In this retrospective cohort study, we presented our real-world experience on management of female germline BRCA1/2 mutation carriers in relation to RRSO strategy. The total and intentional uptake rates of RRSO were 70.1% and 42.7%, respectively. Despite RRSO, incidental ovarian/tubal cancers were identified in 3.7% of the women. BRCA1/2 mutation carriers’ age and occupational status affected their decision on taking RRSO strategy rather than surveillance.
The ovary is an essential organ for maintaining fertility and secreting female sex hormones, especially estrogen. Therefore, women with premature surgical menopause may suffer from an increased risk of bone loss, cardiovascular disease, and decreased cognitive function (7). In addition, they may experience a lower quality of life due to vasomotor symptoms, such as hot flashes, sweating, etc. Moreover, women who experience early menopause may feel that they have lost their femininity. In this aspect, older women, particularly those who have already experienced menopause, are more inclined to undergo RRSO, compared to young, premenopausal women (8).
Women who are employed also tended to choose RRSO strategy, rather than surveillance, possibly because it is more difficult for them to take regular screening tests, compared with unemployed women. Previous studies have shown that family history of cancer and personal history of breast cancer were important factors for BRCA1/2 mutation carriers to undergo RRSO (9, 10). In addition, the type of mutated BRCA gene and menopausal status were significantly associated with RRSO (11). However, we observed inconsistent results, which might originate from the uniqueness of our study population; 86.3% of the mutation carriers had been diagnosed with breast cancer before genetic testing in this study. In general, people who have no personal cancer history are known to be reluctant to undergo BRCA1/2 gene testing, even if they have high-risk factors such as a family history of cancer.
The total uptake rate of RRSO in this study was at the upper end of the range described in previous studies, who reported it as 50–70% with inter-center and inter-country variations (11–13). These variations are due to differences in the characteristics of the study population, sociocultural atmosphere, follow-up period, follow-up strategy, counselling by gynecologists, and so on. In Korea, the tendency to receive RRSO is highly influenced by the policy of the National Health Insurance Service (NHIS). The NHIS started to cover the BRCA1/2 gene test in epithelial ovarian and breast cancer patients with a family history of cancer in April 2012, and RRSO in BRCA1/2 mutated cancer patients in December 2012. Thereafter, the annual number of female cancer patients undergoing BRCA1/2 gene testing and RRSO increased rapidly. Furthermore, in 2017, the NHIS began to cover the BRCA1/2 gene test not only for ovarian and breast cancer patients but also for first-degree families of BRCA-mutated cancer patients.
The intentional uptake rate of RRSO was only 42.7%, which was quite low. We could infer that about half of the patients in the RRSO group wanted to take intensive screening at first, considering the finding that 3.7% of women in the RRSO group were incidentally diagnosed with ovarian/tubal cancers despite no abnormal findings on preoperative evaluation. In literature, the occult ovarian/tubal cancer rate in BRCA1/2 mutation carriers undergoing RRSO was described as 0.6–17% (14–18). Therefore, it is recommended that BRCA1/2 mutation carriers, especially those who completed childbearing, undergo RRSO soon after genetic testing to prevent development of ovarian/tubal cancer and microscopic cancer progression. Nevertheless, neglecting cancer screening after RRSO should be avoided, as risks of developing primary peritoneal cancer and breast cancer still remain (19).
With accumulated evidence that the fallopian tube plays a principal role in the development of ovarian/tubal cancer, some researchers have proposed a risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) strategy for premenopausal women to resolve problems with premature menopause (20, 21). RRESDO is a two-stage surgical alternative to RRSO. In a pilot study, early salpingectomy was done for premenopausal women just after detection of a BRCA1/2 gene mutation. Then, delayed oophorectomy was recommended for patients at age 40 with the BRCA1 gene mutation and age 45 with the BRCA2 gene mutation (22). Most patients who underwent RRESDO, particularly women concerned about sexual dysfunction, were satisfied with their choice of surgery. However, the RRESDO strategy still remains investigational and a clinical trial is required to make this strategy routine (23).
For BRCA1/2 mutation carriers who are reluctant to undergo RRSO, the Korean Society of Gynecologic Oncology (KSOG) recommends transvaginal sonography or serum CA-125 tests every 4 months (24). Such intense screening might offer a better chance for early detection of ovarian cancer, however, robust scientific evidence on this issue is needed.
The current study had several limitations. First, there was bias in the study population towards breast cancer patients. Second, not all possible confounding factors were included. In particular, the causes of amenorrhea, such as natural menopause, surgical menopause, and medication-induced menopause (e.g., tamoxifen, aromatase inhibitor), were not considered. Third, the trend of undergoing RRSO with time was not analyzed. Further prospective cohort studies are warranted in a larger population.
In conclusion, the total uptake rate of RRSO in female germline BRCA1/2 mutation carriers was 70.1%, but the intentional uptake rate was much lower at 42.7%. The uptake rate of RRSO was affected by the carriers’ age and occupational status. Considering the 3.7% of incidental cancer cases in women who underwent RRSO despite no abnormal findings on preoperative evaluation, it is recommended to perform RRSO soon after the confirmation of germline BRCA1/2 mutations.