Combined hormonal contraceptives in BRCA gene mutation carriers: why not?

BRCA mutation carriers and CHC use: discrepancies in the major guidelines and statements from other bodies

Germline mutations in BRCA1 and BRCA2 account for a large proportion of hereditary breast and ovarian cancers. These tumour suppressor genes, respectively, located in chromosome 17q and 13q, and discovered in 1990 [1], play a major role in carrying out important cellular functions such as DNA damage repair.

The lifetime risk of breast and ovarian cancer in BRCA1 mutation carriers by the age of 80 is 72% and 44%, respectively. The risk in BRCA2 mutation carriers is slightly lower: 69% and 17%, respectively. In the normal population, the lifetime risk is 12% for breast cancer and 1.4% for ovarian cancer. Women with BRCA1 or BRCA2 mutations, therefore, have a sixfold higher risk of breast cancer and up to 30–40 fold higher risk of ovarian cancer (especially women with BRCA1mutations), compared with women without these mutations [2]. Ovarian cancer is the most lethal of all gynaecological tumours. Its prevalence has been gradually increasing over recent decades. The reason for its poor prognosis mostly lies in a lack of early detection strategies as well as ineffective treatments for progression after surgical cytoreduction and front-line chemotherapy.

Every year, the American Society of Clinical Oncology carries out a published analysis of major achievements in the field oncology. In 2008, gynaecological oncology was dominated by a single issue: confirmation of a significant risk reduction of ovarian cancer in combined hormonal contraceptive (CHC) users, with at least 30,000 cases of ovarian cancer per year avoided through CHC use [3]. This effect was confirmed by a recent prospective Danish study comprising 21.4 million woman-years that found a protective effect of CHCs related to duration of use. After 10 years of use, current users had a relative risk of 0.26 (95% confidence interval [CI]: 0.16, 0.43) compared with never users [4].

The overall 5-year relative survival rate for women with breast cancer has increased in the past three decades, owing to earlier detection and improvements in treatment [5].

The World Health Organization medical eligibility criteria for contraceptive use (WHO MEC) provide guidance on the safety of various contraceptive methods. The safety of each method is determined on various grounds in the context of medical conditions or medically relevant characteristics. Safety is categorised as follows: category 1 indicates unrestricted use; category 2 indicates that the method can generally be used, but careful follow-up may be required; category 3 indicates that the method can be used but may require expert clinical judgement and/or referral to a specialist contraception provider, because its use is not recommended if other methods are available or acceptable and category 4 indicates that the method poses unacceptable health risks and should not be used.

The fifth edition of the WHO MEC published in 2015 [6] identifies CHC use in women with breast cancer susceptibility genes as category 1:

Women with breast cancer susceptibility genes (such as BRCA1 and BRCA2) have a higher baseline risk of breast cancer than women without these genes. The baseline risk of breast cancer is also higher among women with a family history of breast cancer than among those who do not have such a history. Current evidence, however, does not suggest that the increased risk of breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of combined oral contraceptives.

This is in agreement with the US medical eligibility criteria for contraceptive use [7], published in 2016: ‘Evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs’.

On the other hand, the European Society of Contraception and Reproductive Health Care has recently published a teaching and training document stating that ‘in BRCA1 short-term use of CHCs is possible but longer-term use, especially in teenagers, cannot be recommended’, while in BRCA2 ‘CHC use is possible; however, benefits should be weighed against individual risk, trying to limit duration of use’ [8]. The UK medical eligibility criteria for contraceptive use (UK MEC) [9], published in 2016, hold a similar view. Indeed, CHCs are category 3 in women with known inherited breast cancer gene mutations (such as BRCA1 and BRCA2). However, the following clarification is given:

The very limited evidence in this area suggests that the risk of breast cancer among women with either a family history of breast cancer or with known inherited breast cancer gene mutations is probably not modified by the use of COC.

