CancerCausesand Control,3, 475 - 479
Noncontraceptive hormone use and risk of breast cancer
C. Paul Yang, Janet R. Daling, Pierre R. Band, Richard P. Gallagher, Emily White, and Noel S. Weiss (Received 29 April 1992;accepted in revisedform 16June 1992) All British Columbia (Canada) women under 75 years of age who were diagnosed with breast cancer during 1988-89 were asked to complete a postal questionnaire which included detailed information on menopausal estrogen use. Controls were drawn from the Provincial Voters List, matched by five-year age category to the cases. The present analysis consists of 699 cases and 685 controls who were postmenopausal due to natural causes or to a hysterectomy. There was no overall increase in risk of breast cancer associated with ever-use of unopposed estrogen (odds ratio [OR] = 1.0, 95 percent confidence interval [CI] -- 0.8-1.3). For estrogen use of 10 years or longer, the relative risk [RR] was 1.6 (CI = 1.1-2.5). The risk estimate for current users was somewhat elevated (OR = 1.4, CI = 1.0-2.0). Compared with women who never used hormone preparations, women who had used estrogen plus progestogen had an R R of 1.2 (CI = 0.6-2.2). O u r results suggest that ever-use of estrogen, with or without progestogen, does not appreciably increase the risk of breast cancer. However, long-term and recent use of unopposed estrogen may be associated with a moderately increased risk.
Key words: Breast cancer, Canada, estrogens, progesterone.
Introduction Estrogens are used widely to alleviate menopausal symptoms and to prevent osteoporosis. Any increase in risk for breast cancer associated with this therapy could have a significant public health impact. Epidemiologic studies of menopausal estrogen replacement and the risk of breast cancer have yielded conflicting results. T M While most investigators have found no overall increase in risk, a few studies have reported a small elevation in risk associated with any use of estrogen. 15,19,26,3°Long-term estrogen users have been found
to be at an increased risk of breast cancer by some authors 9d4,21,24but not by others. 13,18,3°Results from the six studies that have investigated the effect of progestogen supplementation on the risk of breast cancer are similarly contradictory. 21;4,28-31We analyzed data from a population-based case-control study conducted in British Columbia (BC), Canada, to evaluate the influence of estrogen therapy, with or without progestogen, on the subsequent risk of breast cancer.
Drs Yang and Band, and Mr Gallagherare with the British Columbia CancerAgency, Vancouver, British Columbia, Canada. Authors are also affiliated with the School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA (Drs Yang, Daling, White, and Weiss),and the Fred Hutchinson CancerResearch Center, Seattle, WA, USA (Drs Daling, White, and Weiss).Address correspondenceto Mr Gallagher, Division of Epidemiology, Biometry and Occupational Oncology, British Columbia Cancer Agency, 600 West lOth Avenue, Vancouver, BC, Canada, VSZ 4E6. Thisproject isfunded partially by Health and Welfare Canada, Grant #6610-1834-55and hy Workers Compensation Board of BC. © 1992 Rapid Communications of Oxford Ltd
Cancer Causes and Control. Vol 3. 1992
475
C P. Yang et al
Methods All female residents of BC who were under 75 years of age and were diagnosed with breast cancer from 1June 1988 through 30 June 1989, were identified through the population-based BC Cancer Registry. The patient's physician was asked by telephone whether it would be appropriate to contact his or her patient. If permission was granted, a questionnaire package was mailed to the patient. Controls were selected at random from the 1989 Provincial Voters List matched by five-year age category to the cases. A questionnaire package identical to that distributed to the cases was mailed to all control subjects. The questionnaire included a detailed history of birth control and noncontraceptive hormone use. Subjects were asked whether they had used estrogen or progestogen preparations at or after menopause. Information on estrogen use was obtained separately for pills, injections and vaginal creams. For each episode, data were collected on brand name, details of timing, duration, and frequency of use. A series of brand names of the drugs commonly prescribed in Canada was listed to assist recall. In addition, data were collected on known or suspected risk factors for breast cancer, including demographic characteristics, lifestyle, occupational arid reproductive history. The eligibility criteria for inclusion in the study were: (i) under 75 years of age; (ii) ability to speak English; and (iii) no history of breast cancer prior to the reference date (date of diagnosis for cases and 1989 for controls). Since eligible voters in BC must have a Canadian citizenship, non-Canadians were considered ineligible for the study. Of the 1,489 cases and 1,502 controls who potentially were eligible to participate, 1,018 (68.3 percent) and 1,025 (68.2 percent), respectively, returned the questionnaire. Since medications that had been initiated shortly before diagnosis could have been prescribed for conditions related to the breast cancer under study, women who first used hormones within the 12 months prior to reference date were considered as nonusers. Current use was defined as use that ended within the year before reference date. Maximum likelihood estimates of the odds ratio (OR), adjusting for confounding factors, were obtained using an unconditional logistic regression model. 32All ORs presented are adjusted for age and, as necessary, additional confounders. Confounding variables were retained in the model when inclusion produced greater than a 10 percent change in the OR for hormone use. The potential confounders that were examined in the model include age, race, marital status, education, body weight in 1986, parity, age at first 476
Cancer Causes and Control. Vol 3. 1992
birth, age at menarche, history of breast biopsy before 1987, and family history of breast cancer.
