IS IT POSSIBLE?. ANZ Journal of Surgery 61:12, 884-891
10
Anna N.A. Tosteson, Milton C. Weinstein. (1991) 12 Cost-effectiveness of hormone replacement therapy after the menopause. Baillière's Clinical Obstetrics and Gynaecology 5:4, 943-959
11
Richard R. Love. (1991) Antiestrogen chemoprevention of breast cancer: Critical issues and research. Preventive Medicine 20:1, 64-78
12
K.-W. von Eickstedt. Sex hormones and related compounds including hormonal contraceptives. Elsevier, 1991:426-443.
13
C. VULLO, V. SANCTIS, M. KATZ, B. WONKE, A. V. HOFFBRAND, B. BAGNI, T. TORRESANI, G. TOLIS, M. MASIERO, A. PALMA, L. BORGATTI. (1990) Endocrine Abnormalities in Thalassemia. Annals of the New York Academy of Sciences 612:1 Sixth Cooley', 293-310
14
D. Sömjen, A. Harell, N. Jaccard, Y. Weisman, A.M. Kaye. (1990) Reciprocal modulation by sex steroid and calciotrophic hormones of skeletal cell proliferation. The Journal of Steroid Biochemistry and Molecular Biology 37:4, 491-499
15
I. Craig Henderson. (1990) What can a woman do about her risk of dying of breast cancer?. Current Problems in Cancer 14:4, 165-230
16
Louis Weinstein, Chhanda Bewtra, J. Chris Gallagher. (1990) Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient. American Journal of Obstetrics and Gynecology 162:6, 1534-1542
17
C. Conrad Johnston, L. Joseph Melton. (1990) Guidelines for osteoporosis prophylaxis. Journal of Bone and Mineral Research 5:5, 423-424
18
(1990) New treatments for osteoporosis. The Lancet 335:8697, 1065-1066
19
Kenneth S. McCarty. (1989) Proliferative stimuli in the normal breast: Estrogens or progestins?. Human Pathology 20:12, 1137-1138
20
John Studd. (1989) HORMONE REPLACEMENT THERAPY AND BREAST CANCER. The Lancet 334:8672, 1164
21
(1989) HORMONE REPLACEMENT THERAPY AND CANCER: IS THERE CAUSE FOR CONCERN?. The Lancet 334:8659, 368
