The clinical management of cancer risk in BRCA1
mutation carriers is complex and is best informed by accurate knowledge of the outcomes of interventions. Most prior studies that have investigated the effect of RRSO or RRM on BC risk either did not examine effects by mutation status 7, 9, 12
or by prior cancer diagnosis 14, 19
. There may be little added benefit of RRSO on BC risk if women have chemotherapy-induced menopause, or if they are already receiving hormonal therapy. We hypothesize that both of these factors are important in determining precise estimates of risk reduction. Our results confirm that RRM is associated with a significant reduction in BC risk. In addition, RRSO is associated with a significant decrease in OC risk in both BRCA1
mutation carriers, and in those with and without a prior BC. There is a significant reduction in BC risk following RRSO in both BRCA1 and BRCA2
mutation carriers with no prior cancer. Overall mortality was improved in women undergoing RRSO.
RRM is a highly effective strategy for BC risk reduction 20, 21
. In our prospective analysis, no
BC were observed after RRM. The observation of no prospectively identified BC cases may be due to biases in prior retrospective studies, or improved surgical techniques in recent prospective analyses.
RRSO is highly effective in reducing ovarian and fallopian tube cancers in both BRCA1
mutation carriers and in those with and without a prior BC. Precise estimates of risk reduction following RRSO are needed to balance the increasingly recognized health risks caused by premature menopause22-26
. We observed no primary peritoneal cancers following RRSO in BRCA2
mutation carriers, although such cancers have been reported 10
. In BRCA1
mutation carriers, RRSO was associated with a 70% reduction in risk of OC in those without a prior BC and 85% in those with a prior BC. Whether these numbers are truly different, reflect censoring from death due to BC, or a protective effect following BC treatment is unknown.
RRSO was associated with a significantly decreased risk of BC in those with no prior BC with both BRCA1
(37% reduction) and BRCA2
mutations (64% reduction). In mutation carriers with a prior BC, RRSO had no effect on second primary BC risk. In women with sporadic BC, the benefit of RRSO when added to standard adjuvant treatment is uncertain and is the subject of multiple ongoing clinical trials. Chemotherapy often leads to cessation of menses, so any effect of ovarian ablation from RRSO may be achieved in some women by chemotherapy. In premenopausal women with estrogen receptor (ER) positive tumors, hormonal therapy in addition to chemotherapy significantly improves disease-free survival27, 28
. Our data are in contrast to prior reports demonstrating benefit of oophorectomy in preventing contralateral BC29, 30
. Differences in adjuvant therapy use could explain these discrepancies; however, a limitation of our study is the absence of detailed treatment information. It is important to note that OC risk is independent of menopause; menopause either naturally occurring or chemotherapy-induced is not known to decrease the risk of OC. Regardless of the effect of oophorectomy on second BC, oophorectomy is essential to reduce the risk of OC, which can be a significant cause of morbidity and mortality in women with early stage breast cancer 29
Our data suggest that RRSO may be associated with a lower BC risk in BRCA2
mutation carriers than in BRCA1
mutation carriers (64% vs. 37%). Kauff et al 15
observed a statistically significant BC risk reduction following RRSO in BRCA2
but not BRCA1
mutation carriers. The potentially larger risk reduction associated with RRSO in BRCA2
compared with BRCA1
mutation carriers is of interest given the high proportion of ER positive breast tumors in BRCA2
mutation carriers compared with BRCA1
. Additional research is required to address this issue.
We are still unable to provide definitive data with respect to the timing of RRSO on the efficacy of BC risk reduction as the numbers in each subgroup remain small with a limited number of events. Eisen et al. 14
reported that the BC risk reduction with RRSO was greater in BRCA1/2
mutation carriers who underwent surgery before age 50 than in women who underwent surgery after age 50. The results of the present analyses are consistent with this finding for unaffected women who undergo RRSO before or after age 50.