Results Table 1 shows the risk of breast cancer according to history of estrogen use. There was no overall increase in risk associated with ever-use of unopposed estrogen (OR -- 1.0, 95 percent confidence interval [CI] = 0.81.3). The risk estimates were all close to unity regardless of the route the medication was administered. No increased risk was found among estrogen-plus-progestogen users (OR -- 1.2, CI = 0.6-2.2), but this estimate is imprecise because there were only 41 combination-hormone users included in the study. There were inadequate data to address the effect of long-term estrogen plus progestogen use on breast cancer risk. Among women who used unopposed estrogen for less than 10 years, no evidence of elevation in risk was seen in any duration category. However, there was a 60 percent increase in risk associated with 10 or more
Table 1. D i s t r i b u t i o n of cases and controls according to h i s t o r y of estrogen use
No hormones Estrogen only Pills only Injections only Vaginal creams only More than one type Any progestogen
Cases
Controls
OR'
(CI) b
430
432
Ref.
Estrogen use 247 234 149 141 25 21 24 28 49 44 22 19
1.0 1.1 1.2 0.9 1.2 1.2
(0.8-1.3) (0.8-1.4) (0.7-2.2) (0.5-1.6) (0.7-1.8) (0.6-2.2)
1.2 0.8 1.0 1.6
(0.7-1.7) (0.5-1.1) (0.6-1.5) (1.1-2.5)
1.4 1.3 0.7 1.0
(1.0-2.0) (0.8-2.2) (0.4-1.2) (0.7-1.4)
Duration of estrogen use (years) Estrogen only < 1 1-4 5-9 10 + Unknown
46 58 44 78 20
42 74 47 51 21
Years since last use Estrogen only < 1 1-4 5-9 10 + Unknown
90 33 25 87 11
67 22 36 89 23
"OR = odds ratio adjusted for age (< 45, 45-54, 55-64, 65-74 years) and type of menopause. b CI = 95% confidence interval.
Estrogens and breast cancer
Table 2. Use of unopposed estrogens for at least five years
among cases and controls according to various factors OR ~
(CI) b
31/286 41/110
1.2 1.0
(0.7-2.1) (0.6-1.9)
25/22
1.9
(0.8-5.3)
Age at first birth (years) I 25 42/159
40/204 34/167
1.4 1.5
(0.9-2.3) (0.8-2.5)
Parity 0 1-2 3+
24/64 50/176 48/190
23/49 37/165 38/218
0.8 1.3 1.4
(0.4-1.7) (0.8-2.3) (0.9-2.4)
Family history No Yes
98/350 24/80
82/394 16/38
1.4 0.8
(1.0-1.9) (0.3-1.8)
Prior breast biopsy No Yes
96/337 26/89
70/375 28/57
1.6 0.6
(1.1-2.3) (0.3-1.2)
Body weight in 1986 (lbs) < 140 55/166 140-159 38/120 160 + 28/141
56/220 22/129 20/76
1.4 1.9 0.7
(0.9-2.2) (1.0-3.5) (0.4-1.4)
Type of menopause Natural Surgical, no or one ovary removed Surgical, both ovaries removed
Cases
Controls
Use 5+ years/ never-use
Use 5+ years/ never-use
36/285 41/106 32/18
O R = odds ratio adjusted for age (< 45, 45-54, 55-64, 65-74 years); subjects with missing values are excluded. b CI = 95% confidence interval.
years of use (OR = 1.6, CI = 1.1-2.5), compared with never users. When recency of use was evaluated, the risk estimate was somewhat increased for current users (OR = 1.4, CI = 1.0-2.0) and for use that ended one to four years before reference date (OR--1.3, CI = 0.8-2.2). No elevation in risk was seen among women who stopped taking estrogen preparation five or more years before the reference date. The risk for five or more years of use of unopposed estrogens, within strata of various factors, are presented in Table 2. For most factors, the risk estimates did not vary appreciably among the strata. For women whose menopause was due to natural causes, hysterectomy with ovarian conservation, or bilateral oophorectomy, the estimates were 1.2 (CI = 0.7-2.1), 1.0 (CI=0.6-1.9) and 1.9 (CI=0.8-5.3), respectively. Among women without a history of breast biopsy prior to diagnosis/reference date, use of estrogen for at least five years was associated with a 60 percent increase in risk (CI = 1.1-2.3).
