Review ArticleHormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits
Introduction
In women with inherited breast cancer susceptibility gene mutations, BRCA1 or BRCA2 (BRCA), the lifetime risk of breast and ovarian cancers is markedly increased. In patients with BRCA1 mutations, cumulative risk of breast and ovarian cancer by age 80 is about 72% and 44% respectively; for BRCA2 mutations, that risk is about 69% and 17% respectively [1,2]. Risk reducing salpingo-oophorectomy (RRSO) is the current standard of care for prevention of ovarian and fallopian tube carcinoma in patients with BRCA mutations. Per the National Comprehensive Cancer Network (NCCN) guidelines, women with BRCA1 mutations are recommended RRSO between age 35 to 40, and upon completion of child bearing [3]. Onset of ovarian cancer in patients with BRCA2 mutations occurs on average 8 to 10 years later than in BRCA1 mutation carriers; therefore it is reasonable to delay RRSO until age 40 to 45 in patients with BRCA2 mutations [3].
For women with BRCA mutations, overall mortality is significantly decreased if they undergo RRSO at the recommended age [[4], [5], [6], [7], [8]]. Among women with BRCA mutations, those who underwent RRSO have lower risk of ovarian cancer compared with women who did not undergo RRSO, including women with a history of breast cancer (hazard ratio (HR) 0.14, 95% confidence interval (CI) 0.04–0.59) and those without a history of breast cancer (HR 0.28, 95% CI 0.12–0.69) [4]. Women who underwent RRSO also had a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (HR 0.63, 95% CI 0.12–0.69), and in BRCA2 mutation carriers (HR 0.63, 95% CI 0.41–0.96). All-cause mortality was lower for BRCA carriers who underwent RRSO (HR 0.40, 95% CI 0.26–0.61), as well as breast cancer specific (HR 0.44, 95% CI 0.26–0.76), and ovarian cancer specific mortality (HR 0.21, 95% CI 0.06–0.80) [4]. The largest reduction in mortality after RRSO was due to a decrease in ovarian cancer specific mortality, which was the predominant reason for improved all-cause mortality in these women. Other studies quote the relative risk of ovarian/fallopian tube/peritoneal cancer after RRSO as 0.04 (95% CI 0.01–0.16) [6] and 0.25 (95% CI 0.08–0.74) [7].
In contrast, women without pathogenic mutations who undergo bilateral salpingo-oophorectomy (BSO) before age 45 and do not use hormone replacement therapy (HRT) have an increased overall mortality [9,10]. In an analysis of long term outcomes in the Nurses' Health Study, over 24 years of follow-up for women with hysterectomy and BSO compared with ovarian conservation, the multivariate HRs were 1.12 (95% CI 1.03–1.21) for total mortality, 1.17 (95% CI 1.02–1.35) for fatal plus nonfatal coronary heart disease, and 1.14 (95% CI 0.98–1.33) for stroke [9]. These results differed with and without HRT, all cause mortality was increased in those under age 50 who had never used HRT (HR 1.41, 95% CI 1.04–1.92), but was not increased in women who were past or current HRT users (HR 1.05, 95% CI 0.94–1.17), this difference was significantly different (p for interaction = 0.03). Rocca et al. found that mortality is significantly higher in women who had undergone bilateral oophorectomy before age 45 than in referent women without oophorectomy (HR 1.67, 95% CI 1.16–2.40, p = 0.006) [10]. These results differed by use of HRT, women who had premature oophorectomy and who did not take estrogen had almost twice the risk of death compared with referent women, HR 1.93 (95% CI 1.25–2.96, p = 0.003); in contrast to those who did take estrogen up to age 45 with HR 1.27 (95% CI 0.67–2.39, p = 0.46) [10].
In addition to increased mortality, surgical menopause can have significant effects on quality of life (QOL). Women who have early menopause may have bothersome symptoms including hot flashes, sleep disturbances, mood changes, and vaginal dryness; these symptoms may be alleviated with HRT. Adverse effects on cognition, mood, cardiovascular, bone and sexual health are also reported with premature or early menopause. HRT may lessen some of these risks, therefore many medical societies recommend providing HRT at least until natural age of menopause [[11], [12], [13], [14], [15]].