The importance of understanding the optimal age at RRSO is underscored by several reports32
in the general population that suggest that oophorectomy in women under age 45 is associated with increased mortality, particularly if HT is not used 26
Although these data are not directly applicable to BRCA1/2
mutations who have markedly increased risks of breast and ovarian cancer and therefore a different risk/benefit profile, issues of timing and the safety of HRT are important. The Women's Health Initiative in postmenopausal women did not demonstrate a cardiovascular benefit overall from HT 33
, but younger women going through natural menopause may derive such benefit 33, 34
. It is possible that BRCA1/2
mutation carriers undergoing abrupt surgical menopause to reduce OC risk and receive HT may derive health benefits. Two prior studies have examined HT in BRCA1/2
mutation carriers. Rebbeck et al.35
examined 462 patients and reported no increased BC risk with post-RRSO HT use. Eisen et al.14
examined HT in women with and without RRSO and observed no increased risk associated with HT. Further work is needed regarding this important issue.BRCA1BRCA1BRCA2BRCA1/2
We observed an association of RRSO with a significant reduction in all-cause, BC-specific, and OC-specific mortality. We previously reported that RRSO was associated with a 90% reduction in BC–specific mortality, a 95% reduction in gynecologic cancer–specific mortality, and a 76% reduction in overall mortality12
. Our present estimates are consistent with those reports. The apparent lesser effect on mortality in BRCA2
mutation carriers may be due to the lower risk of OC in BRCA2
mutation carriers as well as the more aggressive biological features of BRCA1
-associated BC, however, more data is needed to adequately address this important question.
We recognize a number of limitations of the study. We designed our study to maximize follow up time and statistical power. However, this choice could have compromised our results in a number of ways. Our study design was powered to detect effects of RRSO and RRM stratified on BRCA1/2 as well as the other groups defined in the tables. The observation of statistically significant p-values in many strata provides evidence that we had sufficient power for our pre-planned hypotheses. A few strata-specific analyses did not achieve statistical significance, suggesting that we did not have sufficient power to detect some smaller than anticipated effects. Therefore, analyses in some substrata may require additional study after accrual of much larger sample sizes.
Ideally, the evaluation of risk reducing surgery on cancer risk and mortality reduction would involve a randomized trial design. However, it is accepted in the field that a randomized approach would neither be acceptable nor ethical. As a result, this field of research is limited to undertaking observational studies that have methodological limitations. An observational design requires that statistical methods be used to correct for factors that may influence relative risk estimates. We have attempted to correct for a number of limitations of the observational study design by using the recommended analysis approaches of Klaren 36
and Hartmann 37
. However, additional analytical corrections could be considered in future analyses, including the effect of competing risks, or the consideration of time-dependency of RRSO/RRM and other covariates. As a result of these limitations, our results cannot be definitively inferred to be causal in nature.
An additional limitation of an observational study design is the need to determine appropriate follow-up periods for participants. Once choice is whether to follow individuals from the time of ascertainment vs. the time from genetic testing. All individuals in our cohort underwent genetic testing, however some individuals were ascertained prior to their genetic testing; the median ascertainment year was 1999 and median genetic test disclosure date 2001. To address the implications of this choice, we performed an exploratory analysis examining overall mortality using the time of genetic testing (rather than ascertainment) as the starting point, with all other criteria met as in the methods section. With this approach, we see a significant mortality benefit: RRSO was associated with a decreased risk of overall mortality in the entire group (HR=0.36; 0.20-0.62), in BRCA1 mutation carriers (HR 0.42; 0.22-0.81), and in BRCA2 mutation carriers (HR 0.10, 0.01-0.77). However, due to smaller number we lose power to address other questions and therefore have continued to use our initial, preplanned analysis as the primary analysis.
Although all women who chose to forego RRSO were counseled to undergo intensive screening, we do not have detailed information on compliance of these recommendations at all centers. However, there are no data that ovarian cancer screening is effective in reducing the risk of developing ovarian cancer, or in dying from ovarian cancer38
. Therefore, we feel that it is unlikely that compliance would significantly alter our results related to ovarian cancer endpoints of incidence and mortality. Intensive breast cancer surveillance does not reduce the risk of developing breast cancer, but aims to improve early detection. Due to our lack of detailed information on breast MRI compliance, we cannot conclude that RRSO improved breast cancer specific mortality compared to optimal screening; however, we do see that women who choose RRSO are associated with better outcomes in terms of breast cancer risk, ovarian cancer risk, and ovarian cancer specific- survival, none of which would be anticipated to be affected by compliance to intensive breast screening. We also see an association between RRSO and breast-cancer specific and overall survival, when compared to women who have not chosen RRSO. BRCA1BRCA2BRCA1BRCA2