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Does estrogen replacement therapy reduce the risk of fatal breast cancer in postmenopausal women?
Maturitas 27 (1997) 105 – 108
Guest editorial
Does estrogen replacement therapy reduce the risk of fatal breast cancer in postmenopausal women? Dawn B. Willis American Cancer Society, Inc., Atlanta, GA, 30329, USA Accepted 10 March 1997
After decades of epidemiological research, the association of postmenopausal estrogen replacement therapy (ERT)1 with breast cancer remains controversial. Although numerous meta-analyses concur that the relative risk of developing breast cancer in women who have ever taken estrogen is increased by 25–30% after long-term use ( \ 10 years) [1], a meta-analysis is only as accurate as its component studies. Very few of the earlier analyses supply mammographic screening data, and more frequent screening by hormone users might result in a spuriously high detection rate. Other authors have reviewed the epidemiologic literature and concluded that observational studies finding an increased risk of breast cancer associated with ERT might have been influenced by surveillance bias, independent risk factors for breast cancer among ERT users, and the small numbers of women in the long-term group [2,3]. 1
This editorial will refer only to estrogen replacement, since most of the data were collected before progestins became routinely used. Available evidence indicates that, in contrast to the effect on endometrial cancer, progestins are neutral regarding breast cancer risk [11,13].
Even assuming the worst-case scenario, a 30% increase in relative risk will only translate into a 3% increase in absolute risk, if one uses the value of 10% for the absolute risk of developing breast cancer between ages 50 and 80 [4]. Put another way, out of every 100 users of ERT, 13 will develop breast cancer between the ages of 50 and 80 years, but only three of those 13 cases will be related to their hormone use. Since only onefourth of breast cancer patients actually die of their disease, theoretically fewer than one woman in 100 will die of breast cancer related to the use of exogenous hormones. This is a small increase in risk when compared with the 30 women in that same group of 100 hormone users who will be spared an early death from coronary heart disease [5], not to mention the improved quality of life and possibly decreased risk of colon cancer [6] and Alzheimer’s disease [7] that may accompany postmenopausal hormone use. Recent epidemiological evidence suggests that even that one theoretical death in 100 may not occur in actuality. As part of the American Cancer Society’s Cancer Prevention Study II (CPS II), a large prospective cohort of 422 373 post-
0378-5122/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 8 - 5 1 2 2 ( 9 7 ) 0 0 0 2 8 - 5
106
D.B. Willis / Maturitas 27 (1997) 105–108
menopausal women was queried as to estrogen use in 1982 and followed via the US National Death Index and state death certificates through 1991 [8]. The CPS II analysis revealed a 16% decrease in the relative risk of death from breast cancer in women who had ever used estrogen replacement therapy. This study is not the first to report a decreased risk of breast cancer deaths in estrogen users. Earlier investigations by Hunt et al. [9] and Henderson et al. [10] also observed that women who had ever used estrogen were less likely to die of breast cancer than non-users. Only one study, the Nurses’ Health Study of over 69 000 postmenopausal nurses, has found an association of estrogen replacement therapy with increased mortality from breast cancer, and then only in a relatively small subgroup of women — current users of 5 years or longer [11]. Even in the Nurse’s Health Study, former users had no increased risk of fatal breast cancer, no matter how long the duration of use. Statistical association does not equal causation, and epidemiologic studies must subsequently be supported or refuted by basic science and clinical investigation. Is there a plausible biological explanation for the decreased risk of fatal breast cancer associated with ERT use? Many researchers believe that the decreased mortality can be explained by the ‘healthy estrogen user effect’ [12]. Simply stated, women who take estrogen pursue healthier lifestyles than those who do not. They are thinner, less likely to smoke, more likely to exercise, and must participate in regular breast cancer screening programs. Increased screening among ERT users might account for both increased incidence and decreased mortality [13]. The conventional wisdom is that doctors are less likely to prescribe estrogen to women considered at high risk for breast cancer — those with family histories or benign breast cysts. However, in the CPS II study, there was no evidence that this was so; women in these two categories were just as likely to take estrogen as anyone else [8]. In CPS II, there was a moderate interaction of a self-reported history of breast cysts with estrogen, i.e. women with cysts did not show a decreased risk of fatal breast cancer with estrogen use, but remained at a 41% increased relative risk. In
