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Oral Contraceptive Use and the Risk of Breast Cancer

      The clinical impact of the association between oral contraceptive (OC) use and breast cancer risk is important given that OCs are the most commonly prescribed contraceptive agent and that more than a quarter of a million women are diagnosed as having breast cancer in the United States annually. Substantial changes to OC formulations have been made during the past decade, and this review focuses on recent OC trends and risks and benefits. We also have a better understanding of how estrogen affects breast carcinogenesis; research on this topic is ongoing and has the goal of decreasing breast cancer incidence and mortality.

      Abbreviations:

      CI (confidence interval), EE (ethinyl estradiol), HRT (hormone replacement therapy), OC (oral contraceptive), OR (odds ratio), RR (relative risk), SERM (selective estrogen receptor modulator)

      BREAST CANCER

       Incidence and Mortality

      Breast cancer is the most commonly diagnosed noncutaneous cancer in women in the United States and accounts for the second highest number of cancer deaths. In 2007, an estimated 178,000 women were diagnosed as having invasive breast cancer and another 60,000 women as having noninvasive ductal carcinoma in situ.
      • Jemal A
      • Siegel R
      • Ward E
      • Murray T
      • Xu J
      • Thun MJ
      Cancer statistics, 2007.
      The incidence of invasive breast cancer, after peaking in 2000, has been steadily decreasing, as has the mortality rate. The cause of this decrease in incidence is postulated to be multifactorial. One possible factor is the decline in the use of combined hormone replacement therapy (HRT) after the publication of the Women's Health Initiative study in 2002.
      • Clarke CA
      • Glaser SL
      • Uratsu CS
      • Selby JV
      • Kushi LH
      • Herrinton LJ
      Recent declines in hormone therapy utilization and breast cancer incidence: clinical and population-based evidence [letter].
      • Jemal A
      • Ward E
      • Thun MJ
      Recent trends in breast cancer incidence rates by age and tumor characteristics among U.S. women.
      • Ravdin PM
      • Cronin KA
      • Howlader N
      • et al.
      The decrease in breast-cancer incidence in 2003 in the United States.
      This study reported that 5 years of combined HRT (estrogen and progesterone) was associated with a 26% increased risk of invasive breast cancer in postmenopausal women.
      • Writing Group for the Women's Health Initiative Investigators
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.
      Another factor could be the early detection and management of noninvasive and precancerous breast lesions and the subsequent increase in the management of these lesions with selective estrogen receptor modulators (SERMs) as chemoprevention. Additionally, greater emphasis on lifestyle changes, such as increased exercise, decreased postmenopausal obesity, and altered dietary habits, could have contributed to reducing the risk of breast cancer. Finally, more recently, a reported decrease in mammographic screening could have led to a decrease in detection of breast cancer in unscreened women.
      • Breen N
      • A Cronin K
      • Meissner HI
      • et al.
      Reported drop in mammography: is this cause for concern?.
      Whether the incidence of breast cancer will continue to decrease into the next decade is unclear, emphasizing the importance of monitoring this trend over time.
      The decline in breast cancer mortality is encouraging and is thought to be due to multiple factors. Improved screening that results in detection of earlier-stage cancers with better prognosis and increased detection of noninvasive cancers are contributors to this trend. Furthermore, effective adjuvant therapies using systemic and hormonal agents reduce recurrence of local or nodal disease.
      • Berry DA
      • Cronin KA
      • Plevritis SK
      • et al.
      Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators. Effect of screening and adjuvant therapy on mortality from breast cancer.

