Without preventive interventions, women with germline pathogenic variants in BRCA1 or BRCA2 have high lifetime risks for breast cancer and tubo-ovarian cancer. The increased risk for breast cancer starts at a considerably younger age than that for tubo-ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is effective in reducing tubo-ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, but whether it reduces breast cancer risk is less clear. All studies of rrBSO and breast cancer risk are observational in nature and subject to various forms of bias and confounding, thus limiting conclusions that can be drawn about causation. Early studies supported a statistically significant protective association for rrBSO on breast cancer risk, which is reflected by several international guidelines that recommend consideration of premenopausal rrBSO for breast cancer risk reduction. However, these historical studies were hampered by the presence of several important biases, including immortal person-time bias, confounding by indication, informative censoring, and confounding by other risk factors, which may have led to overestimation of any protective benefit. Contemporary studies, specifically designed to reduce some of these biases, have yielded contradictory results. Taken together, there is no clear and consistent evidence for a role of premenopausal rrBSO in reducing breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Women who have inherited pathogenic variants in the BRCA1 or BRCA2 genes (hereafter called mutation carriers) are at high risk of developing breast cancer and tubo-ovarian cancer (1). Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is highly effective at reducing the risk of tubo-ovarian cancer (2–3). In contrast, the role of rrBSO in mitigating breast cancer risk in mutation carriers, while previously widely accepted and incorporated in clinical guidelines (see Table 1), is now less clear and challenged by emerging contradictory evidence (4–10). This article reviews the literature on rrBSO and subsequent risk of first breast cancer for mutation carriers and suggests modifications to existing guidelines based on compilation of new evidence from recent studies.

Table 1.

Cancer risk reduction guidelines for female BRCA1 and BRCA2 mutation carriers without a personal history of breast cancer.

InterventionNCCNNICEESMOACOGeviQ
Lifestyle modificationa Not mentioned Recommended Recommended Not mentioned Discuss 
Chemoprevention Premenopausal - consider Tam Premenopausal - consider Tam Consider Tam Consider Tam, especially for BRCA2 Premenopausal - consider Tam 
 Postmenopausal – consider Tam, raloxifene or AI Postmenopausal – consider Tam or AI   Postmenopausal - consider Tam, raloxifene or AI 
Risk-reducing mastectomy Discussion regarding degree of protection Discussion regarding degree of protection, and potential psychosocial impact Discuss benefits, limitations, potential complications, and psychosocial impact Discuss Offer; greatest benefit ≤40 y 
Risk-reducing salpingo-oophorectomy to reduce tubo-ovarian cancer risk Consider following completion of family, typically between 35 and 40 y for BRCA1 or 40–45 y for BRCA2, unless age at diagnosis in the family warrants earlier consideration Discuss risks and benefits, including discussion of negative impact of surgically induced menopause; consider after completion of family Discuss, taking into account mutation type, patient preferences and family history to determine appropriate age; recommended between ages 35–40 y Discuss between the ages of 35–40 y and after completion of childbearing Recommend from 35 y for BRCA1 and from 40 y for BRCA2; after family completion 
Risk-reducing salpingo-oophorectomy to reduce BC risk Discuss degree of risk reduction for BC; consider after completion of family Discuss risks and benefits, including discussion of negative impact of surgically induced menopause; consider after completion of family Not recommended for reduction of BC risk Discuss premenopausal rrBSO to reduce risk of BC Not recommended for reduction of BC risk 
InterventionNCCNNICEESMOACOGeviQ
Lifestyle modificationa Not mentioned Recommended Recommended Not mentioned Discuss 
Chemoprevention Premenopausal - consider Tam Premenopausal - consider Tam Consider Tam Consider Tam, especially for BRCA2 Premenopausal - consider Tam 
 Postmenopausal – consider Tam, raloxifene or AI Postmenopausal – consider Tam or AI   Postmenopausal - consider Tam, raloxifene or AI 
Risk-reducing mastectomy Discussion regarding degree of protection Discussion regarding degree of protection, and potential psychosocial impact Discuss benefits, limitations, potential complications, and psychosocial impact Discuss Offer; greatest benefit ≤40 y 
Risk-reducing salpingo-oophorectomy to reduce tubo-ovarian cancer risk Consider following completion of family, typically between 35 and 40 y for BRCA1 or 40–45 y for BRCA2, unless age at diagnosis in the family warrants earlier consideration Discuss risks and benefits, including discussion of negative impact of surgically induced menopause; consider after completion of family Discuss, taking into account mutation type, patient preferences and family history to determine appropriate age; recommended between ages 35–40 y Discuss between the ages of 35–40 y and after completion of childbearing Recommend from 35 y for BRCA1 and from 40 y for BRCA2; after family completion 
Risk-reducing salpingo-oophorectomy to reduce BC risk Discuss degree of risk reduction for BC; consider after completion of family Discuss risks and benefits, including discussion of negative impact of surgically induced menopause; consider after completion of family Not recommended for reduction of BC risk Discuss premenopausal rrBSO to reduce risk of BC Not recommended for reduction of BC risk 

Note: All guidelines also recommend intensified breast cancer screening.

Abbreviations: AI, aromatase inhibitor; BC, breast cancer; Tam, tamoxifen; y, years.

aLifestyle modification including maintenance of healthy weight, participation in regular moderate-intensity exercise, minimization of alcohol intake and exogenous estrogen/progesterone exposure.

