B

Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature

DAVID B. THOMAS

Analysis of many of the risk factors for breast cancer suggests that endogenous ovarian hormones are of importance in the genesis of human mammary carcinomas. For example, risk is inversely related to age at menarche, and the younger a woman is at the time of her first full-term pregnancy, the lower her risk, suggesting that endocrinologic changes in a woman's early adult life can alter her susceptibility to breast cancer. Subsequent pregnancies after the first, and prolonged lactation, may reduce risk, whereas a first full-term pregnancy after about age 30 appears to enhance risk, suggesting that endocrinologic alterations during a woman's later reproductive years may also influence her risk. Finally, risk is inversely related to a woman's age at natural menopause or oophorectomy, indicating that endogenous hormonal changes late in reproductive life can have an impact on breast cancer development.

Because endogenous hormones presumably play an important role in breast cancer development, it is reasonable to ask whether exogenous hormones might also alter the risk of breast cancer. Unfortunately, the specific endocrinologic changes that mediate the various

David B. Thomas is professor of Epidemiology at the University of Washington andhead of the Program in Epidemiology, Division of Public Health Sciences, at the Fred Hutchinson Cancer Research Center, Seattle, Washington.



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Oral Contraceptives & Breast Cancer B Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature DAVID B. THOMAS Analysis of many of the risk factors for breast cancer suggests that endogenous ovarian hormones are of importance in the genesis of human mammary carcinomas. For example, risk is inversely related to age at menarche, and the younger a woman is at the time of her first full-term pregnancy, the lower her risk, suggesting that endocrinologic changes in a woman's early adult life can alter her susceptibility to breast cancer. Subsequent pregnancies after the first, and prolonged lactation, may reduce risk, whereas a first full-term pregnancy after about age 30 appears to enhance risk, suggesting that endocrinologic alterations during a woman's later reproductive years may also influence her risk. Finally, risk is inversely related to a woman's age at natural menopause or oophorectomy, indicating that endogenous hormonal changes late in reproductive life can have an impact on breast cancer development. Because endogenous hormones presumably play an important role in breast cancer development, it is reasonable to ask whether exogenous hormones might also alter the risk of breast cancer. Unfortunately, the specific endocrinologic changes that mediate the various David B. Thomas is professor of Epidemiology at the University of Washington andhead of the Program in Epidemiology, Division of Public Health Sciences, at the Fred Hutchinson Cancer Research Center, Seattle, Washington.

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Oral Contraceptives & Breast Cancer risk factors for breast cancer are unknown; thus, it is impossible to predict a priori which exogenous hormonal preparations, if any, would be expected to enhance or reduce risk. It is reasonable, however, to suspect that the effects of these preparations on the risk of breast cancer may vary, depending on their compositions and the time during a woman's life when they are taken. The purpose of this report is to critically review the results of epidemiologic studies of breast cancer in relation to combined oral contraceptives. Risk in relation to various features of use, and use at different times in a woman's life, are considered, as is use by women in various countries, and by women with and without other risk factors for breast cancer. Sequential oral contraceptives contain only an estrogen for approximately two weeks of a cycle of daily use, and an estrogen-progestin combination for an additional week. These preparations have not been adequately studied in relation to breast cancer and are therefore not considered in this review. For the same reason, progestogenonly and triphasic pills are also not considered. Results of studies of benign breast lesions and oral contraceptives are also not included in this review. The author has, however, recently reviewed this topic (Thomas, 1989) and little new information has been published since that review was written. METHODS The author reviewed all reports known to him of case-control and cohort studies of breast cancer in relation to use of oral contraceptives and ascertained estimates of relative risks of breast cancer in relation to various measures of use from each study. When results of multiple studies of a particular exposure were available, the results of each were summarized in tabular form; when appropriate, if sufficient detail was available in the published reports, summary relative risks based on data from all relevant studies, and 95 percent confidence intervals of these summary relative risks, were estimated according to methods developed by Prentice (Prentice and Thomas, 1986). When these estimates were made, a chi-square test for heterogeneity of the estimates from the various studies was also performed. A statistically significant (p < .05) chi-square for heterogeneity suggests that the results of the summarized studies are not consistent and that nonbiological reasons for the variations in findings should be considered. Summary relative risks were calculated separately for case-control and cohort studies because these two investigative techniques are prone to different sources of bias.

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Oral Contraceptives & Breast Cancer RESULTS Risk of Oral Contraceptive Users of All Ages in Developed Countries Table B-1 shows results from 15 case-control studies that were conducted in developed countries and included women of all ages who were at risk of prior exposure to oral contraceptives. Excluded from this table are studies that did not report results for women of all ages combined (Lubin et al., 1982; McPherson et al., 1987); studies that were part of a larger collaborative study (e.g., Ellery et al., 1986); a study that used women with benign breast disease as controls (Clavel et al., 1981); and reports of studies that have been updated by subsequent reports (e.g., Brinton et al., 1982). Only one of the studies summarized in Table B-1 found a relative risk of breast cancer in TABLE B-1 Relative Risks of Breast Cancer in Women in Developed Countries Who Have Ever Used Oral Contraceptives: Case-Control Studies of Women of All Ages at Risk of Exposure First Author (Date) Upper Age Limit (years) No. of Cases/Controls Users Nonusers Estimate of Relative Risk (Confidence Interval) a Henderson (1974) 64 59/69 248/238 0.7[0.5,1.2] Paffenbarger (1977) 50 226/398 226/474 1.1[0.9,1.4] Sartwell (1977) 74 22/34 262/333 0.9(0.5,1.5) Ravnihar (1979) 64 30/65 160/315 0.9[0.6,1.5] Kelsey (1981) 74 30/141 300/1,207 0.9(0.6,1.3) Harris (1982) 54 36/189 73/279 1.0(0.6,1.4) Vessey (1983) 50 537/554 639/622 1.0(0.8,1.2) Rosenberg (1984) 59 397/2,558 794/2,468 0.9(0.8,1.1) Talamini (1985) 79 15/23 353/351 0.7(0.4,1.4) CASH b (1986) 54 2,743/2,802 1,870/1,774 1.0(0.9,1.1) Paul (1986) 54 310/708 123/189 0.9(0.7,1.3) La Vecchia (1986) 60 104/178 672/1,104 1.1(0.8,1.5) Ravnihar (1988) 54 162/467 372/1,522 1.6(1.3,2.1) Stanford (1989) >60 481/515 1,541/1,668 1.0(0.9,1.2) WHO (1990) c 62 438/1,496 716/1,888 1.1(0.9,1.3) Summary relative risk       1.0[1.0,1.1] d a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data. b CASH = Cancer and Steroid Hormone Study. c WHO = World Health Organization. d p value of chi-square test for heterogeneity = .08.

