Encyclopedia
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects:
Primary Health Care
Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the gold standard preventative option for BRCA mutation carriers at high risk for ovarian and breast cancer. RRBSO involves the surgical removal of both ovaries, as well as fallopian tubes, as fallopian tubes are increasingly being recognized as the site of origin for the most common and lethal form of ovarian cancer, high-grade serous ovarian cancer [11,12]. Guidelines from the National Comprehensive Cancer Network (NCCN) reccomend people with BRCA1 mutations to indergo RRBSO between the ages of 35 to 40 and upon completion of childbearing. Since the onset of ovarian cancer among BRCA2 mutations carriers is approximately 8 to 10 years later than in BRCA1 mutations carriers, the recommended timing of RRBSO is delayed to ages 40 to 45 [18]. Despite the effectiveness of undergoing RRBSO at the recommended age, it also induces immediate surgical menopause with an abrupt and significant decline in levels of sex hormones. As a result, surgical menopause is associated with various adverse physical, mental, and cognitive health outcomes [19].
- BRCA
- hereditary breast and ovarian cancer syndrome
- risk-reducing salpingo-oophorectomy
1. Hormone Replacement Therapy following Premenopausal Bilateral Oophorectomy
1.1. General Population
Following premenopausal BO, hormone replacement therapy (HRT) is indicated until the age of the expected natural menopause for women without a personal history of breast cancer [47]. HRT is recommended as a preventative treatment for bone mineral density (BMD) loss and fractures in postmenopausal women [48]. Further, HRT is shown to reduce the risk for CVD among those undergoing premature surgical menopause [33,35]. Estrogen therapy is also reported to decrease the risk of all cause mortality by 40% in women who had BO before the age of 45 [45].
Despite the reported efficacy of HRT in reducing morbidity and mortality associated with menopause, results from the 2002 Women’s Health Initiative (WHI) study led to a significant decline in HRT use overall and has had a lasting effect on perceptions of HRT safety. This was particularly a result of its finding that combined estrogen and progestogen therapy (EPT) increased breast cancer risk [49]. Since then, growing evidence suggests that the type of progesterone may be differentially associated with breast cancer risk [50,51]. A recent population-based study reported that EPT with synthetic progestins was associated with increased odds of breast cancer (OR 1.28 [95% CI 1.22, 1.35]), while EPT with micronized, or bioidentical, progestogens was not associated with breast cancer (OR 0.99 [95% CI 0.55, 1.79]) [52]. Further, a systematic review of micronized progesterone EPT and its impact on breast cancer risk concluded that this formulation of HRT does not increase breast cancer risk for up to 5 years of treatment, and that longer durations of use are likely not associated with breast cancer risk as well [53].
Nevertheless, the WHI results have almost certainly influenced the low HRT uptake in premature surgical menopause patients, including in a Canadian study by Jang et al. [54]. They found that between 2004 and 2014, only 55.3% of women had ever used HRT, with a statistically nonsignificant decline in HRT users throughout the 10-year study period. Further, among HRT users, almost 50% had a prescription history of less than 1 year [54]. Together, these findings highlight that HRT initiation is too low and sustained use in not long enough.
1.2. BRCA Mutation Carriers
While there are noted challenges with HRT use following premature surgical menopause in the general population, there is also complexity for the BRCA mutation population driven by the concern that use may counteract the breast cancer risk reduction of undergoing RRBSO. There are no randomized clinical trials examining HRT use in BRCA mutation carriers following RRBSO [19]. Without this evidence, along with the negative public perceptions of HRT safety, many clinicians and patients remain hesitant to use HRT [19]. This hesitation may be heightened among BRCA1 and BRCA2 mutation carriers due to their differing baseline risks of breast cancer. Women with BRCA1 mutations are commonly hormone receptor-negative, while women with BRCA2 mutations are usually estrogen and progesterone reception-positive [55]. This leads to uncertainty on whether HRT management may influence breast cancer risk differently for these two high-risk populations [19].