Without preventive interventions, the average cumulative lifetime risk of breast cancer for women harboring a BRCA1 or BRCA2 mutation is 72% [95% confidence interval (CI), 65%–79%] and 69% (95% CI, 61%–77%), respectively (1) compared with 13% in the general United States population (11). However, the location of the mutation within the gene, common genetic variants across the genome, family history, lifestyle-related factors, and age all influence risk for individual mutation carriers (1, 12–20). For women with these mutations, breast cancer risk increases rapidly with age from early adulthood and then plateaus to remain at a relatively high constant level throughout the remaining lifetime. This plateau is reached between 31 to 40 years for BRCA1 mutation carriers (incidence 23.5 per 1,000 person-years; 95% CI, 19.1–28.9) and about 10 years later for BRCA2 mutation carriers (incidence 27.5 per 1,000 person-years; 95% CI, 21.6–35.1; ref. 1). Phenotypically, BRCA2-associated breast cancers are usually estrogen receptor (ER)–positive and progesterone receptor (PgR)–positive. Conversely, BRCA1-associated breast cancers are usually ER and PgR-negative (21), although preclinical studies suggest that female hormones do play an important role in the etiology of BRCA1-associated breast cancers (22–28).

In contrast to breast cancer risk, tubo-ovarian cancer risk does not become elevated above the low population level until after age 35 years for BRCA1 mutation carriers or 50 years for BRCA2 mutation carriers (1, 2). In the largest prospective pooled cohort study of mutation carriers, the average risk to age 50 was 8% (95% CI, 6%–12%) for BRCA1 mutation carriers and 0% (95% CI, 0%–2%) for BRCA2 mutation carriers. In that study, mutation carriers of either gene were most likely to develop tubo-ovarian cancer when aged 61 to 70 years (1), although another study suggested that peak incidence may be a decade earlier for BRCA1 mutation carriers (2).

Mutation carriers have several options available to reduce their cancer risk. All major evidence-based guidelines recommend consideration of risk-reducing bilateral mastectomy (rrBM) and chemoprevention to reduce breast cancer risk, and rrBSO to reduce tubo-ovarian cancer risk (see Table 1). The recommendations regarding age for rrBSO to reduce tubo-ovarian cancer risk vary between guidelines, and by mutation type (see Table 1). For example, the US National Comprehensive Cancer Network (NCCN; https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf) and Australian eviQ (https://www.eviq.org.au/cancer-genetics/adult/risk-management/3814-brca1-or-brca2-risk-management-female) suggest that rrBSO should only be performed from age 35 for BRCA1 mutation carriers, and from age 40 for BRCA2 mutation carriers, and only after family completion. Conversely, the United Kingdom (UK) National Institute of Health and Care Excellence (NICE; https://www.nice.org.uk/guidance/cg164) provides little guidance regarding the appropriate age for the procedure, and the European Society of Medical Oncology (ESMO; ref. 29) and the American College of Obstetricians and Gynecologists (ACOG; https://www.acog.org/womens-health/faqs/brca1-and-brca2-mutations) suggest consideration between ages 35 and 40 years without distinguishing between BRCA1 and BRCA2.

In contrast, there is no consensus regarding the use of rrBSO to reduce breast cancer risk. ACOG recommends a discussion regarding premenopausal rrBSO to reduce breast cancer risk, while the NCCN, and NICE recommend a discussion of rrBSO to reduce breast cancer risk after completion of childbearing. These recommendations do not vary by mutation type (see Table 1). In contrast, ESMO (29) and eviQ do not recommend rrBSO for breast cancer risk reduction.

Evidence for an association between rrBSO and breast cancer risk is based on observational studies (3, 4–10, 30–43), which contain inherent biases that must be considered when interpreting their results and applying them to clinical practice. These biases have been discussed since 2003 (see Table 2; refs. 4, 44–46) with most leading to an overestimation of any protective association between rrBSO and breast cancer risk in mutation carriers.

Table 2.

Possible sources of bias in studies of rrBSO and breast cancer risk.

