American Journal of Epidemiology Copyright © 1991 by The Johns Hopkins University School ot Hygiene and Public Health All rights reserved
Vol 134, No 12 Printed in U S A
Breast Cancer Risk after Estrogen Replacement Therapy: Results from the Toronto Breast Cancer Study
Julie R. Palmer,1 Lynn Rosenberg,1 E. Aileen Clarke,2 Donald R. Miller,3 and Samuel Shapiro1
The authors examined noncontraceptive estrogen use in relation to breast cancer risk in women under age 70 in a case-control study conducted in Toronto, Canada. Cases were 607 women with incident primary breast cancer, identified at the time of hospitalization for treatment. They were compared to 1,214 controls matched to the cases on neighborhood and decade of age. Information was obtained through personal interviews conducted in the subjects' homes. Most estrogen users had taken conjugated estrogens, and only 7% had also taken progestogens. Compared with never use, the estimated relative risk for ever use of unopposed conjugated estrogens was 0.9 (95% confidence interval (Cl) 0.6-1.2) after allowance for multiple confounding factors. Relative risk estimates for most duration categories were close to 1.0; the estimate for the longest duration category, >15 years of use, was elevated (1.5, 95% Cl 0.6-3.8), but there was not a significant trend with increasing duration. The estimate for current use or use that ended less than 12 months before interview and had lasted for at least 5 years was 0.9 (95% Cl 0.4-1.9). The results provide evidence against an increase in risk among women who used unopposed conjugated estrogens for less than 15 years and for recent users; for women with durations of at least 15 years, an increase could not be ruled out. Am J Epidemiol 1991;134:1386-95 breast neoplasms; estrogen replacement therapy
Endogenous estrogens are believed to influence breast cancer risk (1), as evidenced
by a higher incidence in women than in men, and increased risks for women who have had an early menarche, late menopause, or late age atfirstbirth (2). Exogenous estrogens promote mammary gland tumors in animals (3). It is possible, therefore, that the risk of breast cancer could be increased in women who take estrogens as postmenopausal replacement therapy. Estrogens are
Received for publication January 16, 1991, and in final form May 20, 1991 1 Slone Epidemiology Unit, School of Public Health, Boston University School of Medicine, Brookline, MA 2 Division of Epidemiology and Statistics, Ontario Cancer Treatment Research Foundation, Toronto, Ontario, Canada. 3 Health Research Associates, Jamaica Plain, MA. Reprint requests to Dr. Julie R. Palmer, Slone Epidemiology Unit, 1371 Beacon Street, Brookline, MA 02146 Supported by the Alcoholic Beverage Medical Research Foundation, Baltimore, MD; the US Food and Drug Administration (cooperative agreement nos. U0I FD01222 and FD-U-000082); Hoflmann-LaRoche, Inc., Nutley, NJ; CIBA-
GEIGY Corporation, Summit, NJ; Hoechst AG, Frankfurt, West Germany, McNeil Pharmaceutical, Spring House, PA, Merrell Dow Pharmaceuticals, Inc., Cincinnati, OH. The authors are indebted to the attending physicians at Princess Margaret Hospital, Sunnybrook Medical Centre, Toronto General Hospital, and Mt. Sinai Hospital for their collaboration; to the interviewers who collected the data, Anne Allen, Rosemary Chepa, Suzanne Gale, Kathleen Gillespie, Lindsay Hall, Linda Harrel, Virginia Hunter, Beverly Linden, Muriel Relton, Shirley Rothery, Irene Servos, Ann Skene-Melvin, Linda West, to Verna Cundari and Phyllis Disenhouse for coordination of data collection; and to Leonard Gaetano and Marguerite Angeloni for data management.
Editor's note: For a discussion of this paper and the accompanying paper by Kaufman el ai, see the Invited Commentary on p. 1396 and the reply by the authors on p. 1401.
1386
Estrogens and Breast Cancer
widely used in countries such as Canada and the United States (4), and a causal relation could therefore have a substantial impact on breast cancer incidence. The relation of estrogen use to breast cancer risk has been examined in many epidemiologic studies, with mixed and inconclusive results (5-26): no association was observed in several studies (5-9, 21, 23, 26), while others have observed a positive association (10-20, 22, 24). We investigated the relation between estrogen use and breast cancer risk in a case-control study of Canadian women, with particular attention given to long-term use.
