New Research Further Illuminates Role of Oral Contraceptives in Ovarian Cancer Prevention

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Ovarian cancer is a silent—and too often deadly—gynecologic cancer, responsible for an estimated 14,000 deaths and more than 22,000 new diagnoses this year.1Although it ranks as the tenth most common cancer diagnosis, it is the fifth most common cause of cancer death among women.1

A major reason why ovarian cancer is associated with significant morbidity and mortality compared to its prevalence is that it has no obvious symptoms or accurate screening tests, leading to diagnosis at later stages.1,2

It has long been observed that use of oral contraceptives (OCs) conveys a protective effect against ovarian cancer that is potentiated with longer duration of use. An analysis of data from 20 epidemiologic studies found ovarian cancer risk decreased by 10% to 12% after 1 year of OC use and by approximately 50% after 5 years of use.3,4

Similarly, data from the Nurses' Health Study confirms an inverse association between risk for epithelial ovarian cancer and duration of OC use, which persists for up to 10 years after discontinuation. This benefit diminishes over time; 20 years after OC discontinuation, women's risk is comparable to that of women who never used OCs.5,6

In a large observational study from the United Kingdom, the use of OCs also has been shown to reduce all-cause (relative risk [RR] = 0.88; 95% CI: 0.82–0.93) and all-cancer–related mortality among women (RR=0.85; 95% CI: 0.75–0.93), including a substantial and significant reduction in mortality due to ovarian cancer (RR=0.53; 95% CI: 0.38–0.72).7

How Do OCs Protect Against Ovarian Cancer?

A study published online in October 2013 looks further into the mechanism by which OCs exert their protective effect. This study, by Faber and colleagues from the Danish Cancer Society Research Center in Copenhagen, Denmark, used data from a population-based case–control study in their country. They identified 554 women with epithelial ovarian cancer and 1,564 age-matched controls.

Use of combined estrogen-progestin OCs or use over time of combined OCs and progestin-only pills led to a decrease in risk for ovarian cancer (Table 1).8 Differences in estrogen (>50 µg vs <50 µg) or progestin doses and cumulative progestin or estrogen doses did not translate to differences in ovarian cancer risk; however, duration of OC use demonstrated an inverse association.8

Table 1: Association Between OC Use and Ovarian Cancer Risk: New Research

Index Patient Scenarios Adjusted Odds Ratio (95% CI)
Danish Case–Control Study 20138
Use of combined OCs only  0.68 (0.53–0.88)*
Use of combined OCs and progestin-only pills  0.50 (0.28–0.87)*
Per additional year of OC use  0.95 (0.92–0.98)
AHRQ Meta-analysis 20136
Ever- versus never-use of OCs  0.73 (0.66–0.81) 
Duration of use: 1–12 months  0.91 (0.78–1.07)* 
Duration of use: >120 months   0.43 (0.37–0.51)*
*Versus never-users as reference, OR=1.00.
P < 0.001.

The investigators concluded that by preventing ovulation, which contributes to ovarian cancer because of the repeated trauma it inflicts on the ovarian surface epithelium, OCs reduce ovarian cancer risk, and this benefit is driven by the duration of anovulation, not the cumulative dose of hormones. Their findings suggest that current OC regimens using very low doses of estrogen and progestin, as long as sufficient to prevent ovulation, are as protective against ovarian cancer as higher dose formulations.8 This finding has important clinical implications because many of the deleterious effects of OCs, including risk for deep venous thrombosis and other thrombotic events, may be mitigated by use of low-dose OCs.

Is Primary Prevention of Ovarian Cancer Using OCs Warranted?