Type of biasDefinition and exampleImpactPossible mitigation strategies
Confounding by indication Confounding by indication may be introduced if women who choose rrBSO have a different BC risk to those who do not have rrBSO. For example, within BRCA1 and BRCA2, there are areas of each gene, which, when mutated, increase TOC risk and decrease BC risk compared with mutations in other regions. Carriers with an inherently higher risk of TOC and lower risk of BC may be more likely to choose rrBSO because they have a stronger family history of TOC (46). The potential benefit of rrBSO on BC risk may be overestimated as women opting to undergo rrBSO may do so because of a strong FHx of TOC and may have been at comparatively lower risk of developing BC (46). The potential impact of confounding by indication may be mitigated by matched sibling cohorts, taking into account the age difference of siblings to prevent introduction of bias associated with start of follow-up (below; ref. 46); however, this strategy can substantially reduce sample size. 
   Adjusting for FHx in the analysis offers partial mitigation of this bias. 
Survival bias from competing risk of TOC This bias is closely related to confounding by indication and describes the observation that women who are at inherently higher risk of TOC than BC, who do not undergo rrBSO, may contribute fewer person-years at risk during follow-up if they die from TOC before censoring for another reason. Overestimation of the protective association between rrBSO and BC risk, further amplifying confounding by indication (46). As per confounding by indication. 
 If these women are overrepresented in the control group, the bias introduced by indication and survival is accentuated (46).   
Informative censoring When a censoring event, for example, rrBM, depends on the study endpoint (BC risk) then the censoring becomes “informative.” Carriers with higher familial BC risk may be more likely to undergo early rrBM, before rrBSO, compared with carriers with lower familial BC risk. The censoring event, rrBM, is considered “informative” because the group of women who undergo rrBM were more likely to develop BC than women who proceed to either rrBSO or other risk-reducing options (4, 46). The potential benefit of rrBSO on BC risk may be overestimated due to an excess of lower risk women in the rrBSO group. This may be partially mitigated by adjusting for family history. 
Cancer-induced testing bias Cancer-induced testing bias explains the observation that diagnosis of BC often prompts genetic testing. Women who are then found to carry a BRCA1 or BRCA2 mutation may be recommended to undergo rrBSO for TOC risk reduction. Thus, an analysis of BC incidence before and after rrBSO may be enriched for BC events in the non-rrBSO period (4, 46). May lead to overestimation of the association between BC risk and rrBSO. Exclusion of women with a personal history of BC prior to genetic testing. Starting the observation period at the time of genetic testing (4, 46). 
Immortal person-time bias Immortal person-time bias relates to the follow-up period that participants survived BC-free before rrBSO. This bias is introduced if the person-time before rrBSO is not allocated to the non-rrBSO group (4). Results in misallocation of observation time away from the non-rrBSO group and consequently, an increase in BC events per person-year in this group, biasing toward a protective association between rrBSO and BC (4). Consider rrBSO as a time-dependent variable and allocate the observation period between the date of genetic testing and rrBSO to the non-rrBSO group (4). 
Confounding by other risk factors Confounding by other risk factors for BC also needs to be taken into account when assessing the efficacy of rrBSO (46). May lead to over- or underestimation of the association between rrBSO and BC risk depending on risk factor. Adjustment for these confounders. 
 E.g., parity - parous women may be more likely to undergo rrBSO compared with nulliparous women. If parous carriers are also at lower risk of BC, the association between rrBSO and reduced BC risk may appear spuriously stronger.   
Missing data Because of the nature of observational studies, it is not always possible to collect data points of interest on all patients (45). Depending on the volume of missing data and its relationship to the main study outcomes, missing data may affect the integrity of the results (45). Imputation methods (66, 67). 
Other Age at rrBSO – if the association between rrBSO and reduced BC risk only occurs for women who have early premenopausal rrBSO and not for those who have peri- or postmenopausal rrBSO (which is biologically plausible), then including women with peri- and postmenopausal rrBSO in the analysis will tend to weaken the association seen between rrBSO and reduced BC risk. Any association between rrBSO and reduced BC risk may be underestimated or missed. Analyses stratified by age at rrBSO. 
 cHRT – women who undergo premenopausal rrBSO may be more likely to receive subsequent cHRT than women who do not have rrBSO. If cHRT increases BC risk in carriers, any association between rrBSO and reduced BC risk may be spuriously weaker. Any association between rrBSO and reduced BC risk may be underestimated or missed. Adjustment for use of cHRT. 
Type of biasDefinition and exampleImpactPossible mitigation strategies
Confounding by indication Confounding by indication may be introduced if women who choose rrBSO have a different BC risk to those who do not have rrBSO. For example, within BRCA1 and BRCA2, there are areas of each gene, which, when mutated, increase TOC risk and decrease BC risk compared with mutations in other regions. Carriers with an inherently higher risk of TOC and lower risk of BC may be more likely to choose rrBSO because they have a stronger family history of TOC (46). The potential benefit of rrBSO on BC risk may be overestimated as women opting to undergo rrBSO may do so because of a strong FHx of TOC and may have been at comparatively lower risk of developing BC (46). The potential impact of confounding by indication may be mitigated by matched sibling cohorts, taking into account the age difference of siblings to prevent introduction of bias associated with start of follow-up (below; ref. 46); however, this strategy can substantially reduce sample size. 
   Adjusting for FHx in the analysis offers partial mitigation of this bias. 
Survival bias from competing risk of TOC This bias is closely related to confounding by indication and describes the observation that women who are at inherently higher risk of TOC than BC, who do not undergo rrBSO, may contribute fewer person-years at risk during follow-up if they die from TOC before censoring for another reason. Overestimation of the protective association between rrBSO and BC risk, further amplifying confounding by indication (46). As per confounding by indication. 
 If these women are overrepresented in the control group, the bias introduced by indication and survival is accentuated (46).   
Informative censoring When a censoring event, for example, rrBM, depends on the study endpoint (BC risk) then the censoring becomes “informative.” Carriers with higher familial BC risk may be more likely to undergo early rrBM, before rrBSO, compared with carriers with lower familial BC risk. The censoring event, rrBM, is considered “informative” because the group of women who undergo rrBM were more likely to develop BC than women who proceed to either rrBSO or other risk-reducing options (4, 46). The potential benefit of rrBSO on BC risk may be overestimated due to an excess of lower risk women in the rrBSO group. This may be partially mitigated by adjusting for family history. 
Cancer-induced testing bias Cancer-induced testing bias explains the observation that diagnosis of BC often prompts genetic testing. Women who are then found to carry a BRCA1 or BRCA2 mutation may be recommended to undergo rrBSO for TOC risk reduction. Thus, an analysis of BC incidence before and after rrBSO may be enriched for BC events in the non-rrBSO period (4, 46). May lead to overestimation of the association between BC risk and rrBSO. Exclusion of women with a personal history of BC prior to genetic testing. Starting the observation period at the time of genetic testing (4, 46). 
Immortal person-time bias Immortal person-time bias relates to the follow-up period that participants survived BC-free before rrBSO. This bias is introduced if the person-time before rrBSO is not allocated to the non-rrBSO group (4). Results in misallocation of observation time away from the non-rrBSO group and consequently, an increase in BC events per person-year in this group, biasing toward a protective association between rrBSO and BC (4). Consider rrBSO as a time-dependent variable and allocate the observation period between the date of genetic testing and rrBSO to the non-rrBSO group (4). 
Confounding by other risk factors Confounding by other risk factors for BC also needs to be taken into account when assessing the efficacy of rrBSO (46). May lead to over- or underestimation of the association between rrBSO and BC risk depending on risk factor. Adjustment for these confounders. 
 E.g., parity - parous women may be more likely to undergo rrBSO compared with nulliparous women. If parous carriers are also at lower risk of BC, the association between rrBSO and reduced BC risk may appear spuriously stronger.   
Missing data Because of the nature of observational studies, it is not always possible to collect data points of interest on all patients (45). Depending on the volume of missing data and its relationship to the main study outcomes, missing data may affect the integrity of the results (45). Imputation methods (66, 67). 
Other Age at rrBSO – if the association between rrBSO and reduced BC risk only occurs for women who have early premenopausal rrBSO and not for those who have peri- or postmenopausal rrBSO (which is biologically plausible), then including women with peri- and postmenopausal rrBSO in the analysis will tend to weaken the association seen between rrBSO and reduced BC risk. Any association between rrBSO and reduced BC risk may be underestimated or missed. Analyses stratified by age at rrBSO. 
 cHRT – women who undergo premenopausal rrBSO may be more likely to receive subsequent cHRT than women who do not have rrBSO. If cHRT increases BC risk in carriers, any association between rrBSO and reduced BC risk may be spuriously weaker. Any association between rrBSO and reduced BC risk may be underestimated or missed. Adjustment for use of cHRT. 