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Oral Contraceptives & Breast Cancer TABLE B-2 Relative Risks of Breast Cancer in Women Who Have Ever Used Oral Contraceptives: Cohort Studies     No. of Cases per 1,000 Person-Years   First Author (Date) Upper Age Limit (years) “Ever” Users “Never” Users Estimate of Relative Risk (Confidence Interval) a Trapido (1981) b >50 0.93 (85) 1.11 (370) 0.84(0.7,1.10) Vessey (1981) c 45 0.50 (39) 0.52 (33) 0.96(0.59,1.63) Kay (1988) c 64 0.64 (143) 0.52 (96) 1.22(0.93,1.60) Romieu (1989) d 65 1.45 (717) 1.76 (1,041) 1.07(0.97,1.19) Mills (1989) e 67 0.93 (29) 1.65 (64) 1.54(0.94,2.53) Summary relative risk         Excluding Mills (1989)       1.04[0.96,1.13] f Including Mills (1989)       1.06[0.97,1.15] g a Confidence interval of 95 percent used; [ ] confidence intervals estimated from published reports. b Conducted in the Boston area. c Study conducted in Britain. d Nurses Health Study (U.S.A.) e Conducted among Seventh Day Adventists (U.S.A.). f p value of chi-square test for heterogeneity = .18. g p value of chi-square test for heterogeneity = .13. women who had ever used oral contraceptives that was significantly greater than 1.0 (Ravnihar et al., 1988), and the summary relative risk is close to unity, with narrow confidence limits. The variability of the relative risk estimates among studies was not statistically significant (p = .08). Table B-2 summarizes relative risk estimates from five cohort studies of women who have ever used oral contraceptives. Results from the Vessey study (1981) have been updated (Vessey et al., 1989) but not reported for women of all ages combined, and the updated results therefore could not be included in this table, or in Table B-4 and Table B-6. The study of Mills and colleagues (1989) was conducted among Seventh Day Adventists, who tend to have rates of breast cancer that are somewhat lower than women in the general U.S. population. Summary relative risks were therefore calculated with and without inclusion of data from that study. Both summary estimates are close to 1.0, with narrow confidence limits that barely include 1.0. The heterogeneity of the estimates from the individual studies could have occurred readily by chance. All of the relative risk estimates from the individual studies have 95 percent confidence intervals that include 1.0; although three are of borderline statistical significance.

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Oral Contraceptives & Breast Cancer TABLE B-3 Relative Risks of Breast Cancer in Long-term Users of Oral Contraceptives in Developed Countries: Case-Control Studies of Women of all Ages at Risk of Exposure       No. of Cases/Controls   First Author (Date) Minimum Years of Use Age of Cases (years) Long-term Users Nonusers Estimate of Relative Risk (Confidence Interval) a Harris (1982) 5 35-54 17/99 73/279 0.8(0.5,1.4) Ravnihar (1988) 7 25-54 34/66 372/1,522 2.4(1.5,3.8) b Paffenbarger (1977) 8 <50 17/26 104/195 1.7[0.9,3.3] Vessey (1983) 8 16-50 66/66 639/622 1.0(0.7,1.5) WHO (1990) c 8 <62 89/206 716/1,888 1.4(1.0,1.9) Rosenberg (1984) 10 20-59 25/128 794/2,468 0.8(0.5,1.3) CASH d (1986) 15 20-54 45/69 1,870/1,774 0.6(0.4,0.9) Paul (1986) 10 25-54 63/130 123/189 1.0[0.7,1.4] Stanford (1989) 15 <40->60 8/13 1,541/1,668 0.7(0.3,1.6) Summary relative risk         1.1[0.9,1.2] e a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data. b p value of test for trend of increasing risk with duration of use < .05. No significant trends were observed in other studies. c WHO = World Health Organization; based on data from three developed countries only (Israel, German Democratic Republic, and Australia). d CASH = Cancer and Steroid Hormone Study. e p value of chi-square test for heterogeneity = .0005. Table B-3 shows estimates from nine case-control studies of the relative risk of breast cancer in long-term users of oral contraceptiges. As in Table B-1, the studies shown are restricted to those in developed countries that include women of all ages at risk of exposure. The summary relative risk is not appreciably or significantly greater than 1.0, although there is considerable variation in results among the various studies. Only one study (Ravnihar et al., 1988) found a significant trend of increasing risk with duration of exposure. Estimates of relative risks in long-term users from four cohort studies are shown in Table B-4. The results from the studies of Trapido (1981) and Romieu and colleagues (1989) refer to duration of use prior to entering the cohort, and do not include women who used oral contraceptives after the cohort was established. The Vessey study (1989) is not included in the table because results were not presented for women of all ages combined. As in Table B-2, summary relative risks are shown including and excluding results from the Seventh Day Adventist Study (Mills et al., 1989), although the numbers of long-term users in that study were too small to influence the value of the summary relative risk appreciably. A (nonsignificant) relative