addition, women with family histories (breast cancer in a first degree relative) had a 45% increased risk of breast cancer, and this risk was lowered by 16% (to 37%) in estrogen users, the same relative decrease observed in women without family histories (from 1.0 to 0.84). However, since the age at which the mother or sister developed breast cancer was not factored into the analysis, the population of breast cancer cases classified as familial was undoubtedly diluted by sporadic cases among first degree relatives. The results should not be interpreted to assume that estrogen is suitable for women with a known genetic susceptibility. We do not know the answer to that question. Women on ERT have a higher incidence of in situ tumors, and invasive cancers in ERT users are usually detected at an earlier stage and smaller size [14]. But, surprisingly, even after correcting for size and stage, women on ERT have as good as or better prognosis than women not on estrogen [15,16]. This is somewhat analogous to the situation regarding endometrial cancer in ERT users. Women taking unopposed estrogen were about 10 times more likely to develop endometrial cancer than women who were not taking replacement estrogen [17]. Yet, ERT users receiving a diagnosis of endometrial cancer were four times less likely to die from their disease than endometrial cancer patients who were not taking estrogen [17]. Although the effects of postmenopausal hormone replacement on the uterus and breast are not the same, just as the effects of endogenous hormones vary with the target tissue, this phenomenon established a precedent for estrogen’s promoting the growth of less aggressive tumors. It is obvious that ovarian function, in particular the total number of ovarian cycles a woman undergoes during her lifetime, is related to increased risk of breast cancer. It is by no means as certain that postmenopausal hormone therapy, which may supply different chemical forms and different dosages of estrogen than endogenous hormones, induces the same degree of risk. A case could easily be made that a constant, low level of estrogen is much better for a woman than the fluctuating levels of a ‘normal’ menstrual cycle. (‘Normal’ is in because the biologically natural state for a woman of reproductive years is pregnant or lactating, not menstruating!)
D.B. Willis / Maturitas 27 (1997) 105–108
One of the most interesting observations of the CPS II study was that estrogen users who underwent an early natural menopause, i.e. before the age of 50, had about half the risk of fatal breast cancer — not only compared to non-users of all ages, but even when compared with women who experienced early menopause but who did not take estrogen [8]. It has long been accepted that early menopause reduces the risk of breast cancer, but the CPS II results suggest that estrogen use decreased the risk of death from the disease even more than early menopause alone. Women on ERT who underwent menopause at the usual age (50 + years) did not have a reduced risk of death from breast cancer, but neither was their risk increased. The evidence from many observational studies suggests that ERT slightly increases the risk of developing in situ or other non-aggressive tumors, while at the same time reduces the chances that an aggressive tumor will develop. In other words, estrogen may prolong tumors in a ‘pre-metastatic state’ [16]. Is it possible that estrogen could increase the incidence of breast cancer and decrease mortality at the same time? Perhaps. Both estrogen and tamoxifen have been reported to increase the expression of the tumor suppressor gene BRCA1 in breast cancer cells in vitro [18]. Estrogen is not generally considered a carcinogen in the sense that it causes the original genetic insult; its role in cancer is believed to be that of a tumor promoter. Estrogen increases mitosis, and every time a cell divides, there is an opportunity for genetic errors to be made. Indeed, mistakes during replication occur all the time, but are usually corrected by active cellular repair mechanisms. The natural role of the BRCA1 protein may be to counteract the proliferative effects of estrogen by controlling tumor spread. Although this hypothesis would advise caution in prescribing estrogen to women with BRCA1 or BRCA2 mutations, it would also suggest that estrogen might be considered for the relief of menopausal symptoms in breast cancer survivors without genetic susceptibility. As more and more younger women are surviving their disease, premature menopause is becoming an important quality of life issue [19]. Clinical trials to determine the effect of hormone replacement in breast cancer survivors are underway.