MATERIALS AND METHODS Data collection
The data were obtained in a case-control study of breast cancer carried out from 1982 to 1986 in Toronto, Canada. The primary purpose was to evaluate the relation of alcohol consumption to breast cancer risk, but the study was designed so that other factors, including estrogen use, could also be evaluated. Eligible subjects were women under 70 years of age who lived in metropolitan Toronto, spoke English, and had no history of cancer. Subjects were interviewed in their homes after giving informed consent. A structured questionnaire administered by trained interviewers elicited information about demographic factors, reproductive factors, medical history, family history of breast cancer, and medication history. To elicit use of estrogens and other female hormones, subjects were asked to report drug use for regulation of menstrual periods, menstrual problems, breast conditions, cessation of postpartum milk flow, maintenance of a pregnancy, change of life, menopause, hot flashes, or sexual difficulties. For each episode of drug use, the name of the drug, indication for use, frequency of use, time since first taken, and duration of use were recorded. Photographs of estrogen pills marketed in Canada and the United States were used to aid recall.
1387
Cases. Cases were women under age 70 years who had histologically confirmed, primary breast cancer, diagnosed no more than 6 months before interview. They were identified at the Princess Margaret Hospital, the major cancer treatment hospital in metropolitan Toronto. Of 800 potential cases, 73 (9 percent) did not participate because their doctors refused, and 97 (12 percent) themselves refused to participate. An additional 23 potential cases (3 percent) were excluded because controls could not be found; thus, the final case series comprised 607 women. Estrogen and progestogen receptor status were determined within 6 weeks of the diagnosis for 528 of the 607 cases (27). Controls. Controls were identified from tax assessment rolls of all residents of Ontario. The maintenance of these records is mandated by provincial law, and the records are partially updated each year and completely updated every 3 years. For each case, the two women (other than next door neighbors) who were in the same decade of age and lived closest to the case were selected. A total of 1,874 eligible controls were contacted: 660 (35 percent) refused to participate and 1,214 (65 percent) were enrolled and interviewed.
Data analysis
Estrogen replacement therapy was defined as oral or injectable unopposed estrogens taken for the following indications: menstrual problems, "change of life," menopause, hot flashes, and sexual difficulties. Only use that occurred in the year before menopause or after the menopause was included. Women who had used estrogens for other purposes (cessation of lactation, breast conditions, and maintenance of a pregnancy) were considered in a separate category; virtually all of this use occurred well before the time of menopause. Four women who had used topical vaginal estrogen cream were also put in this "other use" category. Women who had used combination therapy (progestogens with estrogens) were considered separately. For all comparisons, the
1388
Palmer et al.
reference category was composed of women who had never taken any noncontraceptive estrogen. Because the controls were matched to the cases on neighborhood of residence as well as decade of age, all relative risk estimates were estimated from conditional logistic regression analyses (28). Age at menopause (which was associated with both breast cancer risk (29) and duration of estrogen use) was also controlled in all analyses in the following categories: pre- or perimenopausal, menopause before age 45, menopause at age 45-49, menopause at age 50 or older, and unknown age at menopause because of a hysterectomy without bilateral oophorectomy. Further control for type of menopause (natural or bilateral oophorectomy) did not alter the estimates. Known and potential risk factors for breast cancer (29) and factors thought to be related to estrogen use were controlled in multiple conditional logistic regression models; in addition to age, neighborhood, and age at menopause, these factors were type of menopause, history of breast cancer in a mother or sister, age at menarche, age at first birth, parity, history of cystic breast disease, oral contraceptive use, alcohol consumption, years of education, and number of visits to a physician in the year previous to the year before interview. The multivariate relative risk estimates were closely similar to those adjusted only for the matching factors and age at menopause, and the latter estimates are presented below. Because the study was designed to assess many factors, enrollment was not restricted to postmenopausal women; 41 percent of cases and 42 percent of controls were preor perimenopausal and had virtually no replacement estrogen use. Menopausal status was controlled in every analysis, and the inclusion of pre- and perimenopausal women did not affect the relative risk estimates or confidence intervals. Of the postmenopausal women, 67 percent of cases and 69 percent of controls had a natural menopause, 13 percent of cases and 13 percent of controls had a surgical menopause with bi-