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Oral Contraceptives & Breast Cancer TABLE B-4 Relative Risks of Breast Cancer in Long-term Users of Oral Contraceptives: Cohort Studies       Cases per 1,000 Person-Years (No. of Cases)   First Author/Date MinimumYears of Use Upper Age Limit of Cases (years) Long-term Users Nonusers Estimate of Relative Risk (Confidence Interval) a Trapido (1981) 5 >50 0.96 (15) 1.11 (370) 0.86[0.52,1.43] Kay (1988) 10 65 0.75 (22) 0.52 (96) 1.44(0.91,2.29) Romieu (1989) 10 65 1.73 (63) 1.76 (1,041) 1.09[0.84,1.41] b Mills (1989) 10 67 1.20 (2) 1.65 (64) 1.42(0.34,5.98) Summary relative risk           Excluding Trapido         1.17[0.94,1.46] c Excluding Mills         1.11[0.90,1.36] d No exclusions         1.11[0.91,1.36] e a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data. b Estimated by combining relative risks of 1.09(0.83,1.43) and 1.06(0.49,2.76) for users of 10-15 and >15 years, respectively. c p value of chi-square test for heterogeneity = .57. d p value of chi-square test for heterogeneity = .34. e p value of chi-square test for heterogeneity = .52. TABLE B-5 Relative Risks of Breast Cancer Long After Initial Use of Oral Contraceptives: Case-Control Studies of Women of All Ages for Risk of Exposure       No. of Cases/Controls   First Author/ Date Upper Age Limit of Cases (years) Minimum Years Since First Use Long-term Users Nonusers Estimate of Relative Risk (Confidence Interval) a Harris (1982) 54 15 15/45 73/279 1.4(0.8,2.4) Vessey (1983) 50 12 112/154 639/622 0.7(0.5,1.0) Rosenberg (1984) 59 15 101/347 794/2,468 1.1(0.9,1.4) CASH b (1986) 54 20 Not given 1,872/1,774 0.8(0.7,1.0) La Vecchia (1986) 60 10 63/72 672/1,104 1.5(1.0,2.1) Paul (1986) 54 15 217/431 123/198 0.9[0.7,1.2] Ravnihar (1988) 54 12 60/195 372/1,522 1.4(1.0,2.0) c Stanford (1989) >60 15 98/127 1,541/1,668 0.8(0.6,1.1) WHO (1990) d 62 15 96/350 716/1,888 0.9(0.7,1.2) Summary relative risk         1.0[0.9,1.1]e a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data. b CASH = Cancer and Steroid Hormone Study. c p value of test for trend of increasing risk with duration of use = < .05. No significant trends observed in other studies. d WHO = World Health Organization; based on data from three developed countries only (Israel, German Democratic Republic, and Australia). e p value of chi-square test for heterogeneity = .004.

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Oral Contraceptives & Breast Cancer TABLE B-6 Relative Risks of Breast Cancer Long After Initial Use of Oral Contraceptives: Cohort Studies       Cases per 1,000 Persons (No. of Cases)   First Author (Date) Minimum Years Since First Use Upper Age Limit of Cases (years) Long-term Users Nonusers Estimate of Relative Risk (Confidence Interval) a Trapido (1981) 10 >50 1.13 (31) 1.11 (370) 1.0[0.7,1.5] Vessey (1981) 12 45 0.82 (7) 0.52 (33) 1.6[0.7,3.6] Kay (1988) 10 64 0.96 (17) 0.52 (96) 1.9(1.1,3.1) b Romieu (1989) 20 65 1.75 (143) 1.76(1,041) 1.0(0.9,1.2) Summary relative risk         1.1[0.9,1.3] c a Confidence interval of 95 percent used; [ ] = confidence intervals estimated from published data. b p value of chi-square test for linear trend = .01. No significant trends were observed in other studies. c p value of chi-square test for heterogeneity = .13. risk of 1.11 in long-term users was estimated by combining results from all four studies. When results were considered only from the three studies that provided estimates in users of more than 10 years ' duration, a combined relative risk of 1.17 was obtained; but the 95 percent confidence interval of this estimate also includes 1.0. The results of the four studies are not significantly heterogeneous. No significant trends of increasing risk with longer duration of use were observed in any of the studies. Table B-5 summarizes results from nine case-control studies that attempted to assess risk long after initial exposure to combined oral contraceptives. No consistent increase in risk 10 to 20 years since first exposure is evident. The relative risks of 0.7 and 0.8 in the investigations by Vessey and colleagues (1983) and the Cancer and Steroid Hormone Study (1986), and of 1.4 in the studies by La Vecchia and coworkers (1986) and Ravnihar and colleagues (1988), were of borderline statistical significance; but only the Ravnihar study found a significant trend in risk with time since initial exposure. Although the summary relative risk is close to 1.0, the corresponding chi-square test for heterogeneity is statistically significant (p < .05), suggesting that caution should be exercised in interpreting this summary relative risk estimate. Results from three of four cohort studies (Table B-6) do not show a significant alteration in risk long after initial exposure to oral contraceptives, but one (Kay and Hannaford, 1988) found a significant trend of increasing risk with time since first use. The

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Oral Contraceptives & Breast Cancer reasons for these discrepant findings are not known, but such varying results indicate that interpretations should be made with caution. In the aggregate, the information summarized in Table B-5 and Table B-6 suggests that the use of oral contraceptives has not greatly influenced the risk of breast cancer in women of all ages combined, one to two decades after initial exposure. Risk in Oral Contraceptive Users in Developing Countries Results were recently published from a large hospital-based case-control study that was conducted primarily to determine whether possible relationships between oral contraceptives and breast (and other) cancers differ in developing and developed countries (World Health Organization [WHO], 1990). Such countries tend, respectively, to have relatively lower and higher rates of breast cancer. Based on data from three developed countries (Australia, German Democratic Republic, and Israel) and seven developing countries (Chile, Colombia, China, Kenya, Mexico, the Philippines, and Thailand), relative risks were found to be 1.07 (95 percent confidence interval (CI) = 0.91,1.26) and 1.24 (CI = 1.05,1.47), respectively, in women who had ever used oral contraceptives. The data also showed that women in developing countries had stronger trends of increasing risk with longer duration of use, and of decreasing risk with years since first or last exposure, than women in developed countries. Although it was concluded that a combination of chance and minor sources of bias and confounding could not be ruled out as the cause of the findings in developing countries, no specific reason for the results being spurious was identified, and a causal interpretation must also be considered. Two smaller, population-based case-control studies in Costa Rica (Lee et al., 1987) and China (Yuan et al., 1988) yielded results that are not inconsistent with those of the WHO study. Results from all three investigations are summarized in Table B-7. Summary relative risks, based on data from the three studies, were estimated to be 1.21 (CI = 1.05,1.38) for “ever” users of oral contraceptives, and 1.59 (CI = 1.15,2.20) for long-term users (more than 8 to 10 years of use), respectively. The relative risk estimates from each of the three studies are not significantly heterogeneous. The relative risk for users of oral contraceptives that was observed in the Seventh Day Adventists Study (Mills et al., 1989), which was higher than those in other cohort studies (Table B-2), also supports the idea that relative risks of breast cancer in users of oral contraceptives are higher in low-risk than in high-risk populations.