107
The estrogen-mediated competition between proliferation and tumor suppression is only a hypothesis, but it is one that can be tested in the laboratory and clinic. Larger and more detailed pathological and molecular genetic studies of breast tumors in estrogen users vs. non-users are clearly called for. The only clinical trial of hormone replacement therapy that has been reported so far, a prospective, double-blinded study of 84 matched pairs of continuously hospitalized women, was too small to provide statistically meaningful data, but no women who used hormones developed breast cancer after 22 years of follow-up versus 11.5% cases of breast cancer in the control group [20]. The US Women’s Health Initiative, scheduled to report in 2006, will hopefully provide the first data from a large randomized trial on the risks and benefits of hormone replacement. Only a properly designed randomized trial can settle the question of whether the decreased risk of fatal breast cancer associated with postmenopausal estrogen use is real, and if so, whether it is due to a biological difference in the tumors or to a sociological difference in the users.
References [1] Smith HO, Kammerer-Doak DN, Barbo DM, Sarto GE. Hormone replacement therapy in the menopause: a pro opinion. CA Cancer J Clin 1996; 46: 343 – 363. [2] MacLennan AH, Smith M. Hormone replacement therapy and breast cancer: what are the facts? Med J Aust 1995; 163: 483 – 485. [3] Speroff L. Postmenopausal hormone therapy and breast cancer. Obstet Gynecol 1996; 87(2): 44S – 54S. [4] Miller BA, Ries LAG, Hankey BF et al. (eds) SEER Cancer Statistics Review: 1973 – 1990, National Cancer Institute. NIH Pub. No. 93-2789, 1993; p. IV. 13. [5] Grady D, Rubin SM, Petitti DB et al. Hormone therapy to prevent disease and prolong life in post-menopausal women. Ann Intern Med 1992; 117: 1016 – 1037. [6] Newcomb PA, Storer BE. Postmenopausal hormone use and risk of large bowel cancer. J Natl Cancer Inst 1995; 87: 1067 – 1071. [7] Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 1994; 140: 256 – 261. Willis DB, Calle EE, Miracle-McMahill HL, Heath CW Jr. Estrogen replacement therapy and risk of fatal breast
D.B. Willis / Maturitas 27 (1997) 105–108
108
[9]
[10]
[11]
[12]
[13]
[14]
cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control 1996; 7: 449 – 457. Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol 1990; 97: 1080– 1086. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991; 151: 75–78. Colditz GA, Hankinson SE, Hunter DJ et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589– 1593. Sturgeon SR, Schairer C, Brinton LA, Pearson T, Hoover RN. Evidence of a healthy estrogen user survivor effect. Epidemiology 1995; 6: 227–230. Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN. Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes Control 1994; 5: 491–500. Harding C, Knox WF, Faragher EB, Baildam A, Bundred NJ. Hormone replacement therapy and tumour grade in
.
[15]
[16]
[17]
[18]
[19]
[20]
breast cancer: prospective study in screening unit. Br Med J 1996; 312: 1646 – 1647. Bergvist L, Adami HO, Persson I, Bergstrom R, Druseno UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989; 130: 221 – 228. Bonnier P, Romain S, Giacalone PL, Laffargue F, Martin PM, Peana L. Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstet Gynecol 1995; 85: 11 – 17. Schwartzbaum JA, Hulka BS, Fowler WC, Kaufman DG, Hoberman D. The influence of exogenous estrogen use on survival after diagnosis of endometrial cancer. Am J Epidemiol 1987; 126: 851 – 860. Jensen RA, Thompson ME, Jetton TL et al. BRCA1 is secreted and exhibits properties of a granin. Nature Genet 1996; 12: 303 – 308. Cobleigh MA, Berris RF, Bush T et al. Estrogen replacement therapy in breast cancer survivors. A time for change. J Am Med Assoc 1994; 272: 540 – 545. Nachtigall MJ, Smilen SW, Nachtigall RD, Nachtigall PH, Nachtigall LE. Incidence of breast cancer in a 22-year study of women estrogen-progestin replacement therapy. Obstet Gynecol 1992; 80: 827 – 830.