lateral oophorectomy, and 20 percent of cases and 18 percent of controls had a hysterectomy with retention of one or both ovaries. Among women who had either a natural menopause or a bilateral oophorectomy, the menopause occurred before age 45 in 12 percent of cases and 20 percent of controls. RESULTS
Replacement estrogens without progestogens were taken by 15 percent of the cases and 15 percent of the controls (table 1). After adjustment for the matching factors and for age at menopause, the relative risk estimate for ever use of unopposed estrogen replacement therapy was 1.0 (95 percent confidence interval (CI) 0.7-1.3); the corresponding multivariate estimate was also 1.0. The relative risk estimate for women in the category of "other use" was 1.3 (95 percent CI 0.72.6); virtually all of this use was for short durations. The estimated relative risk for use of estrogens with progestogens was 0.6 (95 percent CI 0.2-2.0); two cases and one control had used combination therapy for 5 or more years. All subsequent analyses were confined to women who had used unopposed estrogens for replacement. Among the 279 users of unopposed replacement estrogens, 78 percent were able to identify the type of estrogen used: among them, 93 percent had taken conjugated estrogens, and 7 percent had used "other estrogens"—diethylstilbestrol, ethinyl estradiol, estradiol, or estropipate. The estimated relative risk for ever use of "other" estrogens was 2.2 (95 percent CI 0.8-6.3), and for 5 or more years of use, based on three exposed cases and two exposed controls, it was 2.6 (95 percent CI 0.4-16) (table 2). For users who could not specify the estrogen preparation, the relative risk estimates were 1.4 (95 percent CI 0.8-2.6) for ever use, and 2.3 (95 percent CI 0.8-6.9) for 5 or more years use (table 2). Five cases and three controls had used more than one type of estrogen. Limited numbers prohibited more detailed analysis of the use of nonconjugated and
Estrogens and Breast Cancer
1389
TABLE 1. Estrogen use among 607 breast cancer cases and 1,214 neighbor controls in a study conducted in Toronto, Canada, 1982-1986 Cases
Controls
Estrogen use No.
Never used Unopposed estrogens, for replacement Conjugated estrogens only Other estrogens Unspecified estrogens More than one type of estrogen Unopposed estrogens, for other indications§ Estrogens taken with progestogens
No.
Relative nsk estimate* (95% confidence interval)
Multivariate relative risk estimatet (95% confidence interval)
493 94
(81) (15)
991 185
(82) (15)
1.0* 1.0(0.7-1.3)
1.0* 1.0(0.8-1.4)
60
(10)
144
(12)
0.8(0.6-1.1)
0.9 (0.6-1.2)
8 21 5
(1) (3) (1)
7 31 3
(0) (3) (0)
2.2 (0.8-6.3) 1.4 (0.8-2.6) 3.7(0.9-16)
2.8 (0.9-8.3) 1.4 (0.7-2.6) 3.9(0.9-17)
16
(3)
24
(2)
1.3 (0.7-2.6)
1.4(0.7-2.7)
4
(1)
14
(1)
0.6 (0.2-2.0)
0.6 (0.2-1.9)
* Adjusted for matching factors and age at menopause. t Estimates from multivariate conditional logistic regression Adjusted for the matching factors and the following factors: type of menopause, age at menopause, age at menarche, parity, age at first birth, family history of breast cancer, history of cystic breast disease, body mass index, education, alcohol consumption, oral contraceptive use, number of physician visits in the previous year. J Reference category. § Cessation of lactation, breast conditions, or maintenance of a pregnancy
unspecified estrogens. The remaining analyses concern use of conjugated estrogens only. The relative risk estimate for ever use of conjugated estrogens relative to never use was 0.8 (95 percent CI 0.6-1.1); the corresponding multivariate estimate was 0.9 (95 percent CI 0.6-1.2). The estimate for use of 15 or more years was 1.4 (95 percent CI 0.63.3); the corresponding multivariate estimate was 1.5 (95 percent CI 0.6-3.8) (trend test according to duration of use by halfdecade, p = 0.7) (table 2). When >15 years of use was divided further into 15-19 and >20 years o ' use, the estimates were 1.2 (based on four exposed cases and seven exposed controls), and 1.6 (based onfiveexposed cases and eight exposed controls), respectively. As shown in table 3, when the analyses were confined to postmenopausal women, the relative risk estimates for durations of conjugated estrogen use longer than 5 years are identical to those estimated for the same use in the overall data set. Other results in postmenopausal women are closely similar