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Oral Contraceptives & Breast Cancer TABLE B-7 Relative Risks of Breast Cancer in Users of Oral Contraceptives in Developing Countries: Summary of Three Case-Control Studies     Cases/Controls               Relative Risk (Confidence Interval) a First Author (Date) Country Nonusers Ever Users Long-term Users Ever Use Long-term Use Lee (1987) Costa Rica 97/427 58/321 6/29 b 1.2 0.9           (0.8,1.8) (0.4,2.6) Yuan (1988) China 435/439 99/95 16/12 b 1.06 1.40           (0.74,1.51) (0.62,3.17) WHO c (1989) Developing countries d 679/6,752 282/2,930 34/211 e 1.24 1.88           (1.05,1.47) (1.27,2.78) Summary relative risk         1.21 1.59           [1.05,1.38] f [1.15,2.20] g a Confidence interval of 95 percent used; [ ] = confidence intervals estimated by approximate methods. b Long-term = longer than 10 years. c WHO = World Health Organization. d Includes Chile, Colombia, China, Kenya, Mexico, the Philippines, and Thailand. e Long-term = longer than 8 years. f p value of chi-square test for heterogeneity = .43. g p value of chi-square test for heterogeneity = .10.

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Oral Contraceptives & Breast Cancer Two possible biological reasons for these results have been proposed. One is that oral contraceptives could exert a small additive effect on risk, independent of the influence of other risk factors (WHO, 1990). Such an effect would give rise to higher relative risks in low-risk populations, even if the absolute increase in risk in users of oral contraceptives was the same in all populations. The other possible hypothesis, developed by Stalsberg and colleagues (1989), is that oral contraceptives enhance risk in low-risk populations by stimulating proliferation of the stem cells of the lobules; this phenomenon occurs to a greater extent in low risk populations (in which the lobular epithelium is not close to being maximally stimulated by other factors) than in high-risk populations (in which the lobular epithelium has reached its maximum proliferative capacity and thus cannot readily respond to the additional stimulus of exposure to oral contraceptives). In support of this hypothesis, Stalsberg and colleagues noted that tubular and lobular carcinomas, which probably arise from the lobular ductal epithelium, are more strongly related to oral contraceptives (and other presumably hormonally mediated risk factors) than are other histological types, which are more likely to arise from ductal epithelium. Risk in Oral Contraceptive Users With and Without Various Risk Factors for Breast Cancer If either of the above explanations for the possible higher relative risks of breast cancer among oral contraceptive users in low-risk populations is correct, then one might expect also to observe higher relative risks in women without other risk factors for breast cancer than in women with such risk factors. Alternatively, if oral contraceptives enhance risk by potentiating the effect of other risk factors, then one would expect to observe higher relative risks in users with the other risk factors than in users without them. Results from studies that assessed risk in users with and without various risk factors are in this section. As shown in Table B-8, the WHO study (WHO, 1990) found a somewhat higher relative risk in users of low socioeconomic status (who tend to be at relatively low risk of breast cancer) than in women of higher status. This was not observed by Miller and colleagues (1989), however. Nulliparous women tend to be at higher risk of breast cancer. Some nulliparous women are infertile and less likely than other women to use oral contraceptives; consequently, several studies (Table B-9), have assessed risk of breast cancer in relation to oral contraceptive use

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Oral Contraceptives & Breast Cancer separately for nulliparous women. The results are inconsistent. Two studies found increasing risk with longer duration of use in young women (Stadel et al., 1989; U.K. National Case-Control Study Group, 1989), and another (Meirik et al., 1986) found significantly elevated relative risks in nulliparous women regardless of duration of use. Other equally well-designed and well-conducted studies, however, found no increase in risk in nulliparous users. Risk of breast cancer increases with the age of a woman at the time of her first live birth. Table B-10 shows relative risks in relation to use of oral contraceptives in women of varying ages at the time of their first live birth. No trends of increasing or decreasing relative risk associated with age at first birth are seen in any study. Women of high parity tend to be at low risk of breast cancer. Table B-11 shows that no studies have shown a trend in relative risks in users of oral contraceptives related to number of children that a woman has had. Table B-12 shows relative risks in users of oral contraceptives who do and do not have a family history of breast cancer. None of the studies summarized showed appreciable differences in the magnitude of relative risks between women with and without various affected relatives. Some studies have shown that obese women are at increased risk of breast cancer, especially in their postmenopausal years. As shown TABLE B-8 Relative Risk of Breast Cancer in Women of Various Socioeconomic Strata Who Have Ever Used Oral Contraceptives First Author (Date) Measure of Socioeconomic Status Level Relative Risk Confidence Interval (95%) Miller (1989) Years of education <13 2.3 Includes 1.0 a     13-16 1.6 Includes 1.0     >17 2.8 Includes 1.0 b WHO c (1990) Socioeconomic index d 4 (low) 1.86 1.07,3.24     3 1.13 0.91,1.40     2 1.14 0.94,1.39     1 (high) 1.12 0.94,1.32 a In multivariate analysis, relative risk = 2.7 (95 percent confidence interval [CI] excludes 1.0). b In multivariate analysis, relative risk = 3.9 (95 percent CI excludes 1.0). c WHO = World Health Organization. d Based on years of education and occupation.