Discussion Many studies, both case-control and cohort, have examined the influence of noncontraceptive estrogen use on the risk of breast cancer. T M Most studies have found no overall increased risk among ever-users and four meta-analyses that pooled results from published studies of this topic, including approximately 15,000 cases, have found virtually no increase in risk of breast cancer among women who ever used e s t r o g e n . 33-36 In our study, ever-users also had a relative risk (RR) of 1.0. Most studies that have evaluated the effect of duration of estrogen use on breast cancer risk have found a small increase in risk among long-term users. 9,14,21,24,31,36 A meta-analysis that pooled data from 16 studies reported a summary RR of 1.3 (CI = 1.2-1.6) among women who had used estrogen for 15 years or longer. 34 We found an RR of 1.6 associated with use of 10 or more years. Our results provide weak support for the hypothesis, recently raised in a cohort study by Colditz et al, that current estrogen users are at an increased risk of breast cancer. 2z This hypothesis is supported by two other prospective studies. 19,26Three case-control studies, however, did not find a similar association? °,3°m Adding progestogen to the estrogen regimen has been shown to offset the increased risk of endometrial cancer due to unopposed estrogen therapy. 37,3sFor this reason, progestogen is being prescribed increasingly to postmenopausal women receiving estrogen replacement therapy. Unfortunately, the potential role of progestogen supplementation in the development of breast cancer is, at present, unknown. Progesterone promotes mammary gland differentiation, a factor that would be expected to discourage the development of cancer. 39 Conversely, studies have shown that the mitotic rate of breast cells increases under the influence of progesterone during the luteal phase, suggesting that the concomitant use of progestogen may increase breast cancer risk. 4° Published studies concerning the effect of combination therapy have been few in number. In a cohort study, Gambrell et aP 8 reported a marked decrease in risk of breast cancer among women taking postmenopausal estrogen together with progestogen. That study has been criticized for failure to adjust for potential confounders and being subject to selection bias. 4~ Another cohort study found an RR of 4.4 in women who used combination therapy for over six years, 21 whereas a small clinical trial showed lower incidence among women receiving estrogen plus progestogen (0/ 84), when compared with women who did not receive any sex hormones (4/84). 29 Results from three caseCancer Causes and Control. Vol3. 1992
477
C. P. Yang et al control studies are similarly contradictory. While Palmer et aP 1 found a small decrease in risk (RR = 0.6, CI = 0.2-2.0), an excess risk was reported by Kaufman et aP ° (RR --- 1.7, CI = 0.9-3.3) and by Ewertz et a124 ( R R = 1.4, CI--1.0-1.9). O u r results suggest that women who ever took estrogen with progestogen are at no appreciable increase in risk, relative to women who used no hormones, but the small number of progestogen users in our population precludes an unambiguous interpretation. There is inadequate information to determine if risk for breast cancer increases with duration of estrogen plus progestogen use. Some limitations of the study must be considered in the interpretation of these results. First, a substantial proportion (about 32 percent) of the eligible subjects did not participate in the study. To the extent that nonparticipation was related to the use of hormones, our RR estimates might be in error. Second, the history of hormone use was ascertained by means of a selfadministered questionnaire, and no validation was attempted. Although we cannot be certain that equally valid information was obtained from cases and controls, it seems unlikely that cases would have more completely recalled long-term use of hormones. Other studies have found good correspondence between assessment of estrogen use via interview and medical r e c o r d r e v i e w . 42-45
References
1. Casagrande J, Gerkins V, Henderson BE, Mack T, Pike MC. Brief communication: Exogenous estrogens and breast cancer in women with natural menopause. JNCI 1976; 56: 839-41. 2. Hoover R, Gray LA, Cole P, MacMahon B. Menopausal estrogens and breast cancer. N EnglJ Med 1976; 295: 401-5. 3. Startwell PE, Arthes FG, Tonascia JA. Exogenous hormones, reproductive history and breast cancer. JNCI 1977; 59: 1589-92. 4. Brinton LA, Williams RR, Hoover RN, et al. Breast cancer risk factors among screening program participants. JNCI 1979; 62: 37-44. 5. Ross RK, Paganini-Hill A, Gerkins VR, et al. A casecontrol study of menopausal estrogen therapy and breast cancer.JAMA 1980; 243: 1635-9. 6. Jick H, Walker AM, Watkins RN, et al. Replacement estrogens and breast cancer. A m J Epidemiol 1980; 112: 586-94. 7. Brinton LA, Hoover RN, Szklo M, et al. Menopausal estrogen use and risk of breast cancer. Cancer 1981; 47: 2517-22. 8. Kelsey JL, Fisher DB, Holford TR, et al. Exogenous estrogens and other factors in the epidemiology of breast cancer.JNCI 1981; 67: 327-33. 9. Hoover R, Glass A, Finkle WD, Azevedo D, Milne K. Conjugated estrogens and breast cancer risk in women. 478