to the results presented in table 2 for the overall study group. Among women under age 60 years, there was no significant increase in risk in any duration category (table 4). Most of the longterm estrogen use occurred among women aged 60-69 years. In this age group, the relative risk estimate for 10 or more years of use was 1.4 (95 percent 0.7-3.2) and for 15 or more years of use it was 2.6 (95 percent CI 0.9-7.0). To evaluate recency of use, we estimated relative risks according to the time elapsed since last use (table 5). The estimated relative risk for use that ended within the year before interview was 0.4 (95 percent CI 0.2-0.9); for use that ended 1-2 years before, the estimate was 5.2 (95 percent CI 2.0-13); and for all other categories, the estimates ranged from 0.4 to 1.0. When the analysis was restricted to women who had used conjugated estrogens for 5 or more years, the estimates were 0.7 (95 percent CI 0.3-1.5) for use that ended in the year before interview and 2.0 (95 percent CI 0.6-7.4) for use that ended 1-2 years before interview. Re-
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Palmer etal
TABLE 2. Duration of use of unopposed estrogens for replacement among breast cancer cases and neighbor controls in a study conducted in Toronto, Canada, 1982-1986
Duration of use (years)
Never used Conjugated estrogens only 15 Unknown duration Other estrogens only 5 Unspecified estrogens only 5 Unknown duration More than one type 5
No. of cases
No of controls
493
991
16 19 11 5 9 0
Relative risk estimate* (95% confidence interval)
Multivariate relative nsk estimatet (95% confidence interval)
1-0*
1.0*
33 50 28 16 15 2
0.9 (0.5-1.7) 0.7 (0.4-1.3) 0.8 (0.4-1.6) 0.6(0.2-1.8) 1.4 (0.6-3.3)
0.9 (0.5-1.8) 0.7 (0.4-1.3) 0.9(0.4-1.8) 0.7 (0.2-1.9) 1.5 (0.6-3.8)
5 3
5 2
2.1 (0.6-7.4) 2.6(0.4-16)
13 7 1
23 7 1
1.1 (0.5-2.3) 2.3 (0.8-6.9)
2 3
1 2
3.9 (0.3-45) 3.6 (0.6-22)
* Adjusted for matching factors and age at menopause. t Estimates from multivariate conditional logistic regression. Adjusted for the matching factors and the following factors: type of menopause, age at menopause, age at menarche, parity, age at first birth, family history of breast cancer, history of cystic breast disease, body mass index, education, alcohol consumption, oral contraceptive use, number of physician visits in the previous year t Reference category.
suits from multivariate analyses were virtually identical. To evaluate latency, we estimated relative risks according to years since first use of conjugated estrogens (20 years) and according to total duration of use (5 years) (table 6). Among women who had taken estrogens for less than 5 years, the estimate for each category of interval since first use was below 1.0. Among women who used estrogens for at least 5 years, the estimate for 10-19 years since first use was 0.5 (95 percent CI 0.2-1.0) and for >20 years it was 2.1 (95 percent CI 0.9-5.0). We estimated relative risks for 5 or more years use compared with never use within strata of various risk factors (table 7). For most factors, the estimates did not vary appreciably among the strata. The largest relative risk estimate, 1.5, was among women whose first birth was before age 25, and the smallest, 0.4, was among those whose first
birth occurred at age 25 or older; neither estimate was statistically significant. We had information on estrogen receptor (ER) status for 528 of the cases: 351 were classified as ER positive (an assay of 10 or more femtomoles per milligram) and 177 as ER negative. Among both ER positive women (and their matched controls) and ER negative women (and their matched controls), the relative risk estimate for 5 or more years use was 1.0. More than half of the women who used conjugated estrogens could not identify the dose, and thus we were unable to evaluate dosage. DISCUSSION
We found no material association between conjugated estrogen use and the risk of breast cancer. There was not a significant trend with increasing duration of estrogen
Estrogens and Breast Cancer
use, and the duration-specific relative risk estimates for use lasting less than 15 years were of the magnitude 0.8 to 1.1. For 15 or more years of use, the point estimate of relative risk was elevated, but it was statistically compatible with no association. The elevated risk among long-term users was concentrated among those who had begun use at least 20 years previously, but, again, the increase was compatible with no association. Because the prevalence of long-term use was greatest in the oldest women, an adverse effect would have been most easily detected in that age group (60-69 years); the estimate for the longest duration category was elevated, 2.6, but for the next longest category it was 0.7. When the data were stratified according to a range of other risk factors for breast cancer, there was no significant evidence of an increased risk for 5 or more years of exposure. Current use or use that ended less than 12 months before interview was not associated with an increased risk. A statistically signifTABLE 3. Duration of use of unopposed estrogens for replacement, among postmenopausal women only, in a study of breast cancer cases and neighbor controls conducted in Toronto, Canada, 1982-1986