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Oral Contraceptives & Breast Cancer TABLE B-25 Relative Risks of Breast Cancer in Women Who Used Combined Oral Contraceptives Near the Age of Menopause First Author (Date) Definition of Exposure Age or Years of Use Relative Risk Confidence Interval (95%) Vessey (1979) Use in past year 41-45 years old 0.85 Not given     46-50 years old 2.57 Not given Jick (1980) Current use 41-45 years old 0.8 0.1,4.6     46-50 years old 4.0 1.8,9.0     51-55 years old 15.5 5.2,46 Rosenberg (1984) Use in past year 40-49 years old 0.9 0.4,1.9     50-59 years old 1.0 0.1,1.7 Yuan (1988) Any use after age 45 Any use 4.00 1.15,16.59 Stanford (1989) Premenopausal years of use after age 40 <2 years 0.95 Includes 1.0     2-3 years 1.46 Includes 1.0     4-5 years 1.03 Includes 1.0     6-7 years 1.18 Includes 1.0     >8 years 1.05 Includes 1.0   Postmenopausal years of use after age 40 <2 years 0.76 Includes 1.0     2-3 years 0.51 Includes 1.0     4-5 years 0.97 Includes 1.0     6-7 years 1.49 Includes 1.0     >8 years 1.00 Includes 1.0 Romieu (1989) Use up to 2 years before diagnosis 40-44 years old 2.66 1.53,4.63     45-49 years old 1.63 0.81,3.27     50-54 years old 1.13 0.28,4.45 up to two years prior to diagnosis was associated with an elevated risk in three age groups above 39 years in the Nurses Health Study (Romieu et al., 1989), the relative risks were lower in 50- to 54-year-old women than in younger women. There is a suggestion of an increase in risk in users of from six to seven years after age 40 in postmenopausal women in the study of Stanford and colleagues (1989), but not in users of eight or more years' duration. Data from other studies should be analyzed to address this issue further, with particular emphasis on use that extends into the sixth decade of life. Individual Formulations and Constituents of Oral Contraceptives In 1983, Pike and coworkers reported that risk of breast cancer was particularly increased in association with use before age 25 of oral contraceptives with a high progestin potency, as determined by the

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Oral Contraceptives & Breast Cancer delay of menses test. This result may have been an artifact, however, that arose from the erroneous classification of one particular product as being of high potency (Armstrong, 1986). For purposes of comparison, results from the CASH Study (Stadel et al., 1985) were presented using the same classification scheme, and relative risks in users of products classified as of high progestin potency were not found to be significantly increased. Relative risks associated with four categories of duration, the longest being greater than 74 months, varied from 1.1 to 1.3 but did not increase with length of exposure. Miller and colleagues (1986) also did not confirm the findings of the Pike study. Relative risks of 1.0 (CI = 0.5,2.2) and 1.1 (CI = 0.4,3.0) were observed in users of two “high progestin potency” pills (Ovral and Ovulen 1, respectively). In 1987, McPherson and coworkers reported an increase in risk in relation to duration of use before a woman's first full-term pregnancy with oral contraceptives that contain the estrogen ethinyl estradiol, but not in relation to similar use of preparations containing mestranol. However, this result was not confirmed by Schlesselman and coworkers (1987) or Vessey and colleagues (1989). Three groups of investigators have reported relative risks in relation to use at any time of preparations containing ethinyl estradiol and mestranol. As shown in Table B-26, no study shows a stronger association with breast cancer for one type of estrogen than the other. Table B-27 similarly shows that no specific type of progestin has been implicated as being particularly associated with breast cancer risk. It should be noted that all of the progestins shown in the table except megestrol acetate are derivatives of 19-nor-testosterone. Formulations containing 17-α-hyroxyprogesterone derivatives (i.e., medroxyprogesterone acetate and chlormadinone) were shown to cause mammary tumors in beagle dogs, and were subsequently withdrawn from the market in many countries, including the United States. These products are in use in some countries of the world and were investigated in the WHO (1990) study. Analyses to assess the relative risk of breast cancer in users of such products are in progress, but results are not yet available. Finally, results from three studies that estimated relative risks of breast cancer in relation to specific pill types are summarized in Table B-28. No single formulation is consistently related to breast cancer across all three studies. Also, relative risks do not appear to be uniformly higher for the higher dose products (shown near the top of each section of the table) than for the lower dose pills. In support of these observations, Ravnihar and colleagues (1988) and Vessey and coworkers (1989) found no appreciable differences in the distributions of cases and controls by type of pill used. In addition, Vessey and colleagues found no difference in the distributions of person-years of exposure of cases and controls to specific formulations.

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Oral Contraceptives & Breast Cancer TABLE B-26 Associations Between Breast Cancer and Dosages of Mestranol and Ethinyl Estradiol in Oral Contraceptives First Author (Date) Dosage Measure of Association Mestranol Ethinyl Estradiol CASH a (1986) <1.0 mg-mo b Relative risk 0.8(0.7,1.1) 1.1(0.8,1.4)   1.0-2.9 mg-mo   1.0(0.8,1.2) 0.9(0.7,1.2)   3.0-4.9 mg-mo   1.1(0.9,1.4) 1.3(0.9,1.9)   >5.0 mg-mo   1.1(0.9,1.3) 0.8(0.5,1.2)   Any use   1.0(0.9,1.1) 1.0(0.8,1.2) U.K. National Case-Control Study Group (1989) <50/<100 micrograms c Relative risk a , d 1.08 1.04   >50/>100 micrograms e   1.03 1.12   Any strength   1.09 1.08 Vessey (1989) 30/50 micrograms f Mean months used in cases/mean months in controls 1.02 1.04   50/100 micrograms g   0.82 0.86   100/__ micrograms h   N.a. 0.60   Any strength   0.95 0.89 N.a. = Not applicable. a CASH = Cancer and Steroid Hormone Study. b mg-mo = Milligram - months of use. c <50 Micrograms ethinyl estradiol or <100 micrograms mestranol. d Estimated from published report by calculating mean relative risks weighted by woman-months of use. e >50 Micrograms ethinyl estradiol or >100 micrograms mestranol. f 30 Micrograms ethinyl estradiol or 50 micrograms mestranol. g 50 Micrograms ethinyl estradiol or 100 micrograms mestranol. h 100 Micrograms ethinyl estradiol. TABLE B-27 Associations Reported in Two Studies Between Breast Cancer and Types of Progestins in Oral Contraceptives Progestin CASH a (1986) Vessey b (1989) Ethynodiol diacetate c 1.1(0.9,1.4) 0.7 Norethindrone 1.1(1.0,1.3) 1.1 Norethindrone acetate c 1.1(0.7,1.6) 1.3 Norethynodrel 0.8(0.6,0.9)   Norgestrel (LorDL) 1.0(0.8,1.3) 1.0 Lynoestrenol c   0.9 Megestrol acetate   0.9 a CASH = Cancer and Steroid Hormone Study. Relative risks in women who only took oral contraceptives with the specific progestin shown. Parentheses indicated 95 percent confidence intervals. b Ratios of mean months of use in cases to mean months of use in controls. c Metabolized to norethindrone (Norethisterone).