      Etiology and Risk Factors

      The etiology of breast cancer is multifactorial and cannot be directly linked to any single factor, including estrogen. The epidemiological literature supports a highly complex interplay between different exposures and host characteristics and between exogenous and endogenous hormones and an individual's genetic makeup. Clinical and laboratory evidence suggests that estrogen acts as a mammary gland carcinogen, with the strongest evidence emerging from the historical experience with SERMs (which block estrogen receptors) and aromatase inhibitors (which substantially reduce estrogen synthesis). In the adjuvant setting, SERMs and aromatase inhibitors have effectively reduced risk of recurrence by blocking estrogen's action on the estrogen receptor and by suppressing estrogen synthesis from androgens, respectively.
      • Yager JD
      • Davidson NE
      Estrogen carcinogenesis in breast cancer.
      Two major potential mechanisms have been postulated by which estrogens increase the risk of breast cancer. The first mechanism is the stimulation of estrogen receptormediated transcription that results in cell proliferation. The second mechanism is direct carcinogenesis via metabolic activation and direct binding of DNA. One hypothesis is that these 2 mechanisms act in an additive or even synergistic fashion to induce carcinogenesis.
      • Santen RJ
      • Yue W
      • Bocchinfuso W
      • et al.
      Estradiol-induced carcinogenesis via formation of genotoxic metabolites.
      • Yager JD
      Endogenous estrogens as carcinogens through metabolic activation.
      Of multiple risk factors for the development of breast cancer, many are directly or indirectly related to endogenous or exogenous estrogen exposure.
      • McPherson K
      • Steel CM
      • Dixon JM
      ABC of breast diseases: breast cancer-epidemiology, risk factors, and genetics.
      Relative risk (RR) is used to compare the magnitude of risk among risk factors. A woman's age is the strongest risk factor for breast cancer, and older women have an RR greater than 10 compared with younger women. Women with a family history of breast cancer in a first-degree relative, particularly in one younger than 50 years, have a higher risk (RR, >2). Reproductive risk factors associated with risk of breast cancer include menarche before age 11 years (RR, 2), menopause after age 54 years (RR, 3), and age greater than 40 years at first full-term pregnancy (RR, 3). Exogenous hormone use is a modifiable risk factor; use of HRT for more than 10 years (RR, 1.35) and current or recent use of oral contraceptives (OCs) (RR, 1.24) are both associated with higher risk. Although caution must be used in directly comparing RRs, current knowledge suggests that OC use is one of the weakest risk factors for breast cancer.

      ORAL CONTRACEPTIVES

       Use and Effectiveness

      More than 100 million women worldwide use OCs. According to a 2005 Morbidity and Mortality Weekly Report,
      • Bensyl DM
      • Iuliano DA
      • Carter M
      • Santelli J
      • Gilbert BC
      Contraceptive use—United States and territories, Behavioral Risk Factor Surveillance System, 2002.
      OCs are the most commonly used contraceptive method for US women. Health care professionals prescribe OCs because they are safe, effective, and well tolerated. Women take them for the same reasons, as well as for convenience.
      The effectiveness of OCs and of the other combination hormonal contraceptives including the patch and ring is 99.7% if used exactly as directed and only slightly lower at 92% if the dose is occasionally taken late or not taken. The effectiveness of other contraceptives ranges from approximately 85% for barrier methods, such as condom, sponge, and diaphragm, to upward of 99% for intrauterine devices, subdermal implants, progesterone injection, and sterilization (in both men and women).
      • Trussell J
      Contraceptive efficacy.

      Estrogen and Progestin COMPONENTS

      Since the introduction of OCs 40 years ago, the progestin and estrogen components have been modified substantially to improve the adverse-effect profile and decrease hormone-associated risks. Desogestrel, norgestimate, and drospirenone are the newer agents; the older progestins are levonorgestrel and norethindrone acetate. The benefits of the newer agents include lower androgenicity and fewer progestogenic adverse effects, such as acne and mood changes. Their effects on lipid-glucose metabolism are neutral, allowing their use in additional patient populations.
      Estrogen doses in the form of ethinyl estradiol (EE) in OCs have decreased from 150 μg in the 1960s to the current 20 μg. Clinical benefits from the lower-dose preparations include lower risks of venous thromboembolic events and estrogenic adverse effects such as nausea, headache, and mastalgia. Today, the most commonly prescribed OC contains 20 to 35 μg of EE.