Cancer Causes and Control. Vol 3. 1992
JNCI 1981; 67: 815-20. 10. Lawson DH, Jick H, Hunter JR, etal. Exogenous estrogens and breast cancer. Am J Epidemiol 1981; 114: 710-13. 11. Hulka BS, Chambless LE, Deubner DC, et al. Breast cancer and estrogen replacement therapy. Am J Obstet Gyneco11982; 143: 638-44. 12. Hiatt RA, Bawol R, Friedman GD, Hoover R. Exogenous estrogen and breast cancer after bilateral oophorectomy. Cancer 1984; 54: 139-44. 13. Kaufman DW, Miller DR, Rosenberg L, et al. Noncontraceptive estrogen use and the risk of breast cancer. JAMA 1984; 252: 63-7. 14. Brinton LA, Hoover R, Fraumeni JF, Jr. Menopausal estrogens and breast cancer risk: an expanded case-control study. BrJ Cancer 1986; 54: 825-32. 15. La Vecchia C, Decarli A, Parazzini F, Gentile A, Liberati C, Franceschi S. Noncontraceptive oestrogens and the risk of breast cancer in women. IntJ Cancer 1986; 38: 853-8. 16. McDonald JA, Weiss NS, Daling JR, Francis AM, Polissat L. Menopausal estrogen use and the risk of breast cancer. Breast Cancer Res Treat 1986; 7: 193-9. 17. Nomura AMY, Kolonel LN, Hirohata T, Lee J. The association of replacement estrogens with breast cancer. IntJ Cancer 1986; 37: 49-53. 18. Buring JE, Hennekens CH, Lipnick RJ, et al. A prospective cohort study of postmenopausal hormone use and risk of breast cancer in US women. ArnJ Epidernio11987; 125: 939-47. 19. Hunt K, Vessey M, McPherson K, Coleman M. Longterm surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. BrJ Obstet Gyneco11987; 94: 620-35. 20. Wingo PA, Layde PM, Lee NC, Rubin G, Ory HW. The risk of breast cancer in postmenopausal women who have used estrogen replacement therapy. JAMA 1987; 257: 209-15. 21. Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogenprogestin replacement. N EnglJ Med 1989; 321: 293-7. 22. Thomas DB, Persing JP, Hutchinson WB. Exogenous estrogens and other risk factors for breast cancer in women with benign breast diseases. JNCI 1982; 69: 1017-23. 23. Rohan TE, McMichael AJ. Non-contraceptive exogenous oestrogen therapy and breast cancer. Med J Aust 1988; 148: 217-21. 24. Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. IntJ Cancer 1988; 42: 832-8. 25. Dupont WD, Page DL, Rogers LW, et al. Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk. Cancer 1989; 63: 948-57. 26. Mills PK, Beeson WL, Phillips RL, Fraser GE. Prospective study of exogenous hormone use and breast cancer in Seventh-day Adventists. Cancer 1989; 64:591-7. 27. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women.JAMA 1990; 264: 2648-53. 28. Gambrell RD, Jr, Maier RC, Sanders BI. Decreased incidence of breast cancer in postmenopausal estrogen-
Estrogens and breast cancer progestogen users. Obstet Gynecol 1983; 62: 435-43. 29. Nachtigall LE, Nachtigall RH, Nachtigall RD,Beckman EM. Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979; 54: 74-9. 30. Kaufman DW, Palmer JR, Mouzon J, et al. Estrogen replacement therapy and the risk of breast cancer: results from the case-control surveillance study. Am J Epidemio11991; 134: 1375-85. 31. Palmer JR, Rosenberg, Clarke EA, et al. Breast cancer risk after estrogen replacement therapy: results from the Toronto breast cancer study. Am J Epidemio11991: 134: 1386-95. 32. Breslow NE, Day NE. Statistical Methods in Cancer
33. 34. 35. 36.
Research Vol. 1. The Analysis of Case-control Studies. International Agency for Research on Cancer, 1980; Lyon, France: IARC Sci. Pub. No. 32: 192. Dupont W, Page D. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991; 151: 67-72. Steinberg K, Thacker S, Smith S, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer.JAMA 1991; 265: 1985-90. Amstrong BK. Oestrogen therapy after menopause--boon or bane? MedJAust. 1988; 148: 213-4. Grady D, Ernster V. Invited commentary: Does postmenopausal hormone therapy cause breast cancer? ArnJ Epidemio11991; 134: 1396-400.
37. Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, Van Belle G. Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 1991; 338: 274-77. 38. Gambrell R, Jr. Prevention of endometrial cancer with progestogens. Maturitas 1986; 8: 159-68. 39. Russo IH, Russo J. Hormone prevention of mammary carcinogenesis: a new approach in anticancer research. Anticancer Res 1988; 8: 1247-64. 40. Key TJA, Pike MC. The role of oestrogens and progestogens in the epidemiology and prevention of breast cancer. EurJ Cancer Clin Onco11988; 24: 29-43. 41. Ernster VL, Cummings SR. Progesterone and breast cancer. Obstet Gyneco11986; 68: 715-7. 42. Spengler RF, Clarke EA, Woolever CA, et al. Exogenous estrogens and endometrial cancer: a case-control study and assessment of potential biases. Am J Epidemio11981; 114: 497-506. 43. Goodman MT, Nomura AMY, Wilkens LR, et al. Agreement between interview information and physician records on history of menopausal estrogen use. Am ] Epidemio11990; 131: 815-25. 44. Paganini-Hill A, Ross RK. Reliability of recall of drug usage and other health-related information. Am J Epidemio11982; 116:114-22. 45. Persson I, Bergkvist L, Adami H-O. Reliability of women's histories of climacteric oestrogen treatment assessed by prescription forms. IntJ Epidemio11987; 16: 222-8.
