Oral contraceptive use and breast cancer risk: current status.

One might have thought that the issue of whether oral contraceptives (OCs) are associated with breast cancer risk would have been settled by now, given that these agents were introduced in the early 1960s and more than 60 case-control and 10 cohort studies, several meta-analyses, a very large pooled analysis, and a major monograph have addressed this issue. On the basis of the accumulated data, the International Agency for Research on Cancer (IARC) classified oral estrogen-progestogen contraceptives as carcinogenic to humans (group 1 carcinogen) in 2005, which is a higher classification than the 1999 IARC evaluation. Of course things have changed, including OC formulations, the epidemiology of breast cancer, and patterns of use of OCs in the population. For example, the dosage of estrogen has decreased, new progestins (eg, desogestrel and norgestimate) have been introduced, the hormonefree interval has been shortened, and new delivery systems have become available. In the United States, breast cancer screening increased dramatically in the 1980s, breast cancer incidence rates increased in both the 1980s and the 1990s, and breast cancer mortality rates began declining in the early 1990s. In terms of use, a greater number of younger women are using OCs, and they are using them with increasing duration. Finally, our understanding of breast cancer pathogenesis has evolved. Animal studies, mathematical modeling, migrant studies, and accumulating results from epidemiological studies suggest that breast tissue is particularly susceptible to carcinogenic insults before differentiation during the first fullterm pregnancy. In this context, the meta-analysis by Kahlenborn et al in the current issue of Mayo Clinic Proceedings allows us to take stock of the current state of our knowledge of OC use and premenopausal breast cancer risk, particularly in relationship to first full-term pregnancy. They conducted a meta-analysis of 39 independent case-control studies that had most cases diagnosed since 1980 to better evaluate the association with breast cancer in the context of more contemporary use patterns. Overall, they found that compared to never use, ever use of OCs was associated with a small but statistically significant increased risk of breast cancer (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.09-1.29), although significant heterogeneity across individual studies could not be readily explained. These results are generally comparable to the Oxford pooled analysis published in 1996, which was based on pooled original data from 54 epidemiological studies (case-control and cohort) representing 53,297 women with breast cancer and 100,239 control patients and was thought to represent about 90% of the epidemiological information on the topic available at that time. In that analysis, a weaker overall risk of breast cancer was found for ever use compared with never OC use (OR, 1.07). The difference in risk between these 2 analyses is likely due in part to the studies included. In the Oxford pooled analysis, 66% of cases were 45 years or older at the time of diagnosis, and 50% of the cases were diagnosed before 1984. In contrast, the current meta-analysis included only premenopausal women (or women <50 years), women who were diagnosed as having breast cancer mainly after 1980, and an additional 6 studies whose recruitment period ended in 1996 or later. Of note, when the results of the Oxford pooled analysis were stratified by menopausal status, evidence showed that risk was somewhat greater for premenopausal (OR, 1.22) vs postmenopausal (OR, 1.08) women for recent (<5 years) OC