Overall, reported rates of HRT use in the BRCA population are low, with studies reporting an uptake of between 8 to 47% following premenopausal RRBSO [56,57,58,59,60,61]. Canadian studies found that while the average age of RRBSO was approximately 40 years, only 44 to 47% of these women received HRT [58,59]. Further, the average duration of treatment was only 3.5 years. Another study found that among the 20% of BRCA mutation carriers who initiated HRT following RRBSO, the average length of treatment was only 2.8 years [57]. Considering the many adverse health consequences of premature surgical menopause, and the success HRT has at minimising these health risks, HRT use among BRCA carriers should ideally be sustained until closer to the average age of natural menopause, if sufficient research supports its safety.
2. HRT Use and Breast Cancer Risk in BRCA Mutation Carriers
To date, eight observational studies have evaluated the effect of HRT on breast cancer risk exclusively in BRCA mutation carriers (Table 1). The Prevention and Observation of Surgical Endpoints (PROSE) prospective cohort study followed 462 BRCA mutation carriers for an average of 3.6 years to investigate breast cancer risk depending on HRT use [62]. In this cohort, 155 women underwent RRBSO at an average age of 42.7, and 93 received HRT. They reported that RRBSO was significantly associated with a reduced risk of breast cancer (HR 0.40 [95% CI 0.18, 0.92]) and this risk reduction was not influenced by the use of HRT (HR 0.37 [95% CI 0.14, 0.96]) [62]. Different formulations of HRT were examined, with 50 women receiving estrogen therapy (ET) and 34 receiving EPT; no difference in breast cancer risk was observed [62]. Six years later, Domchek et al. [63] published an extension and follow-up to the 2005 study from Rebbeck et al. [62]. This prospective cohort study included 1299 BRCA mutation carriers, of which 321 women underwent RRBSO and were subsequently followed for an average of 5.4 years. Post-RRBSO, 45% of women received HRT. Results were in agreement with Rebbeck et al., showing that HRT use following RRBSO was not associated with an increase in risk of breast cancer in BRCA1 and BRCA2 mutation carriers (HR 0.52 [95% CI 0.30, 0.92] and HR 0.24 [95% CI 0.05, 1.03], respectively). Further, in BRCA1 mutation carriers, HRT use without RRBSO was also shown to be associated with a reduced risk of breast cancer (HR 0.29 [95% CI 0.13, 0.69]). Breast cancer risk was not increased for both ET and EPT [63].
Eisen et al. [63] conducted a retrospective matched case-control study, including 236 case-control pairs of BRCA1 mutation carriers. The average duration of HRT use was 3.7 years for cases and 4 years for controls. Compared to women who never used HRT, HRT use was associated with a reduction in breast cancer risk (OR 0.58 [95% CI 0.35, 0.96]). In addition, upon investigating the impact of different formulations of HRT, authors reported a statistically significant reduction in breast cancer risk associated with ET (OR 0.51 [95% CI 0.27, 0.98]) and a statistically nonsignificant risk reduction associated with EPT (OR 0.66 [95% CI 0.34, 1.27]) [64].
An extension of this study was later conducted by Kotsopoulos et al. [65] who reported on 432 match case-control pairs with BRCA1 mutations. Compared to Eisen et al. [64], this study found no association between the risk of breast cancer and the use of HRT (OR 0.80 [95% CI 0.55, 1.16]). The average duration of HRT was 4.42 years and 4.27 years for cases and controls, respectively. ET and EPT were both not associated with increased or decreased odds of breast cancer. Of note, the majority of women in this study, 327 (75.7%), experienced natural menopause. No significant difference was observed when women who experienced natural versus premature surgical menopause were examined separately (surgical menopause: OR 1.06 [95% CI 0.58, 1.96] vs. natural menopause: OR 0.72 [95% CI 0.44, 1.18]) [65].