So why should these women be precluded from using safe hormonal contraceptives throughout their reproductive lifespan?

CHCs and breast cancer risk: results of recent studies

An estimated 140 million women worldwide use CHCs. For this reason, the association between their use and the risk of breast cancer, the most common cancer in women, is a major topic. The issue is controversial and a number of confounding factors undermine confidence in risk assessment. In addition, it is impossible to conduct a prospective controlled randomised trial of CHC use with the number of participants and length of follow-up required to estimate the real risk of breast cancer in comparison with non-users. Current awareness of this topic comes from prospective studies, which have produced contradictory results despite being well designed.

A nationwide prospective cohort study in Denmark involving 1.8 million women aged 15–49 with a mean follow-up of almost 11 years demonstrated a link between hormonal contraceptive use (including the 52 mg levonorgestrel-releasing intrauterine system) and an increased risk of breast cancer [10]. Compared with women who had never used CHCs, the relative risk of breast cancer among all current and recent users of CHCs was 1.20 (95% CI: 1.14, 1.26). The risk of breast cancer increased with duration of use, from 1.09 with less than 1 year of use to 1.38 after more than 10 years of use. One extra breast cancer was diagnosed in every 7690 women using CHCs for 1 year. Among these women, the risk appeared to keep increasing for at least 5 years after discontinuation. This trial confirms a previous suggestion that initiation of CHC use before the age of 20 or before the first full term pregnancy may be associated with an enhanced risk of breast cancer, as hormones act on less differentiated tissue.

The results presented by Mørch et al. were only partially confirmed in a UK study by the Royal College of General Practitioners (RCGP) [11], in particular on risk reduction after suspension of CHCs. The RCGP completed the longest prospective study in the world of the health effects of oral contraception, comprising more than 46,000 women observed for up to 44 years. It demonstrated that ever-users of CHCs incurred a risk of breast cancer close to unity (incidence rate ratio 1.04; 99% CI: 0.91, 1.17). However, unlike Mørch et al. [10], it concluded that the increased breast cancer risk seen in current and recent users was lost within approximately 5 years of stopping CHCs: from 1.48 (99% CI: 1.10, 1.97) for current use and <5 years since last use to 1.12 (99% CI: 0.91, 1.39) for 5–15 years since last use, 1.05 (99% CI: 0.88, 1.24) for 15–25 years since last use and 1.10 (99% CI: 0.94, 1.28) for 25–35 years since last use. Furthermore, they provided no evidence of substantial cancer risk appearing many years after stopping CHCs.

CHCs in women with a family history of breast cancer

The effect of CHC use in women with a family history of breast cancer (first- or second-degree relatives) is also largely controversial, owing to a paucity of studies, lack of statistical power and low homogeneity in both the populations evaluated and the definition of a family history of breast cancer. From three retrospective cohort studies (8500 cases) and seven case-control studies (10,500 cases) in the past 40 years, no association has emerged between CHC use and breast cancer incidence in women with a family history of the disease [12]. By reviewing data from 1470 women (72% at high risk [with about a threefold increased lifetime risk of developing breast cancer] and 23% at intermediate risk [with about a twofold increased lifetime risk of developing breast cancer], using the Modena criteria and the Tyrer–Cuzick model), a recent retrospective cohort study found that the use of CHCs was not associated with increased breast cancer risk (cumulative hazard: never used, 0.17; CHC users, 0.20; p = .998), regardless of the duration of use (cumulative hazard: never used, 0.17, <5 years’ use, 0.20; 5–10 years’ use, 0.14; >10 years’ use, 0.25; p = .414) [13]. This study found that CHC use did not increase breast cancer risk in women with a family history of breast cancer; the results were confirmed in both high-risk and intermediate-risk groups.

