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Oral contraceptives and breast cancer: what's the risk?

Does the use of oral contraceptives, particularly the presence of estrogen and progesterone, increase the risk of breast cancer? And what about a patient who has a BRCA gene mutation, is her risk altered by her genetic mutation? What the data tell us.

Evaluating for the presence of a relationship between oral contraceptives (OCs) and breast cancer is a difficult topic to study because many factors influence breast cancer risk, among them genetic, growth, and tissue factors. The genetic factors include repressor genes, which reduce the risk of cancer, as well as proto-oncogenes, which have the potential to convert from normal cells to active oncogenes (table, page 26). Growth factors also play a role, particularly estrogen and progesterone (which can independently affect the growth of breast cancer tumors), epithelial growth factor, transforming growth factor alpha, and others. In addition, tissue factors--including the basement membrane structure, immune shielding, and angiogenesis--are important in the early development of breast cancer.

Trying to tease out the possible breast cancer risk associated with hormonal contraceptives from the multiple possible contributors to overall risk is a daunting task for many epidemiologists. Keep in mind that there is often a 5-year (or longer) time frame from tumor initiation until diagnosis by mammography or physical examination (FIGURE, page 27). Thus, research studies conducted in a particular time frame may reflect contraceptive use a number of years before the research began and may not reflect patients' current contraceptive use.

Nevertheless, patients maybe concerned about OC use and the risk of breast cancer, and may ask you as their contraceptive expert if there is an association. In this article, I review the major publications addressing this issue.

OCs and breast cancer risk overall

Results from the following 3 major studies examine appropriately the role of OC use in breast cancer.

Collaborative reanalysis. The Collaborative Group on Hormonal Factors in Breast Cancer conducted a large meta-analysis involving 54 studies. (1) Of note, the investigators actually obtained raw data from these 54 studies and conducted their own analysis, which was published in 1995. The total number of women studied included 53,297 with breast cancer and 100,239 controls.

According to the reanalyzed evidence, OC users younger than 35 years had a slightly higher risk of being diagnosed with breast cancer (relative risk [RR], 1.24; 95% confidence interval [CI], 1.15-1.35) than women not using OCs, but the risk declined over time for past users. By age 50, the cumulative risk of breast cancer diagnosis was the same in OC users and nonusers. There was no evidence that OCs, including higher-dose formulations, increased the risk of breast cancer even with longer duration of use. There was no indication that family history modified the risk. (1)

When increases in breast cancer risk are seen in observational studies, the findings could be due to bias, and in this particular instance, detection bias. This could be because OC users undergo more frequent breast examinations than women who do not need to return to their clinician annually for prescriptions. On the other hand, it may reflect that OCs promote some growth of preexisting tumors but are not the etiologic agent.

Case-control study. The Women's CARE (Contraceptive and Reproductive Experiences) Study was a case-control design, with results published in 2002. (2) It was conducted in sites across the United States, and it likely reflects our population. The controls were population-based and were obtained through random-digit dialing. When collected in this manner, the bias that could potentially be introduced with obtaining controls from clinics or hospitals, for example, may be reduced. The study included 4,575 women with invasive breast cancer and 4,682 controls. Study participants were aged 35 to 64 years, and data were collected from 1994 to 1998.

Of note, 77% of case participants and 79% of controls had used OCs, a fact that highlights the difficulty of trying to determine what role OCs may play in breast cancer since they are used widely. The study results showed no increased risk of breast cancer in women who had ever used any type of OC among women aged 35 to 64 years (RR, 0.9; 95% CI, 0.8-1.0). Current or former OC use was not associated with increased risk of breast cancer. In addition, no increased risk was seen for longer periods of use or for higher doses of estrogen. Finally, neither initiation of OC use at a young age nor family history of breast cancer was associated with increased risk.

Large meta-analysis. A 2013 systematic review and meta-analysis by Gierisch and colleagues, sponsored by the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention (CDC), included a number of studies completed since the year 2000. (3) Twenty-three studies--15 case-control and 8 cohort studies--met criteria for meta-analysis to evaluate the association between OC use (ever-use vs never-use) and breast cancer incidence. More than 350,000 women were included in this analysis. (This review also examined OC use on risk of cervical, colorectal, and endometrial cancers.)

[FIGURE OMITTED]

Again, the researchers found that the risk of breast cancer was exceedingly low among ever-users (odds ratio [OR], 1.08; 95% CI, 1.00-1.17). The risk was higher in women with recent OC use, and the risk decreased over time. There was no effect on risk according to duration of use. Importantly, the approximate increase in the lifetime risk of breast cancer among ever-users of OCs, based on these data, was 0.89%.