Abbreviations: cHRT, combined hormone replacement therapy; FHx, family history; TOC, tubo-ovarian cancer.

Historical studies

A meta-analysis by Rebbeck and colleagues (3), published in 2009, evaluated four case–control or cohort studies with nonoverlapping participants that addressed this question (31, 32, 34, 35). These studies included 3,066 BRCA1, 1,116 BRCA2, and a further 1,669 mutation carriers where the specific gene not stated. The results suggested a statistically significant protective association between rrBSO and breast cancer risk for BRCA1 (HR, 0.47; 95% CI, 0.35–0.64) and BRCA2 mutation carriers (HR, 0.47; 95% CI, 0.26–0.84), and when the specific gene mutated was not stated (HR, 0.49; 95% CI, 0.37–0.65; ref. 3). These findings were supported by several subsequent studies with similar results (36, 37); however, analyzed datasets were overlapping. Not surprisingly, these results impacted clinical practice.

Pivotal study

It has recently become clear that the findings of these older studies may be spurious due to the presence of several biases (4, 43). Heemskerk-Gerritsen and colleagues assessed the association between rrBSO and breast cancer risk by analyzing new data from the Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON) nationwide cohort (4). They first replicated the eligibility criteria and analyses of the four major historical studies [30–32, 36; two of which (31, 32) were included in the meta-analysis by Rebbeck and colleagues (3)]. The results were similar to the findings of the original studies with hazard (HR) or odds ratios varying from 0.36 to 0.62, lending support to the intervention. To demonstrate the impact of bias, they reanalyzed the HEBON data using a statistical design that minimized several biases. To reduce cancer-induced testing bias, they started the observation period at receipt of genetic test result or age 30, whichever came last and excluded women diagnosed with breast cancer before the start of observation. To reduce immortal person-time bias, they treated rrBSO as a time-dependent variable, allocating all person-years of observation before rrBSO, as well as the three months following rrBSO, to the non-rrBSO group. Utilizing data from 589 BRCA1 and 233 BRCA2 mutation carriers, with 75 and 14 incident breast cancers respectively, and a median follow-up of 3.2 years, they found no statistically significant association between rrBSO and breast cancer risk for mutation carriers combined (HR, 1.09; 95% CI, 0.67–1.77). The estimates for BRCA1 and BRCA2 mutation carriers analyzed separately were HR, 1.21 (95% CI, 0.72–2.06) and 0.54 (95% CI, 0.17–1.66), respectively. There was also no statistically significant association between premenopausal rrBSO (i.e., before age 51) and breast cancer risk for mutation carriers combined (HR, 1.11; 95% CI, 0.65–1.90). The median age at rrBSO was 45 years (range, 31–67 years). The use of hormone replacement therapy (HRT) was not reported, and data related to other breast cancer risk factors, including parity, were missing (41%), which may have introduced confounding by other risk factors. In addition, confounding by indication, survival bias from competing risk of tubo-ovarian cancer and informative censoring may have been present. Regardless, it was the publication of this pivotal study in 2015 (4) that initiated the ongoing debate and controversy regarding whether rrBSO reduces breast cancer risk for BRCA1 and BRCA2 mutation carriers.

More recent studies

Since Heemskerk-Gerritsen's analysis (4, 43), six further, larger cohort studies have been published that address this question (see Table 3; refs. 6–11). These studies attempted to minimize bias; however, most have potential residual methodologic issues (see Supplementary Table S1). Taken together, these studies do not help reach consensus on whether rrBSO is associated with reduced breast cancer risk.

Table 3.