Guest editorial
Does estrogen replacement therapy reduce the risk of fatal breast cancer in postmenopausal women? Dawn B. Willis American Cancer Society, Inc., Atlanta, GA, 30329, USA Accepted 10 March 1997
After decades of epidemiological research, the association of postmenopausal estrogen replacement therapy (ERT)1 with breast cancer remains controversial. Although numerous meta-analyses concur that the relative risk of developing breast cancer in women who have ever taken estrogen is increased by 25–30% after long-term use ( \ 10 years) [1], a meta-analysis is only as accurate as its component studies. Very few of the earlier analyses supply mammographic screening data, and more frequent screening by hormone users might result in a spuriously high detection rate. Other authors have reviewed the epidemiologic literature and concluded that observational studies finding an increased risk of breast cancer associated with ERT might have been influenced by surveillance bias, independent risk factors for breast cancer among ERT users, and the small numbers of women in the long-term group [2,3]. 1
This editorial will refer only to estrogen replacement, since most of the data were collected before progestins became routinely used. Available evidence indicates that, in contrast to the effect on endometrial cancer, progestins are neutral regarding breast cancer risk [11,13].
Even assuming the worst-case scenario, a 30% increase in relative risk will only translate into a 3% increase in absolute risk, if one uses the value of 10% for the absolute risk of developing breast cancer between ages 50 and 80 [4]. Put another way, out of every 100 users of ERT, 13 will develop breast cancer between the ages of 50 and 80 years, but only three of those 13 cases will be related to their hormone use. Since only onefourth of breast cancer patients actually die of their disease, theoretically fewer than one woman in 100 will die of breast cancer related to the use of exogenous hormones. This is a small increase in risk when compared with the 30 women in that same group of 100 hormone users who will be spared an early death from coronary heart disease [5], not to mention the improved quality of life and possibly decreased risk of colon cancer [6] and Alzheimer’s disease [7] that may accompany postmenopausal hormone use. Recent epidemiological evidence suggests that even that one theoretical death in 100 may not occur in actuality. As part of the American Cancer Society’s Cancer Prevention Study II (CPS II), a large prospective cohort of 422 373 post-
0378-5122/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 8 - 5 1 2 2 ( 9 7 ) 0 0 0 2 8 - 5
106
D.B. Willis / Maturitas 27 (1997) 105–108
menopausal women was queried as to estrogen use in 1982 and followed via the US National Death Index and state death certificates through 1991 [8]. The CPS II analysis revealed a 16% decrease in the relative risk of death from breast cancer in women who had ever used estrogen replacement therapy. This study is not the first to report a decreased risk of breast cancer deaths in estrogen users. Earlier investigations by Hunt et al. [9] and Henderson et al. [10] also observed that women who had ever used estrogen were less likely to die of breast cancer than non-users. Only one study, the Nurses’ Health Study of over 69 000 postmenopausal nurses, has found an association of estrogen replacement therapy with increased mortality from breast cancer, and then only in a relatively small subgroup of women — current users of 5 years or longer [11]. Even in the Nurse’s Health Study, former users had no increased risk of fatal breast cancer, no matter how long the duration of use. Statistical association does not equal causation, and epidemiologic studies must subsequently be supported or refuted by basic science and clinical investigation. Is there a plausible biological explanation for the decreased risk of fatal breast cancer associated with ERT use? Many researchers believe that the decreased mortality can be explained by the ‘healthy estrogen user effect’ [12]. Simply stated, women who take estrogen pursue healthier lifestyles than those who do not. They are thinner, less likely to smoke, more likely to exercise, and must participate in regular breast cancer screening programs. Increased screening among ERT users might account for both increased incidence and decreased mortality [13]. The conventional wisdom is that doctors are less likely to prescribe estrogen to women considered at high risk for breast cancer — those with family histories or benign breast cysts. However, in the CPS II study, there was no evidence that this was so; women in these two categories were just as likely to take estrogen as anyone else [8]. In CPS II, there was a moderate interaction of a self-reported history of breast cysts with estrogen, i.e. women with cysts did not show a decreased risk of fatal breast cancer with estrogen use, but remained at a 41% increased relative risk. In