      Newer Options

      In addition to traditional OCs that are administered monthly, patients can now choose from OCs that are designed for continuous use, have an extended cycle, or have shorter pill-free intervals. Women desire a break from monthly menstrual periods. In a 2002 Harris poll,

      Association of Reproductive Health Professionals. Extended regimen oral contraceptives, Harris Poll. June 14-17, 2002.

      approximately 500 US women aged 18 to 49 years were asked their preferred menstrual frequency. Only a third preferred monthly cycles, whereas two-thirds preferred quarterly menstrual periods or no menstrual periods. This trend was especially evident in women in their later reproductive years, confirming the findings of an earlier European study.
      • den Tonkelaar I
      • Oddens BJ
      Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use.
      Several cycles of active pills can be taken consecutively without placebo pills, resulting in amenorrhea. Shorter pill-free intervals (4 days vs the traditional 7 days) result in a decreased risk of breakthrough ovulation, lighter menstrual flow, and improved control of hormone-withdrawal effects. The last-mentioned improvement can be further enhanced with the addition during the pill-free interval of low-dose EE, available in some cyclic and extended-cycle formulations. The relatively constant hormonal milieu provided by OCs is helpful in decreasing the incidence of estrogen-withdrawal symptoms.
      In addition to providing contraceptive efficacy comparable to that of traditional monthly regimens, continuous and extended-cycle formulations are safe and well tolerated, as increasing evidence shows. A recent study by Miller and Hughes
      • Miller L
      • Hughes JP
      Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial.
      prospectively randomized women to continuous and cyclic regimens of the same OC that contained 20 μg of EE and 100 μg of levonorgestrel for 12 months. Initially, women in the continuous arm had more bleeding/spotting days than those in the cyclic arm; however, within 3 months, this trend had reversed: 68% and 88% of women in the cyclic arm were amenorrheic at 6 months and at 12 months, respectively.
      • Miller L
      • Hughes JP
      Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial.
      Furthermore, the time to conception in OC users was found to be similar to that in non-OC users. In both groups, the median time to conception was 3 months, and the 1-year pregnancy rate was 80%. This trend was noted in short- and long-term OC users, a finding that should allay the fear that these options have a deleterious effect on future fertility.

      Cronin M, Mohner S. Past oral contraception use does not negatively affect time to conception. Abstract presented at the Annual American College of Obsetricians and Gynecologists 55th Annual Clinical Meeting; San Diego, CA; May 7-9, 2007.

      Currently, it is safe for a woman not to experience a monthly menstrual cycle.

      Benefits

      Oral contraceptives offer many noncontraceptive health benefits, including a decreased risk of bone loss, benign breast disease, pelvic inflammatory disease, ectopic pregnancy, and rheumatoid arthritis. They have been found to be helpful during the perimenopausal years in regulating menses and treating vasomotor symptoms. Patients with acne, hirsutism, premenstrual syndrome, and endometriosis symptoms have benefited from treatment with OCs.
      • Burkman R
      The evolution of oral contraceptives: 40 years of continuous improvement.
      • Vercellini P
      • Frontino G
      • De Giorgi O
      • Pietropaolo G
      • Pasin R
      • Crosignani PG
      Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen.
      • Parsey KS
      • Pong A
      An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen.

      Risks and Contraindications

      Although many of the traditional risks and adverse effects of OCs have been minimized with the newer formulations, some absolute and relative contraindications still exist. Women who have a history of venous thromboembolism or who are at risk for these complications, such as pregnant and newly postpartum patients and those immobilized after surgery, are generally not candidates for combination OCs. Women with history of or at risk for coronary artery disease, such as those with uncontrolled hypertension and current smokers older than 35 years, should consider other contraceptive options. Oral contraceptives are relatively contraindicated in patients with a history of migraines including focal auras. In these patients, ischemic stroke risk increases from an odds ratio (OR) of 6.2 to 13.9 with OC use, although the absolute risk remains very low at 19 of 100,000 women per year.
      • Tzourio C
      • Tehindrazanarivelo A
      • Iglésias S
      • et al.
      Case-control study of migraine and risk of ischaemic stroke in young women.
      Breast and other estrogen-dependent cancers as well as liver disease preclude the use of OCs.
      • Steinauer J
      • Autry AM
      Extended cycle combined hormonal contraception.
      It is important to emphasize the risk of unintended pregnancy when effective contraception is not used. In 2003, mortality associated with pregnancy was 12.1 deaths per 100,000 live births; in 2001, mortality associated with termination was 11 deaths per 850,000 legal abortions. In addition, financial and psychosocial implications should be included in patient counseling.
      • Hoyert DL
      Maternal mortality and related concepts.