Does BRCA gene mutation affect breast cancer risk with OC use?

In a 2013 study sponsored by the AHRQ and CDC, Moorman and colleagues performed a meta-analysis to examine the potential contribution of BRCA gene mutations to the risk of breast cancer among OC users. (4) (The risk of ovarian cancer associated with OC use also was examined.) Five total studies, 3 case-control and 2 cohort, pertained to the breast cancer analysis and included 4,555 patients (in 4 studies) and 65,180 person-years (in 1 study).

Investigators found that the overall risk of breast cancer associated with OC use in women who were BRCA mutation carriers was roughly in range of the other studies discussed herein. Furthermore, the calculated OR did not reach statistical significance (OR, 1.21; 95% CI, 0.93-1.58). There was no effect on risk with duration of use.

Unfortunately, data analysis was hampered by the small number of studies and suitable number of participants, and the data were inadequate to analyze the effect of positive family history of breast cancer among individuals who were positive for a BRCA mutation.

Breast cancer risk with progestin-only contraceptives

In a 2016 systematic analysis, Samson and colleagues examined all epidemiologic studies conducted from 2000 to 2015. Due to a paucity of studies and quality of data, only 6 studies that evaluated the risk of breast cancer among users of progestin-only (nonestrogen-containing) contraceptive methods underwent analysis. (5)

Five of the 6 studies reported no association between breast cancer risk and use of any form of progestin-only contraceptive. As progestins are used in various formulations for contraception, such as injectables, implants, and the levonorgestrel intrauterine system, the data were insufficient to analyze breast cancer risk by method. More rigorous study design is needed due to this study's overall small sample sizes, variation in progestins and administration routes, and heterogeneity of the study locations.

My bottom line

There is minimal, if any, risk of breast cancer with OC use. The reported low risk could be due to bias, particularly detection bias, or could represent stimulation of a tumor that is already present (as opposed to OCs being an etiologic agent). It is important to keep in mind that the reduced risk of ovarian and endometrial cancer associated with hormonal contraceptive use likely outweighs any potential breast cancer risk.

There is no evidence that presence of a BRCA mutation significantly affects the risk of breast cancer with OC use. Further, there is no evidence that progestin-only contraceptives increase breast cancer risk, but data are inadequate. As always, consulting the CDC's Medical Eligibility Criteria database (6) can assist in your care of patients with complicated conditions who request contraception.

FAST TRACK

A recent large meta-analysis estimated a 0.89% increase in lifetime breast cancer risk among OC users

A 2016 study of estrogen-free contraception found no risk of breast cancer with various contraceptive routes, but more rigorous study is needed

WATCH FOR

Dr. Burkman's next webcast on venous thromboembolism and hormonal contraception, at obgmanagement.com

References

(1.) Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception. 1996;54(3 suppl):1S-106S.

(2.) Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346(26):2025-2032.

(3.) Gierisch JM, Coeytaux RR, Urrutia RP, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomark Prev. 2013;22(11):1931-1943.

(4.) Moorman PG, Havrilesky LJ, Gierisch JM, et al. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and metaanalysis. J Clin Oncol. 2013;31(33):4188-4198.

(5.) Samson M, Porter N, Orekoya O, et al. Progestin and breast cancer risk: a systematic review. Breast Cancer Res Treat. 2016; 155(1):3-12.

(6.) Centers for Disease Control and Prevention. United States medical eligibility criteria (US MEC) for contraceptive use. MMWR Recomm Rep. 2010;59(RR-4):l-86. http://www.cdc .gov/reproductivehealth/unintendedpregnancy/usmec.htm. Accessed May 18, 2016.

Ronald T. Burkman, MD

This article is based on Dr. Burkinan's webcast: "Hormonal contraception and the risk of breast cancer," found at obgmanagement.com.

Dr. Burkman is Professor, Department of Obstetrics and Gynecology. Tufts University School of Medicine, Boston, Massachusetts, and an obstetrician-gynecologist at Baystate Medical Center, Springfield. He is an OBG Management Contributing Editor.

The author reports no financial relationships relevant to this article.
TABLE Factors in the early development of breast cancer *

Genetic factors     Growth factors      Tissue factors

+ Repressor genes   + Estrogen          Basement membranes
- Proto-oncogenes   + Progesterone      Immune shielding
                    + EGF, TGF[alpha]   Angiogenesis
                    + Insulin

Abbreviations: EGF, epithelial growth factor; TGF[alpha],
transforming growth factor alpha.

* + = increases the risk of breast cancer. - = decreases the
risk of breast cancer.
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Author:Burkman, Ronald T.
Publication:OBG Management
Date:Jun 1, 2016
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