Salpingo-oophorectomy is often offered to unaffected women with a BRCA1 or BRCA2 mutation with the purpose of preventing hereditary ovarian cancer. We have recently reported that performing an oophorectomy on a premenopausal woman with a BRCA mutation reduces all-cause mortality by 70% [Citation1]. In this prospective study, we followed 6000 carriers for 5 years; for all-comers, the hazard ratio for oophorectomy on mortality to age 70 years was 0.31 (95% CI, 0.26–0.38; P = 0.001). For those with breast cancer, all-cause mortality to 70 years was reduced by 60% (HR, 0.39 [95% CI, 0.30–0.50]; P = 0.001). The benefit was similar for BRCA1 and BRCA2 carriers.
Oophorectomy prevented deaths from both breast and ovarian cancer. This may be from the prevention of ovarian/fallopian cancer, the prevention of breast cancer, and from reducing case fatality after a diagnosis of breast cancer. The first benefit has been clearly demonstrated – salpingo-oophorectomy reduces death from ovarian cancer by 80% – although there is a residual lifetime risk of about 4% for peritoneal cancer [Citation1]. Surprisingly, in two recent studies, we and others found no reduction in the risk of breast cancer risk following oophorectomy in BRCA1 carriers [Citation2,Citation3]. In contrast, for BRCA1 carriers who have an oophorectomy after a diagnosis of breast cancer, a reduction in deaths is a consistent finding [Citation4–Citation6].
In the first study, Metcalfe et al. followed a cohort of 676 BRCA1 and BRCA2 mutation carriers with stage I or II breast cancer [Citation4]. For BRCA1 mutation carriers, oophorectomy (before or after diagnosis) reduced breast cancer mortality by 60% (HR, 0.38 [95% CI, 0.19–0.77]; P = 0.007). If performed within 2 years of diagnosis, the hazard ratio was 0.27 (95% CI, 0.11–0.66; P = 0.004). In BRCA2 carriers, the findings did not reach significance (HR, 0.57 [95% CI, 0.23–1.43]; P = 0.23) [Citation4]. Contrary to expectation, mortality was greatly reduced for triple-negative breast cancer patients (HR, 0.07 [95% CI, 0.01–0.51]; P = 0.009). In an extension of this study, Valentini et al. [Citation5] followed 397 young women with breast cancer and a BRCA1 mutation and found that oophorectomy was associated with an 80% reduction in mortality (HR, 0.20 [95% CI, 0.06–0.62]; P = 0.006) [Citation5].
In a recent study from Poland, Huzarski et al. [Citation6] followed a cohort of 476 BRCA1 carriers for a mean of 8.0 years, half of whom underwent oophorectomy. They reported a 70% reduction in breast cancer mortality with oophorectomy after adjustment for other treatments and prognostic factors (HR, 0.30 [95% CI, 0.12–0.76]; P = 0.01) [Citation4]. For women with ER-negative breast cancer, the hazard ratio for breast cancer mortality with oophorectomy was 0.44 (95% CI, 0.22–0.89; P = 0.02), and for women with ER-positive breast cancer, the hazard ratio was 0.71 (95% CI, 0.10–5.11; P = 0.73). The hazard ratio for oophorectomy on all-cause mortality was 0.41 (95% CI, 0.24–0.69; P = 0.001) [Citation6]. In Poland, BRCA2 mutations are rare and there are insufficient data to conclude that the operation is or is not beneficial for BRCA2 carriers.
In a 2010 paper, the PROSE database was used in a historical cohort study of BRCA1 and BRCA2 mutation carriers. Oophorectomy was reported to reduce breast-cancer-specific mortality in BRCA1 mutation carriers by 73% (HR, 0.27 [95% CI, 0.12–0.58]) but not in BRCA2 carriers. Oophorectomy was also associated with a significantly decline in all-cause mortality in BRCA1/BRCA2 carriers with a prior history of breast cancer (HR, 0.30 [95% CI, 0.17–0.52]) [Citation7].
Quality of life and long-term cardiovascular disease, bone health, and possibly cognitive outcomes are concerns of young women who face surgical menopause. Nevertheless, the magnitude of the benefit observed in these studies cannot be ignored, in particular for women with poor prognosis cancers (e.g. node positive). Furthermore, we do not recommend hormone replacement therapy for women with breast cancer in the absence of empiric data to show that it is safe. These data will be difficult to acquire. Given that we cannot explain why oophorectomy benefits women with ER-negative breast cancer, we are reluctant to expose women with breast cancer to exogenous hormones, even if the cancer is ER negative.
It is proposed that some carriers of BRCA1 and BRCA2 mutations may choose not to undergo oophorectomy in favor of fallopian tubes-only surgery. This is perhaps a rational alternative to carriers without breast cancer, but in light of the abovementioned observations of oophorectomy on breast cancer mortality, we recommend that tubes-only surgery be avoided in women with breast cancer in favor of complete salpingo-oophorectomy. To date, no large prospective randomized data are available that compare the impact of salpingectomy alone with complete salpingo-oophorectomy in patients with breast cancer and a BRCA mutation. In any case, when the ovaries are removed for preventive purposes or for the treatment of breast cancer, it is important that both fallopian tubes be removed also as these are considered to be the source of most high-grade serous ovarian cancers.
For BRCA2 mutation carriers, there does not seem to be a clear benefit to oophorectomy in terms of breast cancer mortality benefit and the decision to undergo salpingo-oophorectomy should be based on ovarian cancer risk. In general, it is safe to postpone oophorectomy to age 45 in BRCA2 carriers.
In summary, the data are consistent and suggest that BRCA1 mutation carriers with breast cancer will experience several benefits if oophorectomy is performed shortly after diagnosis. Benefits include a reduction in second primary ovarian cancers and a reduction in deaths from breast cancer. In our opinion, ovarian surgery should be performed within 1 year of diagnosis to optimize the benefit. No specific studies have been done yet to compare the magnitude of the benefit according to time to oophorectomy or to stratify benefit by age at diagnosis. We cannot explain the observed benefit of oophorectomy on mortality for women with ER-negative breast cancers, but we do not think that negative ER-negative status should diminish the recommendation for surgery.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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References
- Finch APM, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547–1553.
- Kotsopoulos J, Huzarski T, Gronwald J, et al. Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2016;109(1):djw177.
- Heemskerk-Gerritsen BA, Seynaeve C, van Asperen CJ, et al. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst. 2015;107(5):djv033.
- Metcalfe K, Lynch HT, Foulkes WD, et al. Effect of oophorectomy on survival after breast cancer in BRCA1 and BRCA2 mutation carriers. JAMA Oncol. 2015;1(3):306–313.
- Valentini A, Lubinski J, Byrski T, et al. The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation. Breast Cancer Res Treat. 2013;142(1):177–185.
- Huzarski T, Byrski T, Gronwald J, et al. Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol. 2013;31(26):3191–3196.
- Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967.