Characteristics of contemporary studies of rrBSO and breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Heemskerk-Gerritsen et al. 2015 (4)Kotsopoulos et al. 2017 (5)Terry et al. 2019 (6)Choi et al. 2021 (7)Mai et al. (GOG-0199) 2020 (8)Mavaddat et al. 2020 (9)Stjepanovic et al. 2020 (10)
N Overall 822 3,694 1,289 1,322 432 3,877 853 
 BRCA1 589 2,969 716 746 242 2,272 444 
 BRCA2 233 725 573 576 189 1,605 409 
Median observation time (years) 3.2 5.6a 10.7b NR NR 5.4 (BRCA1)a 4.3 
      4.9 (BRCA2)a  
N rrBSO/non-rrBSO BRCA1 246/343 1,187/1,782 254/462 166/2,484b 120/122 836/1,436 180/264 
 BRCA2 100/133 355/370 197/376 144/1,781b 102/87 381/1,108 170/239 
Age at rrBSO Median (range) 45 (31–67) 46.3 (13–78) BRCA1: 44 BRCA1: 44.5a,b NR NR 42 (30.5–56.5) 
    BRCA2: 46 BRCA2: 46.9a,b    
 Premenopausal, n (%) NR 1,033d (67) 333d (74) NR 535 (57.8)c NR 337 (39.5) 
N incident BC diagnosis BRCA1/BRCA2 75/14 292/57 116/80 483/373 29/9 269/147 54/42 
 Premenopausal 66 NR 118d NR NR NR NR 
 Postmenopausal 23 NR 78d NR NR NR NR 
rrBSO and BC risk association, 95% CI rrBSO/non-rrBSO Overall 1.09 (0.67–1.77) 0.89 (0.69–1.14) NR NR 1.15 (0.52–2.54) NR NR 
 BRCA1 (all) 1.21 (0.72–2.06) 0.97 (0.73–1.29) 1.2 (0.67–2.12) 0.57 (0.38–0.84) 1.22 (0.50–3.00) 1.23 (0.94–1.61) See below 
 BRCA2 (all) 0.54 (0.17–1.66) 0.68 (0.38–1.21) 0.86 (0.43–1.72) 0.62 (0.41–0. 96) 1.09 (0.20–6.06) 0.88 (0.62–1.24) See below 
 “Premenopausal” rrBSO BRCA1/BRCA2 1.11 (0.65–1.90) NR NR NR 0.84 (0.40–1.77) NR NR 
 “Premenopausal” rrBSO BRCA1 NR 0.84 (0.58–1.21) NR NR 0.84 (0.37–1.91) 1.11 (0.80–1.52) 0.45 (0.22–0.92) 
 “Premenopausal” rrBSO BRCA2 NR 0.17 (0.05–0.61) NR NR 0.73 (0.11–4.82) 0.57 (0.32–1.01) 0.77 (0.35–1.67) 
Heemskerk-Gerritsen et al. 2015 (4)Kotsopoulos et al. 2017 (5)Terry et al. 2019 (6)Choi et al. 2021 (7)Mai et al. (GOG-0199) 2020 (8)Mavaddat et al. 2020 (9)Stjepanovic et al. 2020 (10)
N Overall 822 3,694 1,289 1,322 432 3,877 853 
 BRCA1 589 2,969 716 746 242 2,272 444 
 BRCA2 233 725 573 576 189 1,605 409 
Median observation time (years) 3.2 5.6a 10.7b NR NR 5.4 (BRCA1)a 4.3 
      4.9 (BRCA2)a  
N rrBSO/non-rrBSO BRCA1 246/343 1,187/1,782 254/462 166/2,484b 120/122 836/1,436 180/264 
 BRCA2 100/133 355/370 197/376 144/1,781b 102/87 381/1,108 170/239 
Age at rrBSO Median (range) 45 (31–67) 46.3 (13–78) BRCA1: 44 BRCA1: 44.5a,b NR NR 42 (30.5–56.5) 
    BRCA2: 46 BRCA2: 46.9a,b    
 Premenopausal, n (%) NR 1,033d (67) 333d (74) NR 535 (57.8)c NR 337 (39.5) 
N incident BC diagnosis BRCA1/BRCA2 75/14 292/57 116/80 483/373 29/9 269/147 54/42 
 Premenopausal 66 NR 118d NR NR NR NR 
 Postmenopausal 23 NR 78d NR NR NR NR 
rrBSO and BC risk association, 95% CI rrBSO/non-rrBSO Overall 1.09 (0.67–1.77) 0.89 (0.69–1.14) NR NR 1.15 (0.52–2.54) NR NR 
 BRCA1 (all) 1.21 (0.72–2.06) 0.97 (0.73–1.29) 1.2 (0.67–2.12) 0.57 (0.38–0.84) 1.22 (0.50–3.00) 1.23 (0.94–1.61) See below 
 BRCA2 (all) 0.54 (0.17–1.66) 0.68 (0.38–1.21) 0.86 (0.43–1.72) 0.62 (0.41–0. 96) 1.09 (0.20–6.06) 0.88 (0.62–1.24) See below 
 “Premenopausal” rrBSO BRCA1/BRCA2 1.11 (0.65–1.90) NR NR NR 0.84 (0.40–1.77) NR NR 
 “Premenopausal” rrBSO BRCA1 NR 0.84 (0.58–1.21) NR NR 0.84 (0.37–1.91) 1.11 (0.80–1.52) 0.45 (0.22–0.92) 
 “Premenopausal” rrBSO BRCA2 NR 0.17 (0.05–0.61) NR NR 0.73 (0.11–4.82) 0.57 (0.32–1.01) 0.77 (0.35–1.67) 

Abbreviations: BC, breast cancer; N, number; NR, not reported.

aMean.

bInclusive of BRCA1 and BRCA2 mutation carriers, and other high-risk women.

cNot reported for the subgroup of women without a personal history of breast cancer. Note this subgroup analysis also included women with personal history of breast cancer, so not directly comparable with that for the other studies.

dPremenopausal defined as <50 years old at baseline.

Kotsopoulos and colleagues published a prospective cohort study of 2,969 BRCA1, 725 BRCA2, and 28 BRCA1 or BRCA2 (specific gene unknown) mutation carriers with no prior breast cancer diagnosis, to evaluate the effect of rrBSO on breast cancer risk (5). Of the 3,722 women studied, 857 underwent rrBSO before cohort enrolment and 695 underwent rrBSO after enrolment. The observation period commenced either at completion of the baseline questionnaire or receipt of genetic testing result, whichever was later, to limit cancer-induced testing bias. The mean age at rrBSO was 46.3 years (range, 13–78). With 350 incident breast cancers observed during a mean follow-up period of 5.6 years, there was no statistically significant association between rrBSO and breast cancer risk for BRCA1 (HR, 0.97; 95% CI, 0.73–1.29; P = 0.85) or BRCA2 mutation carriers (HR, 0.68; 95% CI, 0.38–1.21; P = 0.19). rrBSO was also not statistically significantly associated with reduced risk for breast cancer diagnosed under age 50 years for BRCA1 mutation carriers (HR, 0.84; 95% CI, 0.58–1.21; P = 0.34); however, rrBSO was associated with an 83% lower risk of breast cancer diagnosed under age 50 years for BRCA2 mutation carriers (95% CI, 0.05–0.61; P = 0.006). It is unclear why this analysis was limited to breast cancers diagnosed before age 50, rather than examining the effect of rrBSO before age 50 on risk of breast cancer over the entire follow-up period. In light of Heemskerk-Gerritsen and colleagues' publication, Kotsopoulos and colleagues treated rrBSO as a time-dependent variable, mitigating immortal person-time bias and adjusted for parity and other well-described risk factors in a multivariable analysis. They attempted to reduce potential confounding by indication, informative censoring, and survival bias by adjusting for cancer family history (i.e., number of first-degree relatives affected by breast cancer). However, this approach fails to consider more subtle components of family history that affect cancer risk, such as age at breast cancer diagnosis and affected status of more distant relatives (of particular importance where there is paternal inheritance) and therefore provides only partial mitigation.