      OCs VS HRT HORMONES: WHAT ARE THE DIFFERENCES?

      In the wake of the Women's Health Initiative, it is important to remember that all estrogens are not alike and that estrogen doses, although numerically similar between OCs and HRT, are not biologically comparable. Most OCs available today contain EE. Compared to estradiol, the ethinyl group increases the estrogen's potency 4- to 18-fold and prolongs its half-life.
      • Mashchak CA
      • Lobo RA
      • Dozono-Takano R
      • et al.
      Comparison of pharmacodynamic properties of various estrogen formulations.
      Hormone replacement therapy contains either a mix of conjugated estrogens or 17-β-estradiol. Thus, adverse effects attributable to OCs might not always occur with HRT and vice versa.
      Similarly, most progestins currently used in OCs are not the same as those contained in HRT combinations, and thus their potencies and potential risks cannot be readily compared. The exception is drospirenone, a novel antiandrogenic progestin, which has been used in OCs for approximately 5 years and was recently introduced in a postmenopausal combination HRT.

      WHAT IS THE LINK BETWEEN OCS AND BREAST CANCER AND OTHER MALIGNANCIES?

      In 2005, the International Agency for Research in Cancer classified estrogen-progestogen OCs as a group 1 carcinogen, the highest rating, indicating that there is sufficient evidence that these agents are carcinogenic to humans.

      International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. Lyon, France. In press.

      • Cogliano V
      • Grosse Y
      • Baan R
      • et al.
      Carcinogenicity of combined oestrogen-progestagen contraceptives and menopausal treatment.
      This evaluation was based on increased risks of breast and cervical cancer, as well as of liver cancer in populations with a low prevalence of hepatitis B infection. This classification is higher than that reported in the 1999 evaluation.
      • International Agency for Research on Cancer
      The report further concluded that there is convincing evidence in humans that these agents confer a protective effect against cancer in the endometrium and ovaries and suggestive evidence for a protective effect against colorectal cancer.
      The Oxford pooled analysis, published in 1996, contains the most comprehensive data that addressed the issue of OC use and breast cancer risk. It is based on pooling of original data from 54 epidemiological studies enrolling more than 50,000 women with breast cancer and 100,000 controls.
      • 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.
      Key findings from that analysis included a 24% increased risk of breast cancer in current OC users (RR, 1.24; 95% confidence interval [CI], 1.15-1.33), a weaker but still elevated risk in recent OC users (1-9 years after discontinuation), but no increased risk 10 or more years after discontinuation of OCs (RR, 1.01; 95% CI, 0.96-1.05). The risk was also greater in women who began taking OCs before age 20 years and in women who used OCs before the birth of their first child, a time when breast tissue is thought to be more susceptible to carcinogens. This effect was also reported in a more recent meta-analysis by Kahlenborn et al.
      • Kahlenborn C
      • Modugno F
      • Potter DM
      • Severs WB
      Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis.
      Although the aforementioned studies strongly support an association between OCs and breast cancer risk, the RR is small, and the absolute risk (excess breast cancer cases due to OC exposure) is very small. For example, only a small number of additional cases of breast cancer were noted among 10,000 European or North American women in the 10 years after discontinuation of OCs: 0.5 cases, for OC use from age 16 to 19 years; 1.5 cases, for OC use from age 20 to 24 years; and 4.7 cases, for OC use from age 25 to 29 years. This very small excess risk must be put into perspective when counseling women and weighing the overall risks vs benefits of OC use.
      Furthermore, these studies
      • 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.
      • Kahlenborn C
      • Modugno F
      • Potter DM
      • Severs WB
      Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis.
      are based on older data with higher-dose estrogen and older progestin OC formulations. The largest modern study, published in 2002, enrolled more than 4500 patients with breast cancer and 4500 controls aged 35 to 64 years from the United States from 1994 to 1998.
      • Marchbanks PA
      • McDonald JA
      • Wilson HG
      • et al.
      Oral contraceptives and the risk of breast cancer.
      Key findings included no breast cancer risk among current (OR, 1.0; 95% CI, 0.8-1.3) or former (OR, 0.9; 95% CI, 0.8-1.0) OC users and no risk associated with duration of use or dose of estrogen. Moreover, a recent study of OC use in more than 4200 patients with breast cancer found no association between breast cancer mortality and OC use when duration of OC use, time since first use, age at first use, and use of specific formulations were examined.
      • Wingo PA
      • Austin H
      • Marchbanks PA
      • et al.
      Oral contraceptives and the risk of death from breast cancer.
      Breast cancer risks with the newest formulations of OCs are still unknown but are predicted to show no association with the dose and composition of the estrogens and progestins being used. However, future studies will need to evaluate this empirically.

