Oral Contraceptives and Pre-Menopausal Breast Cancer
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: A meta-analysis concluded that the use of oral contraceptives is associated with an increased risk of premenopausal breast cancer, especially with use before a first full term pregnancy
Source: Kahlenborn C, et al. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006;81:1290-1302.
Kahlenborn and colleagues performed a meta-analysis of case-control studies published after 1979 that focused on the use of oral contraceptives and the risk of premenopausal breast cancer.1 According to the methods used, the results of 34 studies indicated a calculated overall increased risk of 1.19 (CI = 1.09-1.29). This risk was present in both nulliparous and parous women. Increasing duration of use did not further increase the risk, but the risk was greater in parous women who used oral contraceptives prior to their first full term pregnancy: OR = 1.44 (CI = 1.28-1.62).
Commentary
Once again, I must raise this important question: Is it appropriate and useful to use the technique of meta-analysis for summarizing information from observational studies? When a subject is being studied like the association between smoking and lung cancer with case-control relative risks of 20 to 30, there is no problem. For that matter, just eyeballing 10 studies with risks of that magnitude is sufficient. But when relative risks are less than 2.0, and multiple studies cover a wide range with large confidence intervals, a clinician is justified in questioning whether a mathematical exercise (especially one that requires subjective judgments regarding each report included in the analysis) is accurate, and ultimately, useful. The authors in the current report tested for homogeneity and even commented that there was clear evidence for differences among the studies, but this didn't discourage them from emphasizing their results and implying carcinogenesis. Case-control studies have different study designs, different patient characteristics, varying success in matching cases and controls, variability in drugs and diagnoses, and varying reliability in data recording. To combine a large number of case control studies into one large, pooled analysis is not bringing together a bunch of apples to make a big apple, but mixing fruits to make a fruit salad.
Thirty-seven studies were included in the calculation of the pooled, overall risk. But let me emphasize the variability. The authors pointed out that 8 of the studies had risks less than 1, and 29 had risks greater than 1. However, in the 29 with risks greater than 1, only 8 had risks that were statistically significant!
Another disturbing item in the discussion is the claim that low-dose oral contraceptives have greater breast cancer risk compared with high-dose regimens, referencing 3 studies. This is pure speculation that just as easily could have been the reverse, citing low-dose studies without an increase in risk. The authors also state that oral contraceptives hyperstimulate breast cell division with their greatest effect in the luteal phase; there is no luteal phase in women on oral contraceptives! The authors add to their speculations by highlighting a possible adverse effect of progestins, referencing one old case-control study of medroxyprogesterone acetate, but the largest, and more recent, study in the literature could not detect an increase in breast cancer risk associated with injectable progestin contraceptives.2 We don't need this kind of selective reporting.
This is not the first meta-analysis of oral contraceptives and breast cancer. There are at least 5 others, and there is a common finding of an increased risk of premenopausal breast cancer in women who used oral contraceptives before a first full term pregnancy. The authors believe that all the results are consistent with the hypothesis that oral contraceptives are carcinogenic. The authors freely use the word "carcinogenic" throughout their discussion of this issue. The implication, of course, is that exposure to the steroid hormones of oral contraceptives initiate new cancers. The authors argue that contemporary women use oral contraceptives with a greater prevalence and for longer durations before a first full term pregnancy, and that breast tissue not subjected to the final differentiation process during pregnancy is more susceptible to carcinogens. However in the highly regarded re-analysis of the world's data from 54 studies in 26 countries, a total of 53,297 women with breast cancer and 100,239 without breast cancer published in 1997, the 20% increase in risk in recent users who began use before age 20 was limied to localized disease.3, 4 It is possible that early and recent use of oral contraceptives affects the growth of a preexisting malignancy, explaining the increase in risk limited to current and recent use and the increase only in localized disease.
If the conclusion of this meta-analysis is correct, the increased risk is small, and because most breast cancer occurs after menopause, the absolute risk is extremely small. But a meta-analysis of case-control studies cannot examine sub-groups or adjust for possible confounding factors. For this reason, large case-control studies must be highly regarded by clinicians. The largest case-control study by far on this subject is that performed by the Centers for Disease Control and Prevention, involving 4,575 American women with breast cancer, aged 35 to 64.5 Initiation at a younger age had no impact. The risk of breast cancer was not increased in current users or past users of oral contraception. There was no adverse effect of increasing duration of use or higher doses of estrogen, with no differences in current or recent users, and no increase in risk in women with a family history of breast cancer. This large American study had consistently negative results. The next largest study, involving women from California, Canada, and Australia, focused on breast cancer diagnosed before age 40, and could not detect an increase in current or past users of oral contraceptives.6
In conclusion, be skeptical of meta-analysis of observational studies. Current and recent use of oral contraceptives may be associated with about a 20% increased risk of premenopausal breast cancer, and this may be limited to localized disease. This would amount to a very small increase in the actual number of cases, but the finding may be due to detection/surveillance bias and accelerated growth of already present malignancies. The very large and more recent case-control studies have been negative and very reassuring. Even in BRCA1 carriers, the use of oral contraceptives has not been associated with an increase in breast cancer before age 50.7
References
- Kahlenborn C, et al. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006;81:1290-1302.
- Strom BL, et al. Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. Contraception. 2004;69:353-360.
- Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347:1713-1727.
- Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception. 1996;54:1S-06S.
- Marchbanks PA, et al. Oral contraceptives and the risk of breast cancer. New Engl J Med. 2002;346:2025-2032.
- Milne RL, et al. Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers. Prev 2005;14:350-356.
- Haile RW, et al. BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers. Prev 2006;15:1863-1870.
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