addition, women with family histories (breast cancer in a first degree relative) had a 45% increased risk of breast cancer, and this risk was lowered by 16% (to 37%) in estrogen users, the same relative decrease observed in women without family histories (from 1.0 to 0.84). However, since the age at which the mother or sister developed breast cancer was not factored into the analysis, the population of breast cancer cases classified as familial was undoubtedly diluted by sporadic cases among first degree relatives. The results should not be interpreted to assume that estrogen is suitable for women with a known genetic susceptibility. We do not know the answer to that question. Women on ERT have a higher incidence of in situ tumors, and invasive cancers in ERT users are usually detected at an earlier stage and smaller size [14]. But, surprisingly, even after correcting for size and stage, women on ERT have as good as or better prognosis than women not on estrogen [15,16]. This is somewhat analogous to the situation regarding endometrial cancer in ERT users. Women taking unopposed estrogen were about 10 times more likely to develop endometrial cancer than women who were not taking replacement estrogen [17]. Yet, ERT users receiving a diagnosis of endometrial cancer were four times less likely to die from their disease than endometrial cancer patients who were not taking estrogen [17]. Although the effects of postmenopausal hormone replacement on the uterus and breast are not the same, just as the effects of endogenous hormones vary with the target tissue, this phenomenon established a precedent for estrogen’s promoting the growth of less aggressive tumors. It is obvious that ovarian function, in particular the total number of ovarian cycles a woman undergoes during her lifetime, is related to increased risk of breast cancer. It is by no means as certain that postmenopausal hormone therapy, which may supply different chemical forms and different dosages of estrogen than endogenous hormones, induces the same degree of risk. A case could easily be made that a constant, low level of estrogen is much better for a woman than the fluctuating levels of a ‘normal’ menstrual cycle. (‘Normal’ is in because the biologically natural state for a woman of reproductive years is pregnant or lactating, not menstruating!)
D.B. Willis / Maturitas 27 (1997) 105–108
One of the most interesting observations of the CPS II study was that estrogen users who underwent an early natural menopause, i.e. before the age of 50, had about half the risk of fatal breast cancer — not only compared to non-users of all ages, but even when compared with women who experienced early menopause but who did not take estrogen [8]. It has long been accepted that early menopause reduces the risk of breast cancer, but the CPS II results suggest that estrogen use decreased the risk of death from the disease even more than early menopause alone. Women on ERT who underwent menopause at the usual age (50 + years) did not have a reduced risk of death from breast cancer, but neither was their risk increased. The evidence from many observational studies suggests that ERT slightly increases the risk of developing in situ or other non-aggressive tumors, while at the same time reduces the chances that an aggressive tumor will develop. In other words, estrogen may prolong tumors in a ‘pre-metastatic state’ [16]. Is it possible that estrogen could increase the incidence of breast cancer and decrease mortality at the same time? Perhaps. Both estrogen and tamoxifen have been reported to increase the expression of the tumor suppressor gene BRCA1 in breast cancer cells in vitro [18]. Estrogen is not generally considered a carcinogen in the sense that it causes the original genetic insult; its role in cancer is believed to be that of a tumor promoter. Estrogen increases mitosis, and every time a cell divides, there is an opportunity for genetic errors to be made. Indeed, mistakes during replication occur all the time, but are usually corrected by active cellular repair mechanisms. The natural role of the BRCA1 protein may be to counteract the proliferative effects of estrogen by controlling tumor spread. Although this hypothesis would advise caution in prescribing estrogen to women with BRCA1 or BRCA2 mutations, it would also suggest that estrogen might be considered for the relief of menopausal symptoms in breast cancer survivors without genetic susceptibility. As more and more younger women are surviving their disease, premature menopause is becoming an important quality of life issue [19]. Clinical trials to determine the effect of hormone replacement in breast cancer survivors are underway.
