Over the years since OCs were first marketed in the early 1960s, pharmaceutical manufacturers have lowered the doses of estrogens and progestins (3
) in the hope of reducing adverse effects. However, use of lower-dose preparations was not associated with lower risk of breast cancer in a combined analysis of 54 studies (1
). If anything, the effect estimates were higher for lower-dose OC use, but the differences in estimates according to dose or time period, which correlates with dose, were not statistically significant.
OC users in recent studies will have taken lower doses of estrogen and progestin than women included in early studies. In the present analyses of women diagnosed with breast cancer after 1992, we found a positive association of OC use with increased breast cancer risk, and it was present among both younger and older women. Results from other reports based on women studied after the early 1990s have been inconsistent. In a follow-up study of Norwegian women, the relative risk estimate was 1.6 (95% CI: 1.2, 2.1) for women who were current or recent OC users at baseline (7
). In a follow-up study in the Netherlands, long-duration OC use was associated with increased breast cancer risk among women aged 55 years or older but not younger women (12
). In a Long Island case-control study of breast cancer, recent OC use and long-duration OC use were associated with increased breast cancer risk among premenopausal women but not among postmenopausal women (11
). In the population-based Carolina Breast Cancer Study, results were close to the null for white women, but OC use within the previous 5 years was associated with increased risk among black women (9
). In a population-based breast cancer study conducted in Los Angeles, California, results for OC use were null (13
). Results from the largest population-based case-control study, the Women's Contraceptive and Reproductive Experiences (CARE) Study, which included 4,575 cases and 4,682 controls, were largely null (10
Numbers were sufficient in the CARE Study to informatively assess associations of duration of OC use and interval since last use with breast cancer risk according to menopausal status, age, and ethnic group (white or black), and there were no associations with increased breast cancer risk. Similarly, there were no differences according to dose of estrogen or type of progestin in the OC formulation. The only significant differences were by study site. Subjects were drawn from Atlanta, Georgia (19%), Detroit, Michigan (16%), Los Angeles, California (27%), Philadelphia, Pennsylvania (16%), and Seattle, Washington (22%). Odds ratios for ever use of OCs were 0.7, 0.7, 1.0, 1.0, and 1.1, respectively, and 95% confidence intervals for the first 2 estimates excluded 1.0 (10
). For current OC use (within the 6 months before the index date), the estimates were 0.8, 0.4, 1.4, 1.7, and 1.2, respectively, and the 95% confidence interval for Detroit excluded 1.0. The authors were not able to explain the discrepancies according to study site and noted that relative risks for a variety of other factors, such as hormone replacement therapy, were consistent across sites.
If an effect of OC use on breast cancer risk is relatively small, one would expect variability of results among studies and within studies, and if recent OC use is more strongly related to risk than more distant use, an association might be weaker or absent among older women or postmenopausal women because of the scarcity of recent users. However, small effects would not be an explanation for the generally null results of the CARE Study, which had excellent power to detect small increases in risk associated with recent and long-duration OC use.
The odds ratios for the association of OC use with breast cancer risk in the present study were larger for black women than for white women, and breast cancer risk in black women decreased with increasing interval since last use and increased with increasing duration of use. However, the number of cases among black women was small, and none of these findings were statistically significant. In the population-based Cancer and Steroid Hormone Study, conducted from 1980 to 1982, there was a suggestion of increasing breast cancer risk with increasing duration of OC use among black women but not among white women (16
); recency of use was not assessed. In the Women's Interview Study of Health, a population-based case-control study conducted from 1990 to 1992, breast cancer risk increased with increasing duration of use among black women but not among white women (15
). Again, recency of use was not assessed. In the Carolina Breast Cancer Study, there was a significant trend of increasing risk with decreasing interval since last use among black women but not among white women (9
). There was also a suggestion of a tendency for breast cancer risk to increase as duration of use increased among black women. Thus, our present findings are consistent with results from several other studies and with findings from our earlier data (14
). However, contrary to this evidence, no increases in risk were observed among black or white OC users in the CARE Study, which was based on large numbers of black and white cases (1,622 and 2,953, respectively) (10
We found no evidence that the association of breast cancer risk with OC use differed according to the ER or PR status of the tumor, in agreement with several previous studies (21
). However, stronger associations with ER-negative tumors than with ER-positive tumors were found among women under age 35 years in the Women's Interview Study of Health (19
), in a case-control study conducted in Australia (20
), and in a case-case study conducted in Los Angeles (13
). The prevalence of ER-negative tumors is greater in black women than in white women (31
), so a stronger association of OC use with ER-negative tumors than with ER-positive tumors would be particularly important for black women. In the present study, numbers were too small to assess OC use in relation to tumor ER/PR status among black women specifically, and to our knowledge no other studies have published informative data on this question.
Selection bias is a particular concern in the present study. The overall participation rate of targeted subjects in the Case-Control Surveillance Study was high, but we could not assess the participation rate specifically among patients with the diagnoses included in the present analyses, because we did not record the diagnoses of people who refused participation. Selective referral of cases and controls (contingent on OC use) to the participating hospitals, which were a mix of teaching/research, cancer, and community hospitals, could have been a source of bias. To reduce the possibility of referral bias, we included in the study only women who lived within a 50-mile radius of the hospital. While we believe that this restriction is likely to have reduced referral bias, we are unable to demonstrate that this was the case. As a further guard against selection bias, we confined the control series to women with diagnoses unrelated to OC use. The prevalence of use was uniform across the various diagnostic categories, suggesting that the selection of controls was appropriate (28
All case-control studies based on interview are subject to reporting bias. Our inquiries about contraception were made in the context of questions about 43 indications for medication use in a study of many cancers, which masked the present hypothesis from participants and interviewers. On the other hand, because the goal of the Case-Control Surveillance Study was to assess a wide range of medications, not just OCs, the interviewers were not able to spend the amount of time that would have been necessary to elicit the most detailed information possible about OC use, nor did they use pictures or packets of OC pills marketed over the years to aid recall. Validation studies indicate that women are able to recall the duration of OC use accurately, with correlation coefficients exceeding 0.8 in some studies, but that recall of the formulation used is appreciably less accurate (32
). In the present study, women did not report the name of the preparation for 46% of their episodes of OC use, and they could not remember the exact dose of the components for an additional 11%. Thus, the inability to assess specific types of OC preparations is a limitation of the present study. However, younger women would probably have used lower-dose OCs than older women (3
), and we found similar and significantly increased odds ratios for OC use among women aged less than 50 years and women aged 50 years or more.
If OC users were more likely to undergo mammography and have their tumors detected, this could have contributed to positive associations with OC use. We lacked data on mammography use, but we did limit the analyses to invasive tumors. Major risk factors for breast cancer were controlled in the analysis.
Previous research based on data from the Case-Control Surveillance Study has found inverse associations of OC use with risk of endometrial cancer (33
) and ovarian cancer (34
) and a positive association with liver cancer (36
), in agreement with the literature (37
). Results on breast cancer risk factors based on the data from the Case-Control Surveillance Study (39
) are similar to findings from other studies (44
). Agreement between these findings supports the validity of the methods and data in the Case-Control Surveillance Study, but complete reassurance about the present results will require confirmation by other studies.
In summary, the present findings suggest that OC use is associated with an increased risk of breast cancer diagnosed in recent years. The data are compatible with a stronger association in black women than in white women and with a contribution of duration of use to risk, especially among black women, but the observed differences in risk by ethnic group or duration were not statistically significant. There were no differences according to hormone receptor status of the tumor. Given the widespread use of OCs, continued evaluation of their possible health effects may be warranted.