Following on from Kotsopoulos and colleagues, Terry and colleagues analyzed data from 716 BRCA1 and 573 BRCA2 mutation carriers from the Prospective Family Study Cohort, encompassing the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab; ref. 6). In their sample, the median age of rrBSO was 44 years for BRCA1 and 46 years for BRCA2 mutation carriers. Incident breast cancer was diagnosed in 116 BRCA1 and 80 BRCA2 mutation carriers during a median follow-up of 10.7 years. To demonstrate the importance of treating rrBSO as a time-dependent variable, Terry and colleagues first treated it as a fixed exposure and observed a statistically significant association between rrBSO and reduced breast cancer risk similar to Rebbeck and colleagues' meta-analysis (BRCA1: HR, 0.40; 95% CI, 0.26–0.67; BRCA2: HR, 0.32; 95% CI, 0.17–0.60). However, there was no statistically significant association when rrBSO was treated as a time-dependent variable (BRCA1: HR, 1.20; 95% CI, 0.67–2.12; BRCA2: HR, 0.86; 95% CI, 0.43–1.72). This supported the conclusions of Heemskerk-Gerritsen and colleagues and emphasizes the potential effect of this bias on these observational studies. The study design reduced cancer-induced testing bias by only including women who were unaffected at the start of the observation period; however, the observation period did not start at the time of genetic testing, so residual cancer-induced testing bias may have been present. Other potential sources of bias may also have been present including confounding by indication, survival bias from competing risk of tubo-ovarian cancer, informative censoring and confounding by other risk factors. Furthermore, Terry and colleagues did not report on the effect for mutation carriers undergoing pre-menopausal rrBSO, although an analysis of women in the upper tertile of breast cancer risk (inclusive of mutation carriers and other high-risk women), showed no difference in risk based on age at rrBSO (<45, 45–49, ≥50 years).

More recently, Choi and colleagues (7) reported findings from further analyses of BCFR data, including 746 women with BRCA1 and 576 with BRCA2 mutations, of which 483 and 373 had breast cancer, respectively. This newer study had the same methodologic issues as Terry and colleagues (6). Some of these potential biases were likely exacerbated by the apparent inclusion of prevalent breast cancer cases at cohort recruitment, and of additional retrospective data back to age 16 years (47). The estimated HRs for BRCA1 and BRCA2 mutation carriers overall were 0.57 (95% CI, 0.38–0.84) and 0.62 (95% CI, 0.41–0.96), respectively, and 0.28 (95% CI, 0.10–0.63) and 0.19 (95% CI, 0.06–0.71), respectively, in the first 5 years following rrBSO. No HRs were estimated for the relationship between premenopausal rrBSO and breast cancer risk (7).

Mai and colleagues have also recently addressed this question using data from the US Gynecologic Oncology Group-0199, a multi-institution, prospective cohort study of women at high risk of tubo-ovarian cancer (8). Considering only women in this study without a personal history of breast cancer (minimizing cancer-induced testing bias), there were 242 BRCA1 and 189 BRCA2 mutation carriers included in the analysis between rrBSO and breast cancer risk, of whom 120 BRCA1 and 102 BRCA2 mutation carriers had rrBSO. rrBSO was treated as a time-dependent variable, mitigating immortal person-time bias. Thirty-eight incident breast cancers were observed during follow-up: 29 in BRCA1 and 9 in BRCA2 mutation carriers. There was no statistically significant protective association between and rrBSO and breast cancer for BRCA1 or BRCA2 mutation carriers combined or separately (HR, 1.15; 95% CI, 0.52–2.54; P = 0.72; BRCA1 HR, 1.22; 95% CI, 0.50–3.00; P = 0.66; and BRCA2 HR, 1.09; 95% CI, 0.20–6.06; P = 0.92, respectively). This held true when the analysis was limited to premenopausal rrBSO (combined HR: 0.84; 95% CI, 0.40–1.77; P = 0.64; BRCA1: HR, 0.84; 95% CI, 0.37–1.91; P = 0.68; BRCA2: HR, 0.73; 95% CI, 0.11–4.82; P = 0.75); however, that analysis also included women with a personal breast cancer history, which, if anything, would lead to an overestimate of any association, through cancer-induced testing bias. Despite being a prospective cohort study specifically designed to address this question, the study had a small number of incident cancers and remained subject to several important biases. The authors recognized potential confounding by indication, especially as women in the rrBSO group were less likely to have a first- or second-degree relative diagnosed with premenopausal breast cancer (P = 0.03). Like other contemporary studies, survival bias from competing risk of tubo-ovarian cancer, informative censoring and confounding by other risk factors may have been present.