      HIGH-RISK WOMEN AND OC USE

      The risk of breast cancer has been reported to be particularly high among OC users with a family history of breast cancer in first-degree relatives compared with women with no such history, but this was noted only for OC use before 1975, when estrogen doses were much higher.
      • Grabrick DM
      • Hartmann LC
      • Cerhan JR
      • et al.
      Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer.
      The Oxford pooled analysis
      • 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.
      and the large US study
      • Marchbanks PA
      • McDonald JA
      • Wilson HG
      • et al.
      Oral contraceptives and the risk of breast cancer.
      found no difference in the association between OC use and breast cancer by family history. Similarly, the association between OC use and breast cancer risk does not appear to be modified for women who have BRCA1 and BRCA2 mutations, although data are more limited.
      • Narod SA
      • Dubé MP
      • Klijn J
      • et al.
      Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
      • Haile RW
      • Thomas DC
      • McGuire V
      • et al.
      BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.
      • Brohet RM
      • Goldgar DE
      • Easton DF
      • et al.
      Oral contraceptives and breast cancer risk in the International BRCA1/2 Carrier Cohort Study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group.

      COUNSELING WOMEN REGARDING OC USE

      In counseling a woman regarding OC use, physicians should (1) discuss the relative and absolute risks (including those associated with unintended pregnancy), benefits, and alternatives in a thorough and individualized manner; (2) present all available and appropriate options clearly, accurately, and without bias; if the data are unclear, the patient should be apprised of this fact; (3) consider the patient's value system and explore her anxiety and fears to help her make an informed choice; and (4) reassess the patient's choice periodically as new information becomes available and as her medical or life situation changes.

      CONCLUSION

      Oral contraceptives are a highly effective, safe, well-tolerated, and convenient contraceptive method for a substantial number of women in the United States. They are contraindicated in certain groups of patients. Given the variety of formulations currently available, therapy can and should be individualized to the patient's needs. Although epidemiological studies have documented a small increased risk of breast cancer associated with use of older OC formulations, recent studies that included newer formulations have not detected an increased risk. Even with the older formulations, the absolute (or excess) risk of breast cancer is minimal. Thus, current evidence suggests that OCs do not play a clinically important role in the risk of breast cancer. This evidence must also be weighed against the effect on other health outcomes and the risks associated with other contraceptive methods and with unintended pregnancy.

      Acknowledgments

      We acknowledge Jillian J. Nickell from the Office of Women's Health at Mayo Clinic's site in Rochester, MN, for assistance with manuscript preparation.

      CME Materials

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