The same research group published a prospective cohort study in 2018, including 872 BRCA1 mutation carriers undergoing RRBSO, a subset of which overlapped with the previous case-control study [66]. They found that HRT use following RRBSO was not associated with an increased risk of breast cancer (HR 0.97 [95% CI, 0.62, 1.52]). However, after a 10-year follow-up period, they observed a significantly lower breast cancer risk among BRCA1 mutation carriers who used ET compared to EPT (12% vs 22%, p = 0.04) [66]. More specifically, each year of ET use led to an observed 8% reduction in breast cancer risk (HR 0.92 [95% CI 0.83, 1.01]), in contrast to EPT use, where each year led to a nonsignificant 8% increase in risk (HR 1.08 [95% CI 0.92, 1.27]). These associations were more pronounced for women who underwent RRBSO before the age of 45, with each year of ET associated with a 18% reduction in breast cancer risk (HR 0.82 [95% CI 0.69, 0.97]), and each year of EPT associated with a nonsignificant 14% increase in breast cancer risk (HR 1.14 [95% CI 0.90, 1.46]). Overall, authors concluded that ET after oophorectomy in BRCA1 carriers does not increase the risk of breast cancer: however, the possible adverse effect of EPT use in this population requires further investigation [66].
More recently, Michaelson-Cohen et al. [67] conducted a retrospective cohort study including 306 BRCA1/2 mutation carriers who underwent RRBSO and were followed for an average of 7.26 years. Results indicated that among women who were 45 years or younger at the time of their RRBSO, HRT did not increase the odds of breast cancer (OR 0.8 [95% CI 0.3, 1.9]). However, women who were older than 45 years at the time of their RRBSO and used HRT were at significantly higher odds of breast cancer (OR 3.43 [95% CI 1.2, 9.8]). No significant differences in breast cancer rates were observed depending on HRT formulation, with the majority of HRT users receiving EPT [67].
Finally, two additional retrospective studies reported data on HRT use following RRBSO and associated breast cancer cases, even though this association was not their main aim. Gabriel et al. [68] examined 73 BRCA mutation carriers and reported that 17.6% of women who used ET and 31% women who did not use HRT developed breast cancer. Similarly, Perri et al. [69] examined 127 matched pairs with BRCA mutations and found that among all breast cancer cases, 20% used HRT and 28% did not (p = 0.178). The hormone status of the other participants was unclear [69]. Together these studies suggest that HRT use was not associated with more cases of breast cancer [67,68].
Despite the lack of randomized clinical trial evidence, there is considerable high quality observation data that suggests that short-term HRT use of between 3-5 years in BRCA mutation carriers following RRBSO-induced premature surgical menopause does not increase the risk of breast cancer. While one study observed an increased risk associated with EPT use among BRCA1 mutation carriers, this finding has yet to be confirmed, and thus warrants further investigation. In addition, further research is needed to assess the safety of HRT use for longer than 5 years in the BRCA population.
Table 1. HRT use and risk of breast cancer in BRCA mutation carriers.
| Study | Design/Follow-up | Sample Size (n) | HRT Type and Duration | Breast Cancer (BC) Outcome |
|---|---|---|---|---|
| Rebbeck et al. [62] | Prospective cohort Mean follow-up: 3.6 years |
Total n = 462 BRCA carriers RRBSO n = 155 Mean age at RRBSO: 42.7 years No RRBSO n = 307 |
Estrogen therapy (ET) n = 93 Estrogen and progesterone combination therapy (EPT) n = 62 |