107
The estrogen-mediated competition between proliferation and tumor suppression is only a hypothesis, but it is one that can be tested in the laboratory and clinic. Larger and more detailed pathological and molecular genetic studies of breast tumors in estrogen users vs. non-users are clearly called for. The only clinical trial of hormone replacement therapy that has been reported so far, a prospective, double-blinded study of 84 matched pairs of continuously hospitalized women, was too small to provide statistically meaningful data, but no women who used hormones developed breast cancer after 22 years of follow-up versus 11.5% cases of breast cancer in the control group [20]. The US Women’s Health Initiative, scheduled to report in 2006, will hopefully provide the first data from a large randomized trial on the risks and benefits of hormone replacement. Only a properly designed randomized trial can settle the question of whether the decreased risk of fatal breast cancer associated with postmenopausal estrogen use is real, and if so, whether it is due to a biological difference in the tumors or to a sociological difference in the users.
References [1] Smith HO, Kammerer-Doak DN, Barbo DM, Sarto GE. Hormone replacement therapy in the menopause: a pro opinion. CA Cancer J Clin 1996; 46: 343 – 363. [2] MacLennan AH, Smith M. Hormone replacement therapy and breast cancer: what are the facts? Med J Aust 1995; 163: 483 – 485. [3] Speroff L. Postmenopausal hormone therapy and breast cancer. Obstet Gynecol 1996; 87(2): 44S – 54S. [4] Miller BA, Ries LAG, Hankey BF et al. (eds) SEER Cancer Statistics Review: 1973 – 1990, National Cancer Institute. NIH Pub. No. 93-2789, 1993; p. IV. 13. [5] Grady D, Rubin SM, Petitti DB et al. Hormone therapy to prevent disease and prolong life in post-menopausal women. Ann Intern Med 1992; 117: 1016 – 1037. [6] Newcomb PA, Storer BE. Postmenopausal hormone use and risk of large bowel cancer. J Natl Cancer Inst 1995; 87: 1067 – 1071. [7] Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 1994; 140: 256 – 261. Willis DB, Calle EE, Miracle-McMahill HL, Heath CW Jr. Estrogen replacement therapy and risk of fatal breast
D.B. Willis / Maturitas 27 (1997) 105–108
108
[9]
[10]
[11]
[12]
[13]
[14]
cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control 1996; 7: 449 – 457. Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol 1990; 97: 1080– 1086. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991; 151: 75–78. Colditz GA, Hankinson SE, Hunter DJ et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589– 1593. Sturgeon SR, Schairer C, Brinton LA, Pearson T, Hoover RN. Evidence of a healthy estrogen user survivor effect. Epidemiology 1995; 6: 227–230. Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN. Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes Control 1994; 5: 491–500. Harding C, Knox WF, Faragher EB, Baildam A, Bundred NJ. Hormone replacement therapy and tumour grade in
.
[15]
[16]
[17]
[18]
[19]
[20]
breast cancer: prospective study in screening unit. Br Med J 1996; 312: 1646 – 1647. Bergvist L, Adami HO, Persson I, Bergstrom R, Druseno UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989; 130: 221 – 228. Bonnier P, Romain S, Giacalone PL, Laffargue F, Martin PM, Peana L. Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstet Gynecol 1995; 85: 11 – 17. Schwartzbaum JA, Hulka BS, Fowler WC, Kaufman DG, Hoberman D. The influence of exogenous estrogen use on survival after diagnosis of endometrial cancer. Am J Epidemiol 1987; 126: 851 – 860. Jensen RA, Thompson ME, Jetton TL et al. BRCA1 is secreted and exhibits properties of a granin. Nature Genet 1996; 12: 303 – 308. Cobleigh MA, Berris RF, Bush T et al. Estrogen replacement therapy in breast cancer survivors. A time for change. J Am Med Assoc 1994; 272: 540 – 545. Nachtigall MJ, Smilen SW, Nachtigall RD, Nachtigall PH, Nachtigall LE. Incidence of breast cancer in a 22-year study of women estrogen-progestin replacement therapy. Obstet Gynecol 1992; 80: 827 – 830.