CHCs in BRCA mutation carriers

In BRCA1 and BRCA2 mutation carriers, bilateral risk-reducing salpingo-oophorectomy can reduce the risk of ovarian and breast cancers by 80% and 50%, respectively [14]. Although health-economic decision models suggest that surgery is both effective and cost-effective in BRCA mutation carriers, it results in premature menopause and is accompanied by potential harm, including an increased risk of cardiovascular diseases. Therefore, although fertility preservation methods such as cryopreservation exist, some women who carry the BRCA mutation prefer alternative and less invasive options that preserve ovarian function and fertility. If CHC use similarly reduces ovarian cancer incidence in high-risk women, these drugs could be a viable prevention strategy for women who have not completed childbearing or who wish to avoid surgery.

A meta-analysis of studies published between 2000 and 2012 evaluated the association between CHC use and breast and ovarian cancer among carriers of BRCA1 and BRCA2 mutations [15]. The results suggested that CHC use reduced the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers, in keeping with observations in the general population (BRCA1: odds ratio [OR]: 0.55 [95% CI: 0.47, 0.66]; BRCA2: OR: 0.65 [95% CI: 0.34, 1.24]; BRCA1/BRCA2 combined: OR: 0.58 [95% CI: 0.46, 0.73]). Moreover, no statistically significant association was found with breast cancer (BRCA1: OR: 1.19 [95% CI: 0.92, 1.55]; BRCA2: OR: 1.36 [95% CI: 0.89, 2.10]; BRCA1/BRCA2 combined: OR: 1.21 [95% CI: 0.93, 1.58]). However, because the data were inadequate to examine the effect of duration or timing of CHC use it remains possible that the risk of breast cancer during CHC use in BRCA mutation carriers is the same as that in CHC users without the mutation. Furthermore, in this population the risk seemed to be increased about twofold in women who started CHC use prior to the age of 20 compared with women who started at or after the age of 20 [15,16]. Despite limitations in the data as well as the need to consider other potential benefits and harms from CHC use, results from this meta-analysis suggest that there is insufficient evidence to recommend CHC use as a chemoprevention strategy in BRCA mutation carriers, if they do not otherwise use CHCs for contraception. Conversely, if women with a BRCA mutation wish to use CHCs for contraception, there is no evidence to discourage their use.

Conclusions

Women with BRCA mutations, especially BRCA1, are at very high risk of ovarian cancer (up to 30–40 times higher than that of the general population). An important protective effect against ovarian cancer through CHC use has been acknowledged for these women as well as for the general population. Furthermore, the reduction in risk clearly increases with duration of use. On the other hand, how breast cancer risk changes during CHC use in both BRCA mutation carriers and in the general population remains unclear: if an increased risk exists, it is in absolute terms much less pronounced than the protection against ovarian cancer and is mainly confined to current and very young users. Unfortunately, all studies on CHC use and breast/ovarian cancer risk are not interventional but observational, and a causal relationship, in particular biological plausibility, as happened in the Women’s Health Initiative for hormonal replacement therapy during the menopause, is hard to prove [17]. Moreover, nowadays, there are solid chances of early detection and effective treatment for breast cancer, as opposed to ovarian cancer. In particular, the 5-year relative survival rates reported by the American Cancer Society are 90% for breast cancer and 47% for ovarian cancer [18]. For this reason, theoretically, in terms of pure prevention of cancer deaths, the prevention of two cases of ovarian cancer (which kills half of those affected), compared with 11 cases of breast cancer (which kills a tenth of those affected), would result in one less death due to cancer.

On these grounds, in the next edition of the WHO MEC there is no reason to preclude CHC use in BRCA mutation carriers. Conversely, a case can be made against precluding them from using safe hormonal contraceptives, thereby preventing a large number of cases of ovarian cancer.

Author contributions

GG and FF conceived the article. GG designed the article and interpreted the data. GG, MS and MCS drafted the manuscript. AT and FF interpreted the data and revised the manuscript. All authors approved the final version.

Disclosure statement

No potential conflict of interest was reported by the authors.