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Oral Contraceptives & Breast Cancer TABLE B-28 Relative Risks of Breast Cancer in Women Who Have Ever Used Specific Types of Oral Contraceptives   Progestin       Micrograms of Mestranol Type Milligrams CASH (1986) a Miller (1989) b U.K. Study c (1989) 100 Ethynodiol diacetate 1.0 1.1(0.9,1.4) 1.1(0.4,2.9) 0.95 100 Norethynodrel 2.5 0.7(0.5,0.9) 2.6(0.6,11)   100 Norethisterone 2.0 1.3(1.0,1.7) 1.9(0.5,7.1) 1.18 80 Norethisterone 1.0 1.0(0.8,1.3) 0.7(0.2,2.6)   75 Lynestrenol 2.5     0.87 75 Norethynodrel 5.0 0.8(0.5,1.3)     60 Norethisterone 10.0 0.6(0.3,1.3)     50 Norethisterone 1.0 1.2(0.9,1.5) 3.3(1.5,7.1) 1.10 Micrograms of Estradiol           50 Ethynodiol diacetate 1.0 1.0(0.6,1.6) 1.0(0.3,3.6) 1.26 50 Lynestrenol 2.5     1.13 50 Megestrol acetate 4.0     0.96 50 Norethisterone acetate 4.0     1.36 50 Norethisterone acetate 3.0     1.09 50 Norethisterone acetate 2.5     1.21 50 Norethisterone acetate 1.0 1.6(0.9,2.8) 1.0(0.2,5.4) 1.11 50 Norgestrel 0.5 0.9(0.7,1.2) 1.8(1.0,3.3) 1.05 d 35 Norethisterone 0.5 0.8(0.5,1.2)   1.18 32 Levonorgestrel 0.09     0.83 30 Norgestrel 0.30 0.7(0.4,1.3) 0.8(0.3,2.1)   30 Levonorgestrel 0.25     1.00 30 Levonorgestrel 0.15     1.08 20 Norethisterone acetate 1.0     1.36 a CASH = Cancer and Steroid Hormone Study; ( ) = confidence interval of 95 percent. b ( ) = confidence interval of 95 percent. c U.K. Study = U.K. National Case-Control Study Group. d Relative risk was estimated by calculating the mean of the relative risks for two different products that contain 0.25 milligrams Levonorgestrel, weighted by woman-months of use.

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Oral Contraceptives & Breast Cancer CONCLUSIONS, INTERPRETATIONS, AND RECOMMENDATIONS FOR FURTHER RESEARCH Oral contraceptives, as they have been used to date, have caused little or no overall increase in the risk of breast cancer in women in developed countries. Risks in women of all ages combined have not been appreciably enhanced by more than a decade of exposure or after a potential latent period of up to two decades. Limited information from developing countries, where rates of breast cancer are much lower than in the developed countries where most studies of oral contraceptives and breast cancer have been conducted, suggests that oral contraceptive use may moderately enhance risk in women in low-risk populations. A possible mechanism for this increase is the stimulation of proliferative activity in the stem cells of the lobular epithelium. Such stimulation may not occur to a measurable extent in high-risk populations of women, whose lobular epithelia may already be maximally stimulated by other (unknown) factors that put these women at high risk. Further studies in low-risk populations are warranted. Oral contraceptives do not appear to have a differential impact on risk in women with and without such risk factors for breast cancer as high socioeconomic status, nulliparity, low parity, a late first fullterm pregnancy (or live birth), or a family history of breast cancer. Compared to risks of breast cancer among countries, which may differ by a factor of 10, the risks in women with and without each of these risk factors differ by a factor of only about 2 or 3. The potential for the lobular epithelium of the breast of women without these risk factors to be further stimulated by oral contraceptives, compared with this potential in women with these factors, may thus be smaller than the differential potential for lobular stimulation in women in low-and high-risk populations. (It may also be too small to measure by epidemiological means.) Further study of the influence of oral contraceptives in women with and without the generally recognized risk factors for breast cancer should not receive high priority. Limited information suggests that oral contraceptives (whether used before or after a benign lesion) may enhance the risk of breast cancer in young women with a prior history of benign breast disease but not in older women with such a history. Because the benign lesions in younger women are more likely than the benign lesions in older women to be fibroadenomas, further study of this issue should include young women in particular. It should also include a slide review to characterize the prior benign lesion histologically. In women of all ages combined, the use of oral contraceptives after benign lesions has not