RRBSO was associated with reduced breast cancer (BC) risk (HR 0.40 [95% CI 0.18, 0.92]) compared to BRCA carriers without RRBSO or HRT use HRT use or any formulation did not influence the BC risk reduction (HR 0.37 [95% CI 0.14, 0.96]) |
| Eisen et al. [64] | Matched case- control |
Total n = 473 postmenopausal BRCA1 carriers | ET n = 28 BC cases and 40 controls EPT n = 19 BC cases and 28 controls Mean duration: BC cases: 4 years Controls: 3.7 years |
Decreased odds of BC risk associated with HRT use (OR 0.58 [95% CI 0.35, 0.96]) ET was associated with a statistically significant decrease in BC odds (OR 0.51 [95% CI 0.27, 0.98]) EPT was associated with a nonsignificant decrease in odds of BC (OR 0.66 [95% CI 0.34, 1.27]) |
| Gabriel et al. [68] | Retrospective cohort |
RRBSO n = 73 BRCA carriers Median age at RRBSO: 42 years |
HRT users n = 33 (45%) ET n = 17 (52%) EPT n = 14 (42%) Median duration: 2.79 years |
ET users: 17.6% developed BC EPT users: 31% developed BC HRT use was not associated with more cases of BC |
| Domchek et al. [63] | Prospective cohort (extension and follow-up from Rebbeck et al., 2005) Mean follow-up: 5.4 years |
Total n = 1229 BRCA carriers Mean age at RRBSO among HRT users: 40.8 years Mean age at RRBSO among non-HRT users: 45 years |
HRT users n = 255 (21%) | HRT use following RRBSO was not associated with an increase in risk of BC in BRCA1 carriers (HR 0.52 [95% CI 0.30, 0.92]) and BRCA2 carriers (HR 0.24 [95% CI 0.05, 1.03]) BC risk was not increased for both ET and EPT |
| Kotsopoulos et al. [65] | Matched case-control (extension from Eisen et al., 2008) | Total n = 864 BRCA1 carriers Pairs of matched BC cases and controls: 432 |
Total HRT users: Cases n = 91 (21%) Controls n = 80 (19%) ET users: Cases n = 46 Controls n = 42 EPT users: Cases n = 28 Controls n = 41 Mean duration: Cases: 4.42 years Controls: 4.27 years |
HRT use was not associated with BC (OR 0.80 [95% CI 0.55, 1.16]) ET and EPT were both not associated with increased or decreased odds of BC. No observed difference between natural menopause (OR 0.72 [95% CI 0.44, 1.18]) and premature surgical menopause (OR 1.06 [95% CI 0.58, 1.96]) |
| Kotsopoulos et al. [66] | Prospective cohort Mean follow-up: 7.6 years |
RRBSO n = 872 BRCA1 carriers Mean age at surgery: 43.4 years |
HRT n = 377 (43%) ET n = 259 (69%) EPT n = 66 (18%) Mean duration: 3.9 years |
HRT use after RRBSO was not associated with an increased risk of BC (HR 0.97 [95% CI 0.62, 1.52]) After 10 years of follow-up, the cumulative incidence of BC was significantly lower among ET users compared to EPT users (12% vs 22%, p = 0.04) Each year of ET use led to an 8% reduction in BC risk (HR 0.92 [95% CI 0.83, 1.01]) Each year of EPT use led to a nonsignificant 8% increase in risk (HR 1.08 [95% CI 0.92, 1.27]) |
| Michaelson-Cohen et al. [67] | Retrospective cohort Mean follow-up: 7.26 years |
RRBSO n = 306 Median age at RRBSO: 44 years |
HRT n = 150 (49%) ET n = 26 (17%) EPT n = 82 (55%) Median duration: 4 years |
RRBSO < 45 years: HRT did not increase the odds of BC (OR 0.8 [95% CI 0.3, 1.9]) RRBSO > 45 years: HRT use was associated with a significantly higher odds of BC (OR 3.4 [95% CI 1.2, 9.8]) |
| Perri et al. [69] | Retrospective cohort Mean follow-up: 8.7 years |
Total n = 254 BRCA carriers RRBSO vs. no RRBSO matched pairs n = 127 Mean age of RRBSO: 42 years |
HRT n = 62 (24.4%) | Among all BC cases, 20% used HRT and 28% did not (p = 0.178) Findings suggest that HRT use was not associated with more cases of BC |
Abbreviations: BC, breast cancer; HR, hazard ratio; OR, odds ratio; HRT, hormone replacement therapy; ET, estrogen therapy; EPT, estrogen and progestogen combination therapy; RRBSO, risk reducing bilateral salpingo-oophorectomy.
This entry is adapted from the peer-reviewed paper 10.3390/cancers15030711
This entry is offline, you can click here to edit this entry!