The role of HRT in BRCA mutation carriers after RRSO is controversial with the main concern being potential augmentation of an already high risk of breast cancer. Much of the data related to risks and benefits of HRT in the general population come from studies of older women undergoing natural menopause, and these data are not necessarily relevant to the question of HRT following premature menopause. For example, the average age of entry into the Women's Health Initiative (WHI) was 63 [16], while RRSO is recommended between age 35 to 45 for BRCA mutation carriers. For the purpose of this review, we will mostly restrict our survey to studies of women undergoing premature surgical menopause.
Studies evaluating HRT and surgical menopause are limited by variations in type, compliance and duration of HRT. Johansen et al. published a cross sectional study comparing women at increased risk of hereditary breast and ovarian cancer after RRSO to average-risk control women who had undergone bilateral salpingo-oophorectomy (BSO) [17]. Among women less than age 52 without history of breast cancer, only 52% of RRSO and 49% of BSO controls reported current use of HRT (odds ratio 1.13, 95% CI 0.72–1.76).
For BRCA mutation carriers, the decision to use HRT is complex and should be discussed in detail before surgery. Some BRCA mutation carriers undergoing RRSO are not candidates for HRT due to a personal history of hormone sensitive breast cancer. For the remainder, the risks of HRT must be balanced against the impact of early menopause on long-term health and quality of life. The goal of this review is to systematically review and present the available data regarding HRT after RRSO in patients with pathogenic BRCA mutations, including the impact on QOL, sexual function, breast cancer risk, cardiovascular, brain and bone health. We also discuss the formulation of HRT and consideration of surgical approaches to risk reduction.
Section snippets
Methods
A review using The National Library of Medicine (PubMed) Database was performed. Over 15 search terms were used, with three main concepts: “hormone replacement”, “BRCA”, and “risk reduction”. The initial search returned over 1000 studies. Articles were included if they examined hormone replacement in women who had undergone RRSO. Only articles published in English were reviewed. Abstracts were reviewed for relevance and all potentially relevant articles were reviewed for inclusion. These
Quality of life (QOL) and sexual function
HRT improves menopause symptoms (e.g. vasomotor symptoms, sexual function, vulvo-vaginal atrophy) and QOL after premature surgical menopause in the general population [13,[18], [19], [20]]. As expected, similar improvements in QOL have been noted in high-risk women and BRCA mutation carriers taking HRT after RRSO. In a retrospective cohort study, Madalinska et al. described the impact of HRT use on endocrine symptoms and sexual functioning in high-risk premenopausal women (total N = 164, 78%
Conclusions
The available literature suggests that HRT may provide benefit to BRCA mutation carriers after RRSO. RRSO is recommended before the average age of menopause. Early surgical menopause has effects on QOL, sexual function, bone health, cardiovascular health and cognitive function. Studies on QOL show benefit of HRT for BRCA mutation carriers after RRSO; HRT users report fewer endocrine symptoms, and better sexual functioning [[21], [22], [23], [24], [25]]. Women who take HRT after RRSO are less
Funding
EMS and BN are supported by a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (SU2C-AACR-DT16-15). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C.
Author contribution
SG and ES conceived of the idea, acquired data and wrote the manuscript in consultation with KP, BN, ML, and RY. All authors reviewed the final manuscript.
Conflict of interest statement
The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this manuscript.
References (56)
- et al.
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies
Am. J. Hum. Genet.
(2003) - et al.
Chambers, cancer care Ontario's practice guidelines initiative gynecology cancer disease site group, systematic review of management options for women with a hereditary predisposition to ovarian cancer
Gynecol. Oncol.
(2004) - et al.
Survival patterns after oophorectomy in premenopausal women: a population-based cohort study
Lancet Oncol.
(2006) - et al.
Hormone replacement therapy in young women with surgical primary ovarian insufficiency
Fertil. Steril.
(2016) - et al.
Sexual activity and functioning after risk-reducing salpingo-oophorectomy: impact of hormone replacement therapy
Gynecol. Oncol.
(2016) - et al.
The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation
Gynecol. Oncol.
(2011) - et al.
Hormone replacement therapy after risk-reducing salpingo-oophorectomy minimises endocrine and sexual problems: a prospective study
Eur. J. Cancer
(2017) - et al.
The effects of pre-operative menopausal status and hormone replacement therapy (HRT) on sexuality and quality of life after risk-reducing salpingo-oophorectomy
Maturitas
(2016) - et al.
Osteoporosis risk and management in BRCA1 and BRCA2 carriers who undergo risk-reducing salpingo-oophorectomy
Gynecol. Oncol.
(2015) - et al.
Can progestin be limited to every third month only in postmenopausal women taking estrogen?
Maturitas
(1995)