CancerCausesand Control.Vol3. 1992 479
Noncontraceptive hormone use and risk of breast cancer
C. Paul Yang, Janet R. Daling, Pierre R. Band, Richard P. Gallagher, Emily White, and Noel S. Weiss (Received 29 April 1992;accepted in revisedform 16June 1992) All British Columbia (Canada) women under 75 years of age who were diagnosed with breast cancer during 1988-89 were asked to complete a postal questionnaire which included detailed information on menopausal estrogen use. Controls were drawn from the Provincial Voters List, matched by five-year age category to the cases. The present analysis consists of 699 cases and 685 controls who were postmenopausal due to natural causes or to a hysterectomy. There was no overall increase in risk of breast cancer associated with ever-use of unopposed estrogen (odds ratio [OR] = 1.0, 95 percent confidence interval [CI] -- 0.8-1.3). For estrogen use of 10 years or longer, the relative risk [RR] was 1.6 (CI = 1.1-2.5). The risk estimate for current users was somewhat elevated (OR = 1.4, CI = 1.0-2.0). Compared with women who never used hormone preparations, women who had used estrogen plus progestogen had an R R of 1.2 (CI = 0.6-2.2). O u r results suggest that ever-use of estrogen, with or without progestogen, does not appreciably increase the risk of breast cancer. However, long-term and recent use of unopposed estrogen may be associated with a moderately increased risk.
Key words: Breast cancer, Canada, estrogens, progesterone.
Introduction Estrogens are used widely to alleviate menopausal symptoms and to prevent osteoporosis. Any increase in risk for breast cancer associated with this therapy could have a significant public health impact. Epidemiologic studies of menopausal estrogen replacement and the risk of breast cancer have yielded conflicting results. T M While most investigators have found no overall increase in risk, a few studies have reported a small elevation in risk associated with any use of estrogen. 15,19,26,3°Long-term estrogen users have been found
to be at an increased risk of breast cancer by some authors 9d4,21,24but not by others. 13,18,3°Results from the six studies that have investigated the effect of progestogen supplementation on the risk of breast cancer are similarly contradictory. 21;4,28-31We analyzed data from a population-based case-control study conducted in British Columbia (BC), Canada, to evaluate the influence of estrogen therapy, with or without progestogen, on the subsequent risk of breast cancer.
Drs Yang and Band, and Mr Gallagherare with the British Columbia CancerAgency, Vancouver, British Columbia, Canada. Authors are also affiliated with the School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA (Drs Yang, Daling, White, and Weiss),and the Fred Hutchinson CancerResearch Center, Seattle, WA, USA (Drs Daling, White, and Weiss).Address correspondenceto Mr Gallagher, Division of Epidemiology, Biometry and Occupational Oncology, British Columbia Cancer Agency, 600 West lOth Avenue, Vancouver, BC, Canada, VSZ 4E6. Thisproject isfunded partially by Health and Welfare Canada, Grant #6610-1834-55and hy Workers Compensation Board of BC. © 1992 Rapid Communications of Oxford Ltd
Cancer Causes and Control. Vol 3. 1992
475
C P. Yang et al
Methods All female residents of BC who were under 75 years of age and were diagnosed with breast cancer from 1June 1988 through 30 June 1989, were identified through the population-based BC Cancer Registry. The patient's physician was asked by telephone whether it would be appropriate to contact his or her patient. If permission was granted, a questionnaire package was mailed to the patient. Controls were selected at random from the 1989 Provincial Voters List matched by five-year age category to the cases. A questionnaire package identical to that distributed to the cases was mailed to all control subjects. The questionnaire included a detailed history of birth control and noncontraceptive hormone use. Subjects were asked whether they had used estrogen or progestogen preparations at or after menopause. Information on estrogen use was obtained separately for pills, injections and vaginal creams. For each episode, data were collected on brand name, details of timing, duration, and frequency of use. A series of brand names of the drugs commonly prescribed in Canada was listed to assist recall. In addition, data were collected on known or suspected risk factors for breast cancer, including demographic characteristics, lifestyle, occupational arid reproductive history. The eligibility criteria for inclusion in the study were: (i) under 75 years of age; (ii) ability to speak English; and (iii) no history of breast cancer prior to the reference date (date of diagnosis for cases and 1989 for controls). Since eligible voters in BC must have a Canadian citizenship, non-Canadians were considered ineligible for the study. Of the 1,489 cases and 1,502 controls who potentially were eligible to participate, 1,018 (68.3 percent) and 1,025 (68.2 percent), respectively, returned the questionnaire. Since medications that had been initiated shortly before diagnosis could have been prescribed for conditions related to the breast cancer under study, women who first used hormones within the 12 months prior to reference date were considered as nonusers. Current use was defined as use that ended within the year before reference date. Maximum likelihood estimates of the odds ratio (OR), adjusting for confounding factors, were obtained using an unconditional logistic regression model. 32All ORs presented are adjusted for age and, as necessary, additional confounders. Confounding variables were retained in the model when inclusion produced greater than a 10 percent change in the OR for hormone use. The potential confounders that were examined in the model include age, race, marital status, education, body weight in 1986, parity, age at first 476
Cancer Causes and Control. Vol 3. 1992
birth, age at menarche, history of breast biopsy before 1987, and family history of breast cancer.