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Oral Contraceptives & Breast Cancer been shown to enhance risk. The suggested study in young women should distinguish between use before and after the prior benign condition. Multiple studies of varying types have not consistently shown women who used oral contraceptives before the birth of their first child, or before the age of 25 years, to be at increased risk of breast cancer. Results among studies are more consistent for an increase in risk in women under the age of 45 who were long-term users of oral contraceptives (regardless of whether use occurred before or after a first birth or a particular age). Such users would, of course, tend to have been young at their initial use. This observed increase in risk is not likely to be due to differential screening for breast cancer in oral contraceptive users. There is suggestive but inconsistent evidence that it could be a result of the pill stimulating growth in preexisting tumors. Alternatively, oral contraceptives, when used early in life, could be causing a small absolute increase in risk in young women. It is of extreme importance to determine which of these two possible biological mechanisms may be operating. If it is the former, then oral contraceptives are not causing any new breast cancers; if it is the latter, they are, and this could theoretically continue and become even more of a problem with the aging of the cohort of women who have been exposed early in life. Rigorous epidemiological studies should therefore be conducted to continue monitoring for any enhanced risk of breast cancer among women in birth cohorts exposed at a young age to prolonged use of oral contraceptives. Such studies should not be confined to women below a specific arbitrary age. They should include a pathological component to measure indices of proliferative activity and determine the likely cells of origin of the tumors (whether ductal or lobular). The analyses of both the histologic and epidemiological data should be planned to provide evidence for or against the two above-mentioned biological mechanisms. Studies of survival in women with breast cancer would also be of value. If oral contraceptive users have more favorable survival than nonusers, this pattern would be evidence for a screening bias (or suggest that breast tumors that develop in response to oral contraceptives are less aggressive than other breast tumors). If survival is less favorable in users than in nonusers, this pattern would be evidence that oral contraceptives stimulate tumor growth (or suggest that breast tumors that develop in response to oral contraceptives are more aggressive than other breast tumors). Limited evidence suggests that use of oral contraceptives near the time of menopause may increase a woman's risk of breast cancer. A

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Oral Contraceptives & Breast Cancer possible mechanism for this is endocrinologic simulation of a delayed menopause by the exogenous estrogens and progestins. Further investigation of this issue is also warranted, perhaps most efficiently by reanalysis of data from existing studies, to estimate relative risks in relation to duration of use in women in their late 40s and 50s. No difference in possible associations with breast cancer has been observed between oral contraceptive formulations that contain mestranol and those that contain ethinyl estradiol. This finding is not surprising because the former is metabolized to the latter and the active estrogen is thus the same in both types of preparations. The progestins in almost all contraceptives that have been considered in studies of breast cancer to date are derivatives of 19-nor-testosterone. None have consistently been shown to be more strongly associated with breast cancer than others. Results of studies of oral contraceptives that contain 17-α-hydroxyprogesterone derivatives have not been published. Recent studies from New Zealand (Paul et al., 1989) and Costa Rica (Lee et al., 1987) have shown a possible increase in risk of breast cancer in some categories of users of the long-acting progestational agent depot-medroxyprogesterone acetate (DMPA), which is a 17-α-hydroxyprogesterone derivative. Results from the WHO (1990) study of both DMPA and oral contraceptives that contain chlormadinone are pending. In view of the existing findings on DMPA and reports of these progestational agents causing breast cancer in beagle dogs, additional studies of breast cancer in relation to products with these types of progestins may be warranted, particularly if the results from the WHO study are not reassuring. ACKNOWLEDGMENTS The statistical analyses reported in this appendix were performed by Elizabeth A. Noonan. The author thanks James Schlesselman and David Skegg for their helpful comments. REFERENCES Armstrong, B. K. 1986. Oral contraceptives and breast cancer (letter). Lancet 1: 552 . Brinton, L. A., R. Hoover, M. Szklo, and J. F. Fraumeni, Jr. 1982. Oral contraceptives and breast cancer. International Journal of Epidemiology 11: 316-322 . (CASH) Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development . 1986. Oral contraceptive use and the risk of breast cancer. New England Journal of Medicine 315: 405-411 . Clavel, F., M. Le, and A. LaPlanche. 1981. Breast cancer and use of antihypertensive

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Oral Contraceptives & Breast Cancer Possible effects of different pattern of use International Journal of Epidemiology 18: 527-532 McPherson, K., P. A. Coope, and M. P. Vessey. 1986. Early oral contraceptive use and breast cancer: Theoretical effects of latency. Journal of Epidemiology and Community Health 40: 289-294 McPherson, K., M. P. Vessey, A. Neil, R. Doll, L. Jones, and M. Roberts. 1987. Early oral contraceptive use and breast cancer: Results of another case-control study. British Journal of Cancer 56: 653-660 Meirik, O., E. Lund, H. O. Adami, R. Bergstrom, T. Christofferson, and P. Bergsjo, 1986. Oral contraceptive use and breast cancer in young women. A joint nationalcase-control study in Sweden and Norway. Lancet 2: 650-654 Meirik, O., T. M. M. Farley, E. Lund, H. O. Adami, T. Christofferson, and P. Bergsjo. 1989. Breast cancer and oral contraceptives: Patterns of risk among parous and nulliparous women—further analysis of the Swedish-Norwegan material Contraception 39: 471-475 Miller, D. R., L. Rosenberg, D. W. Kaufman, D. Schottenfeld, P. D. Stolley, and S. Shapiro. 1986. Breast cancer risk in relation to early oral contraceptive use. Obstetrics and Gynecology 68: 863-868 Miller, D. R., L. Rosenberg, D. W. Kaufman, P. Stolley, M. E. Warshauer, and S. Shapiro. 1989. Breast cancer before age 45 and oral contraceptive use: New findings American Journal of Epidemiology 129: 269-280 Mills, P. K., W. L. Beeson, R. L. Phillips, and G. E. Fraser. 1989. Prospective study of exogenous hormone use and breast cancer in Seventh-Day Adventists. Cancer 64: 591-597 Olsson, H., T. R. Moller, and J. Ranstam. 1989. Early oral contraceptive use and breast cancer among premenopausal women: Final report from a study in southern Sweden. Journal of the National Cancer Institute 81: 1000-1004 Paffenbarger, R. S., E. Fasal, M. E. Simmons, and J. B. Kampert. 1977. Cancer risk as related to use of oral contraceptives during fertile years. Cancer 39: 1887-1891 Paffenbarger, R. S., J. B. Kampert, and H. G. Chang. 1980. Characteristics that predict risk of breast cancer before and after the menopause. American Journal of Epidemiology 112: 258-268 Paul, C., D. C. G. Skegg, G. F. S. Spears, and J. M. Kaldor. 1986. Oral contraceptives and breast cancer: A national study. British Medical Journal 293: 723-726 Paul, C., D. C. G. Skegg, and G. F. S. Spears. 1989. Depot medroxyprogesterone (DepoProvera) and risk of breast cancer British Medical Journal 299: 759-762 Paul, C., D. C. G. Skegg, and G. F. S. Spears. 1990. Oral contraception and breast cancer in New Zealand. Pp. 85-94 in Oral Contraceptives and Breast Cancer, R. D. Mann, ed. Park Ridge, N.J.: The Parthenon Publishing Group. Pike, M. C., B. E. Henderson, J. T. Casagrande, I. Rosario, and G. E. Gray. 1981. Oral contraceptive use and early abortion as risk factors for breast cancer in young women. British Journal of Cancer 43: 72-76 Pike, M. C., B. E. Henderson, M. D. Krailo, A. Duke, and S. Roy. 1983. Breast cancer in young women and use of oral contraceptives: Possible modifying effect of formulation and age at use. Lancet 2: 926-930 Prentice, R. L., and D. B. Thomas. 1986. On the epidemiology of oral contraceptives and disease. Advances in Cancer Research 49: 285-401 Ravnihar, B., D. G. Seigel, and J. Lindtner. 1979. An epidemiologic study of breast cancer and benign breast neoplasia in relation to the oral contraceptive and estrogen use. European Journal of Cancer 15: 395-405 Ravnihar, B., M. Primic Zakelj, K. Kosmelj, and J. Stare. 1988. A case-control study of breast cancer in relation to oral contraceptive use in Slovenia. Neoplasma 35: 109-120