Duration of use (years)
Relative risk estimate* No of No. of (95% cases controls confidence interval)
Never used 260 Conjugated estrogens only 15 9 Unknown 0 Other estrogens only
Vol 134, No 12 Printed in U S A
Breast Cancer Risk after Estrogen Replacement Therapy: Results from the Toronto Breast Cancer Study
Julie R. Palmer,1 Lynn Rosenberg,1 E. Aileen Clarke,2 Donald R. Miller,3 and Samuel Shapiro1
The authors examined noncontraceptive estrogen use in relation to breast cancer risk in women under age 70 in a case-control study conducted in Toronto, Canada. Cases were 607 women with incident primary breast cancer, identified at the time of hospitalization for treatment. They were compared to 1,214 controls matched to the cases on neighborhood and decade of age. Information was obtained through personal interviews conducted in the subjects' homes. Most estrogen users had taken conjugated estrogens, and only 7% had also taken progestogens. Compared with never use, the estimated relative risk for ever use of unopposed conjugated estrogens was 0.9 (95% confidence interval (Cl) 0.6-1.2) after allowance for multiple confounding factors. Relative risk estimates for most duration categories were close to 1.0; the estimate for the longest duration category, >15 years of use, was elevated (1.5, 95% Cl 0.6-3.8), but there was not a significant trend with increasing duration. The estimate for current use or use that ended less than 12 months before interview and had lasted for at least 5 years was 0.9 (95% Cl 0.4-1.9). The results provide evidence against an increase in risk among women who used unopposed conjugated estrogens for less than 15 years and for recent users; for women with durations of at least 15 years, an increase could not be ruled out. Am J Epidemiol 1991;134:1386-95 breast neoplasms; estrogen replacement therapy
Endogenous estrogens are believed to influence breast cancer risk (1), as evidenced
by a higher incidence in women than in men, and increased risks for women who have had an early menarche, late menopause, or late age atfirstbirth (2). Exogenous estrogens promote mammary gland tumors in animals (3). It is possible, therefore, that the risk of breast cancer could be increased in women who take estrogens as postmenopausal replacement therapy. Estrogens are
Received for publication January 16, 1991, and in final form May 20, 1991 1 Slone Epidemiology Unit, School of Public Health, Boston University School of Medicine, Brookline, MA 2 Division of Epidemiology and Statistics, Ontario Cancer Treatment Research Foundation, Toronto, Ontario, Canada. 3 Health Research Associates, Jamaica Plain, MA. Reprint requests to Dr. Julie R. Palmer, Slone Epidemiology Unit, 1371 Beacon Street, Brookline, MA 02146 Supported by the Alcoholic Beverage Medical Research Foundation, Baltimore, MD; the US Food and Drug Administration (cooperative agreement nos. U0I FD01222 and FD-U-000082); Hoflmann-LaRoche, Inc., Nutley, NJ; CIBA-
GEIGY Corporation, Summit, NJ; Hoechst AG, Frankfurt, West Germany, McNeil Pharmaceutical, Spring House, PA, Merrell Dow Pharmaceuticals, Inc., Cincinnati, OH. The authors are indebted to the attending physicians at Princess Margaret Hospital, Sunnybrook Medical Centre, Toronto General Hospital, and Mt. Sinai Hospital for their collaboration; to the interviewers who collected the data, Anne Allen, Rosemary Chepa, Suzanne Gale, Kathleen Gillespie, Lindsay Hall, Linda Harrel, Virginia Hunter, Beverly Linden, Muriel Relton, Shirley Rothery, Irene Servos, Ann Skene-Melvin, Linda West, to Verna Cundari and Phyllis Disenhouse for coordination of data collection; and to Leonard Gaetano and Marguerite Angeloni for data management.
Editor's note: For a discussion of this paper and the accompanying paper by Kaufman el ai, see the Invited Commentary on p. 1396 and the reply by the authors on p. 1401.
1386
Estrogens and Breast Cancer
widely used in countries such as Canada and the United States (4), and a causal relation could therefore have a substantial impact on breast cancer incidence. The relation of estrogen use to breast cancer risk has been examined in many epidemiologic studies, with mixed and inconclusive results (5-26): no association was observed in several studies (5-9, 21, 23, 26), while others have observed a positive association (10-20, 22, 24). We investigated the relation between estrogen use and breast cancer risk in a case-control study of Canadian women, with particular attention given to long-term use.