Results Table 1 shows the risk of breast cancer according to history of estrogen use. There was no overall increase in risk associated with ever-use of unopposed estrogen (OR -- 1.0, 95 percent confidence interval [CI] = 0.81.3). The risk estimates were all close to unity regardless of the route the medication was administered. No increased risk was found among estrogen-plus-progestogen users (OR -- 1.2, CI = 0.6-2.2), but this estimate is imprecise because there were only 41 combination-hormone users included in the study. There were inadequate data to address the effect of long-term estrogen plus progestogen use on breast cancer risk. Among women who used unopposed estrogen for less than 10 years, no evidence of elevation in risk was seen in any duration category. However, there was a 60 percent increase in risk associated with 10 or more
Table 1. D i s t r i b u t i o n of cases and controls according to h i s t o r y of estrogen use
No hormones Estrogen only Pills only Injections only Vaginal creams only More than one type Any progestogen
Cases
Controls
OR'
(CI) b
430
432
Ref.
Estrogen use 247 234 149 141 25 21 24 28 49 44 22 19
1.0 1.1 1.2 0.9 1.2 1.2
(0.8-1.3) (0.8-1.4) (0.7-2.2) (0.5-1.6) (0.7-1.8) (0.6-2.2)
1.2 0.8 1.0 1.6
(0.7-1.7) (0.5-1.1) (0.6-1.5) (1.1-2.5)
1.4 1.3 0.7 1.0
(1.0-2.0) (0.8-2.2) (0.4-1.2) (0.7-1.4)
Duration of estrogen use (years) Estrogen only < 1 1-4 5-9 10 + Unknown
46 58 44 78 20
42 74 47 51 21
Years since last use Estrogen only < 1 1-4 5-9 10 + Unknown
90 33 25 87 11
67 22 36 89 23
"OR = odds ratio adjusted for age (< 45, 45-54, 55-64, 65-74 years) and type of menopause. b CI = 95% confidence interval.
Estrogens and breast cancer
Table 2. Use of unopposed estrogens for at least five years
among cases and controls according to various factors OR ~
(CI) b
31/286 41/110
1.2 1.0
(0.7-2.1) (0.6-1.9)
25/22
1.9
(0.8-5.3)
Age at first birth (years) I 25 42/159
40/204 34/167
1.4 1.5
(0.9-2.3) (0.8-2.5)
Parity 0 1-2 3+
24/64 50/176 48/190
23/49 37/165 38/218
0.8 1.3 1.4
(0.4-1.7) (0.8-2.3) (0.9-2.4)
Family history No Yes
98/350 24/80
82/394 16/38
1.4 0.8
(1.0-1.9) (0.3-1.8)
Prior breast biopsy No Yes
96/337 26/89
70/375 28/57
1.6 0.6
(1.1-2.3) (0.3-1.2)
Body weight in 1986 (lbs) < 140 55/166 140-159 38/120 160 + 28/141
56/220 22/129 20/76
1.4 1.9 0.7
(0.9-2.2) (1.0-3.5) (0.4-1.4)
Type of menopause Natural Surgical, no or one ovary removed Surgical, both ovaries removed
Cases
Controls
Use 5+ years/ never-use
Use 5+ years/ never-use
36/285 41/106 32/18
O R = odds ratio adjusted for age (< 45, 45-54, 55-64, 65-74 years); subjects with missing values are excluded. b CI = 95% confidence interval.
years of use (OR = 1.6, CI = 1.1-2.5), compared with never users. When recency of use was evaluated, the risk estimate was somewhat increased for current users (OR = 1.4, CI = 1.0-2.0) and for use that ended one to four years before reference date (OR--1.3, CI = 0.8-2.2). No elevation in risk was seen among women who stopped taking estrogen preparation five or more years before the reference date. The risk for five or more years of use of unopposed estrogens, within strata of various factors, are presented in Table 2. For most factors, the risk estimates did not vary appreciably among the strata. For women whose menopause was due to natural causes, hysterectomy with ovarian conservation, or bilateral oophorectomy, the estimates were 1.2 (CI = 0.7-2.1), 1.0 (CI=0.6-1.9) and 1.9 (CI=0.8-5.3), respectively. Among women without a history of breast biopsy prior to diagnosis/reference date, use of estrogen for at least five years was associated with a 60 percent increase in risk (CI = 1.1-2.3).