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Oral Contraceptives & Breast Cancer Romieu, I., W. C. Willett, G. A. Colditz, M. J. Stampfer, B. Rosner, C. H. Hennekens, and F. E. Speizer. 1989. Prospective study of oral contraceptive use and risk of breast cancer in women. Journal of the National Cancer Institute 81: 1313-1321 Rosenberg, L., D. R. Miller, D. W. Kaufman, S. P. Helmrich, P. D. Stolley, D. Schottenfeld, and S. Shapiro. 1984. Breast cancer and oral contraceptive use. American Journal of Epidemiology 119: 167-176 Sartwell, P. E., F. G. Arthes, and J. A. Tonascia. 1977. Exogeneous hormones, reproductive history and breast cancer. Journal of the National Cancer Institute 59: 1589-1592 Schlesselman, J. J., B. V. Stadel, P. Murray, and S. Lai. 1987. Breast cancer risk in relation to type of estrogen contained in oral contraceptives. Contraception 36: 595-613 Schlesselman, J. J., B. V. Stadel, P. Murray, and S. Lai. 1988. Breast cancer in relation to early use of oral contraceptives: No evidence of latent effect. Journal of the American Medical Association 259: 1828-1833 Stadel, B. V., and J. J. Schlesselman. 1986. Oral contraceptive use and the risk of breast cancer in women with a “prior” history of benign breast disease. American Journal of Epidemiology 123: 373-382 Stadel, B. V., G. L. Rubin, L. A. Webster, J. J. Schlesselman, and P. A. Wingo. 1985. Oral contraceptives and breast cancer in young women. Lancet 2: 970-973 Stadel, B. V., J. J. Schlesselman, and P. A. Murray. 1989. Oral contraceptives and breast cancer. Lancet 1: 1257-1258 Stalsberg, H., D. B. Thomas, E. A. Noonan, and the WHO Collaborative Study of Neoplasia and Steroid Contraceptives 1989. Histologic types of breast carcinoma in relation to international variation and breast cancer risk factors. International Journal of Cancer 44: 399-409 Stanford, J. L., L. A. Brinton, and R. N. Hoover. 1989. Oral contraceptives and breast cancer: Results from an expanded case-control study. British Journal of Cancer 60: 375-381 Talamini, R., C. La Vecchia, S. Franceschi, F. Colombo, A. Decarli, E. Grattoni, E. Grigoletto, and G. Tognoni. 1985. Reproductive and hormonal factors and breast cancer in a northern Italian population. International Journal of Epidemiology 14: 70-74 Thomas, D. B. 1989. The breast. Pp. 38-68 in Safety Requirements for Contraceptive Steroids, F. Michal, ed. Cambridge: Cambridge University Press. Trapido, E. J. 1981. A prospective cohort study of oral contraceptives and breast cancer Journal of the National Cancer Institute 67: 1011-1015 U.K. National Case-Control Study Group. 1989. Oral contraceptive use and breast cancer risk in young women. Lancet 1: 973-982 Vessey, M. P., R. Doll, K. Jones, K. McPherson, and D. Yeates. 1979. An epidemiological study of oral contraceptives and breast cancer British Medical Journal 1: 1755-1778 Vessey, M. P., K. McPherson, and R. Doll. 1981. Breast cancer and oral contraceptives: Findings in Oxford-Family Planning Association Contraceptive Study. British Medical Journal 282: 2093-2094 Vessey, M. P., K. McPherson, D. Yeates, and R. Doll. 1982. Oral contraceptive use and abortion before first term pregnancy in relation to breast cancer risk. British Journal of Cancer 45: 327-331 Vessey, M., J. Baron, R. Doll, K. McPherson, and D. Yeates. 1983. Oral contraceptives and breast cancer: Final report of an epidemiological study. British Journal of Cancer 47: 455-462

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Oral Contraceptives & Breast Cancer Vessey, M. P., K. McPherson, L. Villard-Mackintosh, and D. Yeates. 1989. Oral contraceptives and breast cancer: Latest findings in a large cohort study. British Journal of Cancer 59: 613-617 (WHO) World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. 1990. Breast cancer and combined oral contraceptives: Results from a multinational study. British Journal of Cancer 61: 110-119 Yuan, J., M. Yu, R. K. Ross, Y. T. Gao, and B. E. Henderson. 1988. Risk factors for breast concer in Chinese women in Shanghai. Cancer Research 48: 1949-1953