MATERIALS AND METHODS Data collection
The data were obtained in a case-control study of breast cancer carried out from 1982 to 1986 in Toronto, Canada. The primary purpose was to evaluate the relation of alcohol consumption to breast cancer risk, but the study was designed so that other factors, including estrogen use, could also be evaluated. Eligible subjects were women under 70 years of age who lived in metropolitan Toronto, spoke English, and had no history of cancer. Subjects were interviewed in their homes after giving informed consent. A structured questionnaire administered by trained interviewers elicited information about demographic factors, reproductive factors, medical history, family history of breast cancer, and medication history. To elicit use of estrogens and other female hormones, subjects were asked to report drug use for regulation of menstrual periods, menstrual problems, breast conditions, cessation of postpartum milk flow, maintenance of a pregnancy, change of life, menopause, hot flashes, or sexual difficulties. For each episode of drug use, the name of the drug, indication for use, frequency of use, time since first taken, and duration of use were recorded. Photographs of estrogen pills marketed in Canada and the United States were used to aid recall.
1387
Cases. Cases were women under age 70 years who had histologically confirmed, primary breast cancer, diagnosed no more than 6 months before interview. They were identified at the Princess Margaret Hospital, the major cancer treatment hospital in metropolitan Toronto. Of 800 potential cases, 73 (9 percent) did not participate because their doctors refused, and 97 (12 percent) themselves refused to participate. An additional 23 potential cases (3 percent) were excluded because controls could not be found; thus, the final case series comprised 607 women. Estrogen and progestogen receptor status were determined within 6 weeks of the diagnosis for 528 of the 607 cases (27). Controls. Controls were identified from tax assessment rolls of all residents of Ontario. The maintenance of these records is mandated by provincial law, and the records are partially updated each year and completely updated every 3 years. For each case, the two women (other than next door neighbors) who were in the same decade of age and lived closest to the case were selected. A total of 1,874 eligible controls were contacted: 660 (35 percent) refused to participate and 1,214 (65 percent) were enrolled and interviewed.
Data analysis
Estrogen replacement therapy was defined as oral or injectable unopposed estrogens taken for the following indications: menstrual problems, "change of life," menopause, hot flashes, and sexual difficulties. Only use that occurred in the year before menopause or after the menopause was included. Women who had used estrogens for other purposes (cessation of lactation, breast conditions, and maintenance of a pregnancy) were considered in a separate category; virtually all of this use occurred well before the time of menopause. Four women who had used topical vaginal estrogen cream were also put in this "other use" category. Women who had used combination therapy (progestogens with estrogens) were considered separately. For all comparisons, the
1388
Palmer et al.
reference category was composed of women who had never taken any noncontraceptive estrogen. Because the controls were matched to the cases on neighborhood of residence as well as decade of age, all relative risk estimates were estimated from conditional logistic regression analyses (28). Age at menopause (which was associated with both breast cancer risk (29) and duration of estrogen use) was also controlled in all analyses in the following categories: pre- or perimenopausal, menopause before age 45, menopause at age 45-49, menopause at age 50 or older, and unknown age at menopause because of a hysterectomy without bilateral oophorectomy. Further control for type of menopause (natural or bilateral oophorectomy) did not alter the estimates. Known and potential risk factors for breast cancer (29) and factors thought to be related to estrogen use were controlled in multiple conditional logistic regression models; in addition to age, neighborhood, and age at menopause, these factors were type of menopause, history of breast cancer in a mother or sister, age at menarche, age at first birth, parity, history of cystic breast disease, oral contraceptive use, alcohol consumption, years of education, and number of visits to a physician in the year previous to the year before interview. The multivariate relative risk estimates were closely similar to those adjusted only for the matching factors and age at menopause, and the latter estimates are presented below. Because the study was designed to assess many factors, enrollment was not restricted to postmenopausal women; 41 percent of cases and 42 percent of controls were preor perimenopausal and had virtually no replacement estrogen use. Menopausal status was controlled in every analysis, and the inclusion of pre- and perimenopausal women did not affect the relative risk estimates or confidence intervals. Of the postmenopausal women, 67 percent of cases and 69 percent of controls had a natural menopause, 13 percent of cases and 13 percent of controls had a surgical menopause with bi-