A second new study, published in July 2013 in conjunction with a new Agency for Healthcare Research and Quality (AHRQ) report, provides the results of a systematic review and meta-analysis of 24 case-control and cohort studies. This study found a 27% reduction in ovarian cancer risk associated with ever- versus never-use of OCs.9 This meta-analysis also confirms a strong inverse association between duration of OC use and ovarian cancer risk: the protective effect of OC use diminishes over time and disappears 20 years after treatment discontinuation.9

Related: Oral Contraceptives Not Linked to Ovarian, Breast Cancer in High-Risk Women

In terms of primary prevention, several limitations must be considered. First, almost all the data supporting ovarian cancer risk reduction are from case-control and cohort studies, and the potential for designing and carrying out prospective randomized controlled trials is small because of cost, number of women needed to participate, and time involved.2,9 Second, while reducing overall cancer-related mortality and risk for several cancers, OC use also is associated with a small but significant increase among current users in breast cancer risk (< 1% of total breast cancer cases and 7% of premenopausal breast cancer cases) which diminishes with time after discontinuation.

However, to date, no substantial increase in breast cancer–related mortality has been observed. In a 2013 meta-analysis conducted by the AHRQ, the relative risk for breast cancer associated with OC use was 1.08 (95% CI: 1.00-1.17). Breast cancer risk appears to be highest for women with long durations of OC use prior to a first full-term pregnancy, a fact which must be factored into any benefit-harm calculation.6,10

AHRQ has recently published an exhaustive review of data to determine whether a role for OCs in primary prevention of ovarian (or other) cancers is warranted. Their conclusion is that the incident harms associated with OC use will outweigh the benefit of prevented cases of ovarian cancer for most women. Any negative effects of OCs for most women are reassuringly small, but the benefits are not sufficiently large to recommend OCs as primary prevention for ovarian cancer.6

However, individual women may derive benefit; for example, women carrying BRCA1, who have an outsized risk for developing ovarian cancer. The AHRQ analysis of ever- versus never-use of OCs for such women predicted a net gain of almost 10 months of life associated with OC use compared with 2 months for the general population.6

Summary

Ovarian cancer, while relatively rare, is often diagnosed at advanced stages and is associated with poor long-term prognosis. Further, no reliable risk factors, aside from family history and BRCA1 status, have been identified. An abundance of epidemiologic evidence supports a reduction in ovarian cancer risk with extended use of OCs, thought to be related to long-term suppression of ovulation.

Because OC use carries risks, particularly for thrombotic events, consideration must be given to counseling women about the benefits and harms associated with OC use for cancer prevention. At present, AHRQ does not recommend routine use of OCs for primary prevention of ovarian cancer.



References

1. American Cancer Society. Cancer Facts & Figures, 2013. Atlanta: American Cancer Society, 2013.

2. Guha M. The pill and ovarian cancer prevention. JNCI. 2013;105(3):154-156.

3. National Cancer Institute. Oral Contraceptives and Cancer Risk. Fact Sheet. http://www.cancer.gov/cancertopics/factsheet/Risk/oral-contraceptives. March, 2012. Last accessed October 24, 2013.

4. Hankinson SE, Colditz GA, Hunter DJ, et al. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol. 1992;80(4):708-714.

5. Tworoger SS, Fairfield KM, Colditz GA, et al. Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk. Am J Epidemiol. 2007;166(8):894-901.

6. Havrilesky LJ, Gierisch JM, Moorman PG, et al. Oral Contraceptive Use for the Primary Prevention of Ovarian Cancer. Evidence Report/ Technology Assessment No. 212. Executive Summary. AHRQ Publication No. 13-E002-EF. Rockville, MD: Agency for Healthcare Research and Quality. June 2013. http://effectivehealthcare.ahrq.gov/ehc/products/416/1530/cancer-ovarian-contraceptives-executive-130611.pdf. Last accessed October 24, 2013.

7. Hannaford PC, Iverson L, MacFarlane TV, et al. Mortality among contraceptive pill users: cohort evidence from the Royal College of General Practitioners' Oral Contraceptive Study. BMJ. 2010;340:c927.

8. Faber MT, Jensen A, Frederiksen K, et al. Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer. Cancer Causes Control. 2013;[epub ahead of print] doi: 10.1007/s10552-013-0296-8.

9. Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive pills as primary prevention for ovarian cancer. A systematic review and meta-analysis. Obstet Gynecol. 2013;122:139-147.

10. Cibula D, Gompel A, Mueck AO, et al. Hormonal contraception and risk of cancer. Human Reprod Update. 2010;16(6):631-650.

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