Discussion Many studies, both case-control and cohort, have examined the influence of noncontraceptive estrogen use on the risk of breast cancer. T M Most studies have found no overall increased risk among ever-users and four meta-analyses that pooled results from published studies of this topic, including approximately 15,000 cases, have found virtually no increase in risk of breast cancer among women who ever used e s t r o g e n . 33-36 In our study, ever-users also had a relative risk (RR) of 1.0. Most studies that have evaluated the effect of duration of estrogen use on breast cancer risk have found a small increase in risk among long-term users. 9,14,21,24,31,36 A meta-analysis that pooled data from 16 studies reported a summary RR of 1.3 (CI = 1.2-1.6) among women who had used estrogen for 15 years or longer. 34 We found an RR of 1.6 associated with use of 10 or more years. Our results provide weak support for the hypothesis, recently raised in a cohort study by Colditz et al, that current estrogen users are at an increased risk of breast cancer. 2z This hypothesis is supported by two other prospective studies. 19,26Three case-control studies, however, did not find a similar association? °,3°m Adding progestogen to the estrogen regimen has been shown to offset the increased risk of endometrial cancer due to unopposed estrogen therapy. 37,3sFor this reason, progestogen is being prescribed increasingly to postmenopausal women receiving estrogen replacement therapy. Unfortunately, the potential role of progestogen supplementation in the development of breast cancer is, at present, unknown. Progesterone promotes mammary gland differentiation, a factor that would be expected to discourage the development of cancer. 39 Conversely, studies have shown that the mitotic rate of breast cells increases under the influence of progesterone during the luteal phase, suggesting that the concomitant use of progestogen may increase breast cancer risk. 4° Published studies concerning the effect of combination therapy have been few in number. In a cohort study, Gambrell et aP 8 reported a marked decrease in risk of breast cancer among women taking postmenopausal estrogen together with progestogen. That study has been criticized for failure to adjust for potential confounders and being subject to selection bias. 4~ Another cohort study found an RR of 4.4 in women who used combination therapy for over six years, 21 whereas a small clinical trial showed lower incidence among women receiving estrogen plus progestogen (0/ 84), when compared with women who did not receive any sex hormones (4/84). 29 Results from three caseCancer Causes and Control. Vol3. 1992
477
C. P. Yang et al control studies are similarly contradictory. While Palmer et aP 1 found a small decrease in risk (RR = 0.6, CI = 0.2-2.0), an excess risk was reported by Kaufman et aP ° (RR --- 1.7, CI = 0.9-3.3) and by Ewertz et a124 ( R R = 1.4, CI--1.0-1.9). O u r results suggest that women who ever took estrogen with progestogen are at no appreciable increase in risk, relative to women who used no hormones, but the small number of progestogen users in our population precludes an unambiguous interpretation. There is inadequate information to determine if risk for breast cancer increases with duration of estrogen plus progestogen use. Some limitations of the study must be considered in the interpretation of these results. First, a substantial proportion (about 32 percent) of the eligible subjects did not participate in the study. To the extent that nonparticipation was related to the use of hormones, our RR estimates might be in error. Second, the history of hormone use was ascertained by means of a selfadministered questionnaire, and no validation was attempted. Although we cannot be certain that equally valid information was obtained from cases and controls, it seems unlikely that cases would have more completely recalled long-term use of hormones. Other studies have found good correspondence between assessment of estrogen use via interview and medical r e c o r d r e v i e w . 42-45
References
1. Casagrande J, Gerkins V, Henderson BE, Mack T, Pike MC. Brief communication: Exogenous estrogens and breast cancer in women with natural menopause. JNCI 1976; 56: 839-41. 2. Hoover R, Gray LA, Cole P, MacMahon B. Menopausal estrogens and breast cancer. N EnglJ Med 1976; 295: 401-5. 3. Startwell PE, Arthes FG, Tonascia JA. Exogenous hormones, reproductive history and breast cancer. JNCI 1977; 59: 1589-92. 4. Brinton LA, Williams RR, Hoover RN, et al. Breast cancer risk factors among screening program participants. JNCI 1979; 62: 37-44. 5. Ross RK, Paganini-Hill A, Gerkins VR, et al. A casecontrol study of menopausal estrogen therapy and breast cancer.JAMA 1980; 243: 1635-9. 6. Jick H, Walker AM, Watkins RN, et al. Replacement estrogens and breast cancer. A m J Epidemiol 1980; 112: 586-94. 7. Brinton LA, Hoover RN, Szklo M, et al. Menopausal estrogen use and risk of breast cancer. Cancer 1981; 47: 2517-22. 8. Kelsey JL, Fisher DB, Holford TR, et al. Exogenous estrogens and other factors in the epidemiology of breast cancer.JNCI 1981; 67: 327-33. 9. Hoover R, Glass A, Finkle WD, Azevedo D, Milne K. Conjugated estrogens and breast cancer risk in women. 478