lateral oophorectomy, and 20 percent of cases and 18 percent of controls had a hysterectomy with retention of one or both ovaries. Among women who had either a natural menopause or a bilateral oophorectomy, the menopause occurred before age 45 in 12 percent of cases and 20 percent of controls. RESULTS
Replacement estrogens without progestogens were taken by 15 percent of the cases and 15 percent of the controls (table 1). After adjustment for the matching factors and for age at menopause, the relative risk estimate for ever use of unopposed estrogen replacement therapy was 1.0 (95 percent confidence interval (CI) 0.7-1.3); the corresponding multivariate estimate was also 1.0. The relative risk estimate for women in the category of "other use" was 1.3 (95 percent CI 0.72.6); virtually all of this use was for short durations. The estimated relative risk for use of estrogens with progestogens was 0.6 (95 percent CI 0.2-2.0); two cases and one control had used combination therapy for 5 or more years. All subsequent analyses were confined to women who had used unopposed estrogens for replacement. Among the 279 users of unopposed replacement estrogens, 78 percent were able to identify the type of estrogen used: among them, 93 percent had taken conjugated estrogens, and 7 percent had used "other estrogens"—diethylstilbestrol, ethinyl estradiol, estradiol, or estropipate. The estimated relative risk for ever use of "other" estrogens was 2.2 (95 percent CI 0.8-6.3), and for 5 or more years of use, based on three exposed cases and two exposed controls, it was 2.6 (95 percent CI 0.4-16) (table 2). For users who could not specify the estrogen preparation, the relative risk estimates were 1.4 (95 percent CI 0.8-2.6) for ever use, and 2.3 (95 percent CI 0.8-6.9) for 5 or more years use (table 2). Five cases and three controls had used more than one type of estrogen. Limited numbers prohibited more detailed analysis of the use of nonconjugated and
Estrogens and Breast Cancer
1389
TABLE 1. Estrogen use among 607 breast cancer cases and 1,214 neighbor controls in a study conducted in Toronto, Canada, 1982-1986 Cases
Controls
Estrogen use No.
Never used Unopposed estrogens, for replacement Conjugated estrogens only Other estrogens Unspecified estrogens More than one type of estrogen Unopposed estrogens, for other indications§ Estrogens taken with progestogens
No.
Relative nsk estimate* (95% confidence interval)
Multivariate relative risk estimatet (95% confidence interval)
493 94
(81) (15)
991 185
(82) (15)
1.0* 1.0(0.7-1.3)
1.0* 1.0(0.8-1.4)
60
(10)
144
(12)
0.8(0.6-1.1)
0.9 (0.6-1.2)
8 21 5
(1) (3) (1)
7 31 3
(0) (3) (0)
2.2 (0.8-6.3) 1.4 (0.8-2.6) 3.7(0.9-16)
2.8 (0.9-8.3) 1.4 (0.7-2.6) 3.9(0.9-17)
16
(3)
24
(2)
1.3 (0.7-2.6)
1.4(0.7-2.7)
4
(1)
14
(1)
0.6 (0.2-2.0)
0.6 (0.2-1.9)
* Adjusted for matching factors and age at menopause. t Estimates from multivariate conditional logistic regression Adjusted for the matching factors and the following factors: type of menopause, age at menopause, age at menarche, parity, age at first birth, family history of breast cancer, history of cystic breast disease, body mass index, education, alcohol consumption, oral contraceptive use, number of physician visits in the previous year. J Reference category. § Cessation of lactation, breast conditions, or maintenance of a pregnancy
unspecified estrogens. The remaining analyses concern use of conjugated estrogens only. The relative risk estimate for ever use of conjugated estrogens relative to never use was 0.8 (95 percent CI 0.6-1.1); the corresponding multivariate estimate was 0.9 (95 percent CI 0.6-1.2). The estimate for use of 15 or more years was 1.4 (95 percent CI 0.63.3); the corresponding multivariate estimate was 1.5 (95 percent CI 0.6-3.8) (trend test according to duration of use by halfdecade, p = 0.7) (table 2). When >15 years of use was divided further into 15-19 and >20 years o ' use, the estimates were 1.2 (based on four exposed cases and seven exposed controls), and 1.6 (based onfiveexposed cases and eight exposed controls), respectively. As shown in table 3, when the analyses were confined to postmenopausal women, the relative risk estimates for durations of conjugated estrogen use longer than 5 years are identical to those estimated for the same use in the overall data set. Other results in postmenopausal women are closely similar
