Oral Contraceptives and Breast Cancer
Source: Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996;347:1713-1727.
A collaborative group composed of an enormous number of epidemiologists and cancer investigators from around the world has reanalyzed data from 54 studies in 26 countries, a total of 53,297 women with breast cancer and 100,239 without breast cancer, in order to assess the relationship between the risk of breast cancer and the use of oral contraceptives. This group was established in 1992 to collect the world's data on this subject. The principal investigators of all previous studies were invited to collaborate in this effort. Original data could not be retrieved for 11 studies, and one research group refused to participate in this undertaking. Once the data were collected, they were reanalyzed.
Oral contraceptives were grouped into three categories: low-, medium-, and high-dose (which correlated with < 50 mcg, 50 mcg, and > 50 mcg of estrogen.) At the time of diagnosis, 9% of women with breast cancer were under age 35, 25% were ages 35-44, 33% were ages 45-54, and 33% were 55 and older. A similar percentage of women with breast cancer (41%) and women without breast cancer (40%) had used combined oral contraceptives at some time in their lives. Overall, the relative risk of breast cancer in ever-users of oral contraceptives was slightly elevated: RR = 1.07; 95% CI, 1.03-1.10, which is statistically significant. Most of the studies were case-control studies with population controls, and they did not yield an increase in relative risk; the case-control studies with hospital controls and the prospective studies had, overall, a slightly increased risk.
The relative risk analyzed by duration of use was barely elevated and not statistically significant, even when long-term use, virtually continuous, was analyzed. Women who began use as teenagers had a statistically significant increased relative risk (RR = 1.22). In other words, recent users who began use before age 20 had a higher relative risk compared with recent users who began at later ages. The evidence was strong for a relationship with time since last use, an elevated risk being significant for current users and in women who had stopped use 1-4 years before (recent use). These associations were apparent for breast cancers diagnosed at all age groups, although for women who began use before age 20, the relative risk associated with current or recent use declined with increasing age at diagnosis. These patterns of risk were similar in nulliparous women compared to parous women, and in parous women, regardless of whether oral contraceptives were begun before or after the birth of the first child. No influence on this risk was observed with the following: a family history of breast cancer, age of menarche, country of origin, ethnic groups, body weight, alcohol use, years of education, and the design of the study.
The breast cancers in women who had previously used oral contraceptives were more localized, with less metastasis, compared to tumors in never-users. The effect of current or recent use was apparent in localized tumors, but the relative risk of metastatic disease was not significantly elevated in recent users and was reduced after five years of use. Thus, there was an excess of localized tumors in the recent users of oral contraceptives.
There was no variation according to specific type of estrogen or progestin in the various products. Importantly, there was no statistically significant effect of low-, medium-, or high-dose preparations.
Data were limited for progestin-only methods. The authors indicate that the results were similar to those with combined oral contraceptives, but a close look at the numbers reveals that not one relative risk reached statistical significance.
The authors conclude that while women are taking combined oral contraceptives, and in the 10 years after stopping, there is a small increase in the risk of breast cancer. (See Table 1.)
Ten or more years after stopping use, there is no increased risk of breast cancer. The risk of metastatic disease in ever-users compared to localized tumors is reduced: RR = 0.88; 95% CI, 0.81-0.95. The usual risk factors for breast cancer, including family history, did not influence the results.
Table 1
Increase in risk of breast cancer with oral contraceptive use
Oral contraceptive use Increase in risk of breast cancer
Current users RR = 1.24; 95% CI, 1.15-1.33
1-4 years after stopping RR = 1.16; 95% CI, 1.08-1.23
5-9 years after stopping RR = 1.07; 95% CI, 1.02-1.13
Comment by Leon Speroff, MD
The most important thing to say about this massive undertaking, which yielded about 400 relative risk estimates, is that it is good news. No major adverse impact of oral contraceptives emerged. Indeed, the slight risk could be due to surveillance bias. If the slight risk is real, the overall impact could reduce the risk of breast cancer in older age (yet to be assessed by epidemiologic studies).
Even though the data indicate that women who begin use before age 20 have higher relative risks of breast cancer during current use and in the five years after stopping, this is a time period when breast cancer is very rare; and thus, there would be little impact on the actual number of breast cancers. (See Table 2.) Breast cancer is more common in older years, and 10 or more years after stopping the risk was not increased (RR = 1.01; 95% CI, 0.96-1.05). Furthermore, those tumors that occur are more likely to be localized, according to this analysis.
Table 2
Incidence estimates of breast cancer in oral contraceptive use in North America and Europe
Age of use Excess number of cancers per 10,000
Use from age 16-19 0.5 (95% CI, 0.3-0.7)
Use from age 20-24 1.5 (95% CI, 0.7-2.3)
Use from age 25-29 4.7 (95% CI, 2.9-6.5)
The very slight increase in numbers is so small that it is hard to measure. The difference between localized disease and metastatic disease is statistically greater and should be observable. Thus, many years after stopping oral contraceptive use, the main effect is protection against metastatic disease.
What other explanation could account for an increased risk associated only with current or recent use, no increase with duration of use, and a return to normal 10 years after exposure? It is possible that this situation is analogous to that of pregnancy. Recent studies indicate that pregnancy transiently increases the risk of breast cancer (for a period of several years) after a woman's first childbirth, and this is followed by a lifetime reduction in risk (N Engl J Med 1994;331:5). And some have found that a concurrent or recent pregnancy adversely affects survival (Lancet 1994;343:1587). It is argued that breast cells that have already begun malignant transformation are adversely affected by the hormones of pregnancy, while normal stem cells become more resistant because of a pregnancy. Perhaps early and recent use of oral contraceptives also accelerates the growth of an early malignancy, explaining the limitation of the finding to current and recent use and the increase in localized disease. With the accumulation of greater numbers of older women previously exposed to oral contraceptives, a protective effect may become evident.
The risk in current and recent users also raises the possibility of surveillance (detection) bias. It is possible that because of oral contraceptive use, these women have their tumors detected earlier. The greater risk in women who began use before age 20 could reflect differential reporting and is also not great enough to be beyond chance. The large population of women who began oral contraceptive use as teenagers will just in the next decade be reaching the age when breast cancer is more prevalent- obviously more work for epidemiologists to address the important question of the late impact in past users.
There certainly is no reason here to change our prescribing and use of oral contraceptives. The statistical effect is small and could prove not to be real. I would proffer that the association is real, and that data from ongoing studies will indicate in the next 3-5 years that previous users of oral contraceptives have a reduced risk of breast cancer that is diagnosed in older years.
Editor's note: An incomplete version of the following article ran in the previous issue of The Physician's Therapeutics and Drug Alert. We have reprinted the article in its entirety and regret any confusion this may have caused.
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