Type and Dosage of Oral Contraceptives
The specific oral contraceptive formulation might be important in determining cancer risk, but studies of this issue are difficult to perform, because study participants may not be able to remember specific formulations and may use a number of formulations over time, because very large studies are needed to have sufficient statistical power to examine individual brands, and because no satisfactory classification system exists for categorizing specific oral contraceptive formulations by their effect on breast tissue. Although only a few studies have evaluated this issue, overall, no consistent evidence is seen of a differential effect according to type or dosage of either estrogen or progestin.40 Limited data exist regarding the influence of the newer oral contraceptive formulations on breast cancer risk.

Interactions with Other Breast Cancer Risk Factors
Interactions of oral contraceptive use with other breast cancer risk factors have been evaluated in many studies. However, limited statistical power in these analyses has resulted in wide confidence limits and thus a limited ability to detect true differences; moreover, the categorization of oral contraceptive use was generally “ever use” versus “never use,” a crude and uninformative exposure definition. Possible interactions with other breast cancer risk factors were first evaluated in detail, with oral contraceptive use defined in terms of recency and age at first use, in the collaborative pooling project. Overall, the relationship between oral contraceptive use and breast cancer did not vary appreciably with family history of breast cancer, weight, alcohol intake, or other breast cancer risk factors.

Progestin-Only Contraceptives
Progestin-only contraceptives include progestin-only pills (“minipill”), depot-medroxyprogesterone (DMPA), and implantable levonorgestrel (Norplant). Although the progestin-only pill has been evaluated in few studies, no increase in breast cancer risk has been observed for women who have “ever used” this contraceptive. In the studies in which duration of use was evaluated, longer-term users were observed to have either a similar or lower risk of breast cancer compared with those who had never used this contraceptive. DMPA, an injectable contraceptive, also has received limited study in relation to breast cancer risk. In the most comprehensive study of this relationship, no significant increase in risk was observed with increasing duration of use (relative risk for more than 3 years of use versus no use was 0.9; 95% confidence interval, 0.6 to 1.4), although both long-term users who began use before age 25 years and users younger than age 35 years overall were observed to have a modest increase in breast cancer risk. Levonorgestrel, a long-acting contraceptive that is implanted subdermally, was introduced in the United States in 1990. No epidemiologic data have been published on levonorgestrel’s effect, if any, on breast cancer risk. Further epidemiologic research is needed for each of these drugs, particularly DMPA and levonorgestrel.

Summary of Oral Contraceptives and Breast Cancer Risk
Results of more than 50 studies have provided considerable reassurance that breast cancer risk increases little, if any, with oral contraceptive use in general, even among women who have used oral contraceptives for 10 or more years. A relatively consistent finding among previous case control studies, however, is an increase in risk among young women who used oral contraceptives for extended durations. This observation has not been confirmed by the larger prospective studies, although these studies included few very young women (younger than 35 years of age), the age group in which the increased relative risk was most consistently observed. In the recent pooled analysis, however, long-term use among young women was not independently associated with an increase in breast cancer risk. Rather, current users and recent users (those with fewer than 10 years since last use) were observed to have a modest elevation in risk compared with those who had never used oral contraceptives. This relationship most likely could not be discerned from the individual studies, because duration of use, rather than recency of use, was often reported. Among young women, the long-term users are more likely to be recent users,and thus large data sets (e.g., the pooled analysis) are needed to determine the independent effect of these variables.

Current and recent users, the group that appears to have a modest increase in risk, are generally young (younger than 45 years of age) and thus have a low absolute risk of breast cancer. Hence, a modest increase in their risk results in few additional cases of breast cancer. Nevertheless, this apparent increased risk among current and recent users should be considered in the overall decision of whether to use oral contraceptives.

Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz

W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
B. Rockhill: Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts
D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts
G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts

References