to the results presented in table 2 for the overall study group. Among women under age 60 years, there was no significant increase in risk in any duration category (table 4). Most of the longterm estrogen use occurred among women aged 60-69 years. In this age group, the relative risk estimate for 10 or more years of use was 1.4 (95 percent 0.7-3.2) and for 15 or more years of use it was 2.6 (95 percent CI 0.9-7.0). To evaluate recency of use, we estimated relative risks according to the time elapsed since last use (table 5). The estimated relative risk for use that ended within the year before interview was 0.4 (95 percent CI 0.2-0.9); for use that ended 1-2 years before, the estimate was 5.2 (95 percent CI 2.0-13); and for all other categories, the estimates ranged from 0.4 to 1.0. When the analysis was restricted to women who had used conjugated estrogens for 5 or more years, the estimates were 0.7 (95 percent CI 0.3-1.5) for use that ended in the year before interview and 2.0 (95 percent CI 0.6-7.4) for use that ended 1-2 years before interview. Re-
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TABLE 2. Duration of use of unopposed estrogens for replacement among breast cancer cases and neighbor controls in a study conducted in Toronto, Canada, 1982-1986
Duration of use (years)
Never used Conjugated estrogens only 15 Unknown duration Other estrogens only 5 Unspecified estrogens only 5 Unknown duration More than one type 5
No. of cases
No of controls
493
991
16 19 11 5 9 0
Relative risk estimate* (95% confidence interval)
Multivariate relative nsk estimatet (95% confidence interval)
1-0*
1.0*
33 50 28 16 15 2
0.9 (0.5-1.7) 0.7 (0.4-1.3) 0.8 (0.4-1.6) 0.6(0.2-1.8) 1.4 (0.6-3.3)
0.9 (0.5-1.8) 0.7 (0.4-1.3) 0.9(0.4-1.8) 0.7 (0.2-1.9) 1.5 (0.6-3.8)
5 3
5 2
2.1 (0.6-7.4) 2.6(0.4-16)
13 7 1
23 7 1
1.1 (0.5-2.3) 2.3 (0.8-6.9)
2 3
1 2
3.9 (0.3-45) 3.6 (0.6-22)
* Adjusted for matching factors and age at menopause. t Estimates from multivariate conditional logistic regression. Adjusted for the matching factors and the following factors: type of menopause, age at menopause, age at menarche, parity, age at first birth, family history of breast cancer, history of cystic breast disease, body mass index, education, alcohol consumption, oral contraceptive use, number of physician visits in the previous year t Reference category.
suits from multivariate analyses were virtually identical. To evaluate latency, we estimated relative risks according to years since first use of conjugated estrogens (20 years) and according to total duration of use (5 years) (table 6). Among women who had taken estrogens for less than 5 years, the estimate for each category of interval since first use was below 1.0. Among women who used estrogens for at least 5 years, the estimate for 10-19 years since first use was 0.5 (95 percent CI 0.2-1.0) and for >20 years it was 2.1 (95 percent CI 0.9-5.0). We estimated relative risks for 5 or more years use compared with never use within strata of various risk factors (table 7). For most factors, the estimates did not vary appreciably among the strata. The largest relative risk estimate, 1.5, was among women whose first birth was before age 25, and the smallest, 0.4, was among those whose first
birth occurred at age 25 or older; neither estimate was statistically significant. We had information on estrogen receptor (ER) status for 528 of the cases: 351 were classified as ER positive (an assay of 10 or more femtomoles per milligram) and 177 as ER negative. Among both ER positive women (and their matched controls) and ER negative women (and their matched controls), the relative risk estimate for 5 or more years use was 1.0. More than half of the women who used conjugated estrogens could not identify the dose, and thus we were unable to evaluate dosage. DISCUSSION
We found no material association between conjugated estrogen use and the risk of breast cancer. There was not a significant trend with increasing duration of estrogen
Estrogens and Breast Cancer
use, and the duration-specific relative risk estimates for use lasting less than 15 years were of the magnitude 0.8 to 1.1. For 15 or more years of use, the point estimate of relative risk was elevated, but it was statistically compatible with no association. The elevated risk among long-term users was concentrated among those who had begun use at least 20 years previously, but, again, the increase was compatible with no association. Because the prevalence of long-term use was greatest in the oldest women, an adverse effect would have been most easily detected in that age group (60-69 years); the estimate for the longest duration category was elevated, 2.6, but for the next longest category it was 0.7. When the data were stratified according to a range of other risk factors for breast cancer, there was no significant evidence of an increased risk for 5 or more years of exposure. Current use or use that ended less than 12 months before interview was not associated with an increased risk. A statistically signifTABLE 3. Duration of use of unopposed estrogens for replacement, among postmenopausal women only, in a study of breast cancer cases and neighbor controls conducted in Toronto, Canada, 1982-1986
Duration of use (years)
Relative risk estimate* No of No. of (95% cases controls confidence interval)
Never used 260 Conjugated estrogens only 15 9 Unknown 0 Other estrogens only