Mavaddat and colleagues recently published the largest study addressing this issue, using international, multi-center prospective pooled cohort data (9). It included 2,272 BRCA1 and 1,605 BRCA2 mutation carriers from three large consortia – the International BRCA1/2 Carrier Cohort Study (IBCCS), the kConFab Follow-up Study and the BCFR. Notably, the IBCCS cohort overlaps with that analyzed by Heemskerk-Gerritsen and colleagues (4) and the kConFab and BCFR cohorts overlap with those in Terry and colleagues (6) and Choi and colleagues (7). Cancer-induced testing bias was minimized by excluding women affected with breast cancer at the start of the observation period and by commencing observation after mutation testing (in 97% of enrolled women). rrBSO was treated as a time-dependent variable, with the addition of a latency period immediately after rrBSO (and at commencement of observation). During 5.4 and 4.9 years of follow-up respectively, a total of 269 and 157 incident breast cancer cases were diagnosed in BRCA1 and BRCA2 mutation carriers, respectively. In the primary analysis, there was no statistically significant association between rrBSO and breast cancer risk in BRCA1 (HR, 1.23; 95% CI, 0.94–1.61) or BRCA2 (HR, 0.88; 95% CI, 0.62–1.24) mutation carriers. For women with BRCA2 mutations, the HR for those who underwent rrBSO prior to the age of 45 was 0.68 (95% CI, 0.40–1.15), whereas that for rrBSO after age 45 was 1.07 (95% CI, 0.69–1.64). There was some evidence of a stronger association with increasing time since rrBSO for BRCA2 mutation carriers (Ptrend = 0.011), with a HR, 0.51 five years after rrBSO (95% CI, 0.26–0.99; P = 0.046) overall, and HR, 0.39 (95% CI, 0.16–0.97) in women undergoing rrBSO ≤45 years. These findings should be interpreted with caution as there was substantial variation in this HR between individual cohort studies included in the analysis (Pheterogeneity = 0.005; ref. 9). Like the others, this study is subject to possible bias from informative censoring. Women undergoing rrBSO were more likely to have a family history of tubo-ovarian cancer (P < 0.001), suggesting potential confounding by indication, although no statistically significant difference was observed in their family history of breast cancer among first- and second-degree relatives and a statistical adjustment was made to account for this. The authors also adjusted for parity, age at first birth and HRT, limiting confounding by other risk factors.

Stjepanovic and colleagues (10) conducted an analysis of data from five prospectively maintained registries in Spain and the United States, including 444 BRCA1 and 409 BRCA2 mutation carriers aged ≤51 years, 337 of whom underwent rrBSO before age 51. During the median 4.3 years of follow-up, 96 women developed incident breast cancer (54 with BRCA1 mutations and 42 with BRCA2 mutations). The median age of premenopausal rrBSO was 42 years (range, 30.5–50.9) in BRCA1 and 43.5 years (range, 33.7–50.9) in BRCA2 mutation carriers. In contrast to some of the other recent studies, a statistically significant protective association between rrBSO and breast cancer risk was reported for BRCA1 mutation carriers (HR, 0.45; 95% CI, 0.22–0.92; P = 0.03), but there was no statistically significant association for BRCA2 mutation carriers (HR, 0.77; 95% CI, 0.35–1.67; P = 0.51). They concluded that this evidence was sufficient to continue to recommend premenopausal rrBSO for BRCA1 mutation carriers (10). Stjepanovic and colleagues reduced several biases, including immortal person-time bias by treating rrBSO as a time-dependent variable and adding a 3-month latency after rrBSO. Cancer-induced testing bias was removed by commencing the observation time at receipt of mutation results, or at age 30, whichever occurred later and excluding women with a prior cancer diagnosis (10). However, the authors were unable to control for differences in family history or other potential confounding and therefore, the threat of confounding by indication and other risk factors persists. A sensitivity analysis that excluded women undergoing rrBM yielded similar results to the primary analysis, although this does not completely exclude the possibility of informative censoring (4). The authors went on to conduct a meta-analysis of findings from theirs and four published studies (4–6, 41) to determine the association between premenopausal rrBSO and breast cancer risk. Utilizing the two studies that distinguished rrBSO before or after age 50 (5, 41) alongside their own data in a subsequent analysis, Stjepanovic and colleagues observed a HR, 0.61 (95% CI, 0.36–1.02) for BRCA1 and HR, 0.43 (95% CI, 0.18–1.01) for BRCA2 mutation carriers (10).

Other options to reduce breast cancer risk

rrBM is the most effective breast cancer risk reduction intervention for mutations carriers. rrBM was associated with an 87% and 82% reduction in breast cancer risk for BRCA1 and BRCA2 mutation carriers, respectively, in a meta-analysis of four studies (36, 37, 48–50). Similar to studies of rrBSO, all rrBM studies were observational and subject to bias; however, there is clear biologic plausibility that rrBM may reduce breast cancer risk. Discussion of rrBM is recommended by NCCN, NICE, ESMO, ACOG, and Australian eviQ guidelines; however, uptake is variable (51–53), so alternatives are desirable.

The use of chemoprevention in women with BRCA1 and BRCA2 mutations is also endorsed in guidelines. Unlike rrBM or rrBSO, it has the advantage of being a reversible intervention if women experience side-effects or change their mind.

Despite high-quality data supporting the efficacy of chemoprevention for noncarriers at high risk of breast cancer (54–57), and evidence that the risk reduction persists for many years after cessation of the medication (55–56), data pertaining to mutation carriers are extremely limited. The only randomized trial of aromatase inhibitors for primary breast cancer prevention in carriers was underpowered but reported no protective association between letrozole and breast cancer in postmenopausal women (HR, 1.29; 95% CI, 0.4–3.9; ref. 58). The NSABP-P1 study of tamoxifen for breast cancer prevention estimated a risk ratio for breast cancer of 1.67 (95% CI, 0.32–10.7) for BRCA1 and 0.38 (95% CI, 0.06–1.56) for BRCA2 mutation carriers randomized to tamoxifen (59). This study had limited power due to only 8 BRCA1 and 11 BRCA2 mutation carriers identified among 288 incident breast cancer cases. Given that the point estimate for BRCA2 was considerably less than 1 however, these findings are often interpreted to indicate that tamoxifen may be efficacious for risk reduction in this population, although there remains considerable uncertainty. Enrolment of women onto randomized clinical trials of new potential chemopreventive agents is encouraged (https://www.breastcancertrials.org.au/current-clinical-trials/brca-p).

