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Appendix B: Oral Contraceptives and Breast Cancer: Review of the Epidemiological Literature
Pages 102-142

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From page 102...
... 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.
From page 103...
... 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~.
From page 104...
... 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 Estimate of Relative Upper No. of Risk Age Limit Cases/Controls (Confidence First Author (Date)
From page 105...
... 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)
From page 106...
... ep 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 contraceptives.
From page 107...
... ep 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 Upper Age Minimum No.
From page 108...
... 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.
From page 109...
... 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)
From page 111...
... 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.
From page 112...
... 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.
From page 113...
... aConfidence interval of 95 percent used. by value of test for trend = .005.
From page 114...
... Risks were elevated in all three studies that confined analyses to young women (Lees et al., 1978; Paffenbarger et al., 1980; lanerich et al., 1983) with two of the studies showing an increasing risk with TABLE Bell Relative Risks of Breast Cancer in Women Who Have Ever Used Oral Contraceptives by Number of Children First Author/Date Number of Children (Study Design)
From page 115...
... Pike and colleagues (1981) confined their analyses ofdata from young women to use of oral contraceptives before a woman's first pregnancy.
From page 116...
... Such studies are in progress, however. Because oral contraceptives apparently protect against benign breast lesions, the assessment of the risk of breast cancer in users of oral contraceptives With prior benign lesions becomes complex.
From page 117...
... a a( ) = Confidence interval of 95 percent.
From page 118...
... It should also be noted that in two of the studies in Table B-16 TABLE B-15 Relative Risk of Breast Cancer in Women Who Used Oral Contraceptives Before and After Diagnosis of a Benign Breast Lesion Estimate of Relative Risk (Confidence Interval) a First Author (Date)
From page 119...
... . given given <12 12-47 248 o <47 48-95 296 209 35 46 26 22 18 268 60 26 11 11 235 27 43 46 48 15 12 51 73 32 13 6 1,946 149 133 91 Not 214 41 33 25 12 15 472 147 82 41 52 273 26 29 23 75 4 29 11 56 71 33 10 REVIEW OF THE EPIDEMIOLOGICAL LITERATURE 119 TABLE B-16 Relative Risks of Breast Cancer in Relation to Duration of Use of Oral Contraceptives Before First Full-term Pregnancy: Case-Control Studies First Author (Date)
From page 120...
... 1 Calculated by combining relative risks of 2.2(0.5,9.8)
From page 121...
... One cohort study (Vessey et al., 1989) found relative risks of 0.92 and 1.21 in women who had used oral contraceptives before age 25 for less than four years and for four or more years, respectively (based on 17 and 1 exposed cases, respectively)
From page 122...
... did not specifically publish results of use before age 25, the reports that have TABLE B-18 Relative Risks of Breast Cancer in Relation to Duration of Use of Oral Contraceptives Before a Woman's First Full-term Pregnancy, After Varying Potential Latent Periods Excluding Use Before First Full-term Pregnancy Within the Following Months of Use Years Prior to Diagnosis Before First First Author Full-term No 6 10 14 20 (Date) a Pregnancy Exclusions Years Years Years Years McPherson (1987)
From page 123...
... d relative risk aConfidence interval of 95 percent used; [ ] = confidence intervals estimated from published data.
From page 124...
... Table B-20 shows estimates from 13 studies of the relative risk of breast cancer in women under age 45 who have ever used oral contraceptives.
From page 125...
... bValue computed by combining relative risks of 0.8 and 1.3 in women in the age groups 20-29 and 30-39 years. CValue computed by combining relative risks of 4.6 and 0.84 in women in the age groups 25-34 and 35-44 years.
From page 126...
... In addition, one of these studies (Olsson et al., 1989) reported that the relative risk of breast cancer in women who had ever used oral contraceptives increased with decreasing age at first use.
From page 127...
... The other study (La Vecchia et al., 1986) reported a relative risk of 0.87 in women under age 40 who had ever used oral contraceptives.
From page 128...
... One is that the proportion of cases under age 45 in most of the studies of women of all ages was relatively small, and the increased risk in young women may have contributed too little to the overall estimated value of the relative risk to elevate it appreciably above unity. A second possible interpretation is that women who have used oral contraceptives may tend to have their tumors diagnosed earlier than do nonusers, due to more screening or breast self-examination (screening bias)
From page 129...
... A consideration of the histological features of breast tumors that have developed in users of oral contraceptives provides some suggestion that these products may stimulate tumor growth. Romieu and colleagues (1989)
From page 130...
... all found trends of increasing relative risk in young women with duration of use (Tables B-21
From page 131...
... Yet, individuals characterized by such use were not more likely than other users or nonusers to have smaller tumors or more localized disease at diagnosis. A small increase in risk in women who had used oral contraceptives for more than three years before age 25 was also observed in that study and such users did tend to have small tumors, but users of shorter duration, with an equally high relative risk, did not.
From page 132...
... 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
From page 133...
... . 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.
From page 134...
... Relative risks in women who only took oral contraceptives with the specific progestin shown. Parentheses indicated 95 percent confidence intervals.
From page 135...
... National Case-Control Study Group. dRelative risk was estimated by calculating the mean of the relative risks for two different products that contain 0.25 milligrams Levonorgestrel, weighted by womanmonths of use.
From page 136...
... 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)
From page 137...
... 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)
From page 138...
... 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.
From page 139...
... 1978. Oral contraceptives and breast disease in premenopausal northern Albertan women.
From page 140...
... 1977. Cancer risk as related to use of oral contraceptives during fertile years.
From page 141...
... 1987. Breast cancer risk in relation to type of estrogen contained in oral contraceptives.
From page 142...
... 1990. Breast cancer and combined oral contraceptives: Results from a multinational study.


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