Cancer Causes and Control. Vol 3. 1992
JNCI 1981; 67: 815-20. 10. Lawson DH, Jick H, Hunter JR, etal. Exogenous estrogens and breast cancer. Am J Epidemiol 1981; 114: 710-13. 11. Hulka BS, Chambless LE, Deubner DC, et al. Breast cancer and estrogen replacement therapy. Am J Obstet Gyneco11982; 143: 638-44. 12. Hiatt RA, Bawol R, Friedman GD, Hoover R. Exogenous estrogen and breast cancer after bilateral oophorectomy. Cancer 1984; 54: 139-44. 13. Kaufman DW, Miller DR, Rosenberg L, et al. Noncontraceptive estrogen use and the risk of breast cancer. JAMA 1984; 252: 63-7. 14. Brinton LA, Hoover R, Fraumeni JF, Jr. Menopausal estrogens and breast cancer risk: an expanded case-control study. BrJ Cancer 1986; 54: 825-32. 15. La Vecchia C, Decarli A, Parazzini F, Gentile A, Liberati C, Franceschi S. Noncontraceptive oestrogens and the risk of breast cancer in women. IntJ Cancer 1986; 38: 853-8. 16. McDonald JA, Weiss NS, Daling JR, Francis AM, Polissat L. Menopausal estrogen use and the risk of breast cancer. Breast Cancer Res Treat 1986; 7: 193-9. 17. Nomura AMY, Kolonel LN, Hirohata T, Lee J. The association of replacement estrogens with breast cancer. IntJ Cancer 1986; 37: 49-53. 18. Buring JE, Hennekens CH, Lipnick RJ, et al. A prospective cohort study of postmenopausal hormone use and risk of breast cancer in US women. ArnJ Epidernio11987; 125: 939-47. 19. Hunt K, Vessey M, McPherson K, Coleman M. Longterm surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. BrJ Obstet Gyneco11987; 94: 620-35. 20. Wingo PA, Layde PM, Lee NC, Rubin G, Ory HW. The risk of breast cancer in postmenopausal women who have used estrogen replacement therapy. JAMA 1987; 257: 209-15. 21. Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogenprogestin replacement. N EnglJ Med 1989; 321: 293-7. 22. Thomas DB, Persing JP, Hutchinson WB. Exogenous estrogens and other risk factors for breast cancer in women with benign breast diseases. JNCI 1982; 69: 1017-23. 23. Rohan TE, McMichael AJ. Non-contraceptive exogenous oestrogen therapy and breast cancer. Med J Aust 1988; 148: 217-21. 24. Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. IntJ Cancer 1988; 42: 832-8. 25. Dupont WD, Page DL, Rogers LW, et al. Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk. Cancer 1989; 63: 948-57. 26. Mills PK, Beeson WL, Phillips RL, Fraser GE. Prospective study of exogenous hormone use and breast cancer in Seventh-day Adventists. Cancer 1989; 64:591-7. 27. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women.JAMA 1990; 264: 2648-53. 28. Gambrell RD, Jr, Maier RC, Sanders BI. Decreased incidence of breast cancer in postmenopausal estrogen-
Estrogens and breast cancer progestogen users. Obstet Gynecol 1983; 62: 435-43. 29. Nachtigall LE, Nachtigall RH, Nachtigall RD,Beckman EM. Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979; 54: 74-9. 30. Kaufman DW, Palmer JR, Mouzon J, et al. Estrogen replacement therapy and the risk of breast cancer: results from the case-control surveillance study. Am J Epidemio11991; 134: 1375-85. 31. Palmer JR, Rosenberg, Clarke EA, et al. Breast cancer risk after estrogen replacement therapy: results from the Toronto breast cancer study. Am J Epidemio11991: 134: 1386-95. 32. Breslow NE, Day NE. Statistical Methods in Cancer
33. 34. 35. 36.
Research Vol. 1. The Analysis of Case-control Studies. International Agency for Research on Cancer, 1980; Lyon, France: IARC Sci. Pub. No. 32: 192. Dupont W, Page D. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991; 151: 67-72. Steinberg K, Thacker S, Smith S, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer.JAMA 1991; 265: 1985-90. Amstrong BK. Oestrogen therapy after menopause--boon or bane? MedJAust. 1988; 148: 213-4. Grady D, Ernster V. Invited commentary: Does postmenopausal hormone therapy cause breast cancer? ArnJ Epidemio11991; 134: 1396-400.
37. Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, Van Belle G. Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 1991; 338: 274-77. 38. Gambrell R, Jr. Prevention of endometrial cancer with progestogens. Maturitas 1986; 8: 159-68. 39. Russo IH, Russo J. Hormone prevention of mammary carcinogenesis: a new approach in anticancer research. Anticancer Res 1988; 8: 1247-64. 40. Key TJA, Pike MC. The role of oestrogens and progestogens in the epidemiology and prevention of breast cancer. EurJ Cancer Clin Onco11988; 24: 29-43. 41. Ernster VL, Cummings SR. Progesterone and breast cancer. Obstet Gyneco11986; 68: 715-7. 42. Spengler RF, Clarke EA, Woolever CA, et al. Exogenous estrogens and endometrial cancer: a case-control study and assessment of potential biases. Am J Epidemio11981; 114: 497-506. 43. Goodman MT, Nomura AMY, Wilkens LR, et al. Agreement between interview information and physician records on history of menopausal estrogen use. Am ] Epidemio11990; 131: 815-25. 44. Paganini-Hill A, Ross RK. Reliability of recall of drug usage and other health-related information. Am J Epidemio11982; 116:114-22. 45. Persson I, Bergkvist L, Adami H-O. Reliability of women's histories of climacteric oestrogen treatment assessed by prescription forms. IntJ Epidemio11987; 16: 222-8.
CancerCausesand Control.Vol3. 1992 479