A detailed discussion of lifestyle factors is beyond the scope of this article, but population recommendations for healthy living, such as maintaining a healthy weight, participating in regular moderate-intensity exercise, minimizing alcohol intake and minimizing exposure to combined exogenous estrogen and progesterone, should be applied (14).

Despite concerted efforts over 20 years to ascertain whether, and to what extent, rrBSO reduces breast cancer risk in unaffected BRCA1 and BRCA2 mutation carriers, there remains uncertainty and no consensus. Yet this question is of critical interest to clinicians and the women they care for, as it underpins advice regarding strategies to reduce breast cancer risk. Randomized trials of premenopausal rrBSO versus no rrBSO are not considered feasible, because women are unlikely to accept such a randomization. The absence of randomized trial data means that clinical decision making is reliant on data from observational studies that have important limitations. The observational studies to date have contained several types of bias and while some recent studies have made attempts to minimize this problem, residual bias likely persists. Some biases cannot be fully mitigated in an observational study design, and others, such as confounding by indication, have mitigation strategies that are very difficult to achieve without severely limiting the sample size.

On the basis of the seven recent, more methodologically robust studies (4–10) highlighted in this review (Table 3), there is not clear and consistent evidence of a protective effect of rrBSO on breast cancer risk for either BRCA1 or BRCA2 mutation carriers. It may be most relevant to focus on studies of premenopausal rrBSO, given that any protective association between rrBSO and breast cancer risk would only be biologically plausible for premenopausal rrBSO, because postmenopausal rrBSO does not alter circulating levels of female hormones. Of the four studies (5, 8–10) that assessed the association between premenopausal rrBSO and breast cancer risk in BRCA1 mutation carriers (using the average age of menopause in the general population, 50 or 51 years, as a surrogate for actual menopausal status), only Stjepanovic and colleagues (10) showed a clear protective association. The other three studies reported HRs between 0.84 and 1.11, and confidence intervals including 1. Conversely, all four studies (6, 9–11) of rrBSO in premenopausal BRCA2 mutation carriers reported point estimates <1 (HR, 0.17–0.77); however, apart from Kotsopoulos and colleagues (5), the CI included 1 in the other three studies (see Table 3). Of note, Kotsopoulos and colleagues only included breast cancers diagnosed before age 50, which differs from the design of the other studies. Despite the wide confidence intervals, given that the point estimates for premenopausal rrBSO for BRCA2 were consistently <1, it is plausible that a clear protective association was not demonstrated due to underpowered individual analyses. An individual participant data meta-analysis may help to clarify this point, although the problem of residual confounding and bias will not be overcome by meta-analytic techniques.

Overall, considering the limitations of the published studies and their conflicting results, the current evidence does not support a recommendation that BRCA1 or BRCA2 mutation carriers should consider premenopausal rrBSO specifically to reduce to their risk of first breast cancer. This review of the evidence does not address the role of BSO for treatment of breast cancer or prevention of a second breast cancer event. Premenopausal rrBSO is associated with both long- and short-term morbidities, many of which are irreversible (60–65). Although some of these may be alleviated by HRT, caution is needed when considering combined HRT for women with BRCA1 or BRCA2 mutations who are already at heightened risk of breast cancer. Based on all the evidence presented, we strongly advise that rrBSO should be postponed until the latest possible age at which a woman may still derive the maximum cancer risk reduction from the procedure. Given the uncertainty regarding the reduction in breast cancer risk conferred by rrBSO, the optimal age for the procedure in women with no personal history of breast cancer should be driven by tubo-ovarian cancer risk. For BRCA1 mutation carriers, tubo-ovarian cancer risk increases above that of the general population from the mid-30s (1) and guidelines recommend rrBSO between age 35 and 40 years, if childbearing is complete. However, for BRCA2 mutation carriers, tubo-ovarian cancer risk is lower and increases later (1), so unless there is a family history of early-onset tubo-ovarian cancer, rrBSO could reasonably be delayed until age 45 years (which is at the upper end of the age range of 40–45 years recommended by NCCN). Research into the role of salpingectomy and delayed oophorectomy is ongoing (https://clinicaltrials.gov/ct2/show/NCT02321228, https://clinicaltrials.gov/ct2/show/NCT01907789), but such an approach cannot currently be considered a standard of care for reducing tubo-ovarian cancer risk.

No randomized studies of rrBSO and breast cancer risk have been conducted, nor are they likely to be. The protective association between rrBSO and breast cancer risk suggested by early observational studies with designs that exposed them to considerable bias has not been clearly confirmed in seven subsequent contemporary observational studies with generally, more robust study designs. Thus, although rrBSO is considered optimal for mutation carriers to reduce risk of tubo-ovarian cancer, we contend that it should not currently be utilized specifically to provide protection against first breast cancer and thus, in women without a personal history of breast cancer, rrBSO should be delayed until the age at which tubo-ovarian risk reduction becomes relevant. Meanwhile, rrBM is the most effective way of reducing breast cancer risk; however, for women who find rrBM unacceptable, close surveillance together with modification of lifestyle-related risk factors and consideration of chemoprevention (especially for BRCA2 mutation carriers) and modification of lifestyle-related risk factors are reasonable options.

M.L. Friedlander reports grants, personal fees, and other support from AstraZeneca, grants and personal fees from Novartis, personal fees from GSK, Lilly, Takeda, MSD, ACT Genomics, and nonfinancial support from Abbvie outside the submitted work. K.-A. Phillips reports grants from National Health and Medical Research Council during the conduct of the study, and K.-A. Phillips is a co-author on several of the articles describing observational studies that are the subject of this review. No disclosures were reported by the other authors.

No new data were generated or analyzed in support of this research.

K.-A. Phillips is a National Health and Medical Research Council (Australia) Leadership Fellow.

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