Uptake Rate of Risk-Reducing Salpingo-Oophorectomy and Surgical Outcomes of Female Germline BRCA1/2 Mutation Carriers: A Retrospective Cohort Study.

Ovarian cancer, one of the most lethal gynaecological malignancies, is a global burden, with 313959 new cases and 207252 deaths estimated in 2020. 1 Due to a lack of appropriate screening tools for ovarian cancer, most patients are diagnosed at an advanced stage. Accordingly, the prognosis of ovarian cancer is poor, with the likelihood of 5-year survival reported to be 23% in stage III and only 11% in stage IV. Various efforts have focused on diagnosing ovarian cancer at an early stage through risk prediction and prevention. Identifying genetic predisposition offers opportunities for cancer prevention. The BRCA1 and BRCA2 genes are the most commonly mutated genes in ovarian cancer patients. These autosomal dominant mutations account for approximately 90% of hereditary ovarian cancers and 30%–70% of hereditary breast cancers. 2 People with these genetic mutations have a higher chance of developing breast and ovarian cancers. The cumulative risk of breast cancer at age 70 is 45%–85% in individuals with the BRCA1/2 gene mutation compared to the 11% risk of the general population. In addition, the cumulative risk of ovarian cancer at age 70 is 39%–46% for the BRCA1 mutation and 10%–27% for the BRCA2 mutation, compared to the 1.3%–1.9% risk of the general population. 3 4 These cancers develop 10 years earlier than non-hereditary cancers, and the most common histologic type in ovarian cancer is high-grade serous carcinoma (HGSC). Risk-reducing salpingo-oophorectomy (RRSO) is currently regarded as one of the most protective tools for BRCA1/2 mutation carriers. Typically, RRSO is recommended between the ages of 35 and 40 for the BRCA1 mutation, between ages 40 and 45 for the BRCA2 mutation, and upon completion of childbearing. 5 Otherwise, intensive screening for ovarian cancer is recommended: transvaginal ultrasonography combined with serum CA-125 may be considered from age 30 to 35, although benefits of this are uncertain. Many factors affecting the patients’ decisions are known to undergo RRSO, such as personal or family history of breast cancer, individual family plan, social atmosphere, and so on. At our hospital, the BRCA1/2 gene tests on high-risk patients have been conducted since 2005. This study presents a 15-year experience of RRSO in female germline BRCA1/2 mutation carriers at a tertiary institutional hospital in Korea. We also investigated significant factors that might affect the carriers’ decisions.

Among the study population (n=117), 111 and 6 women consulted with gynecologic oncology faculty and non-gynecologic oncology faculty, respectively. During a median observation period of 18.8 months, 82 of the 117 BRCA1/2 mutation carriers received RRSO; therefore, the total uptake rate of RRSO was calculated as 70.1%. The women's characteristics at the time of the BRCA1/2 gene test are shown in Table 1 . The mean age for the gene test was 46.8 years, and more than half (53.0%) of the study participants received the gene testing at ≥45 years of age. Women in the RRSO group were significantly older ( p =0.002) and had higher employment rate ( p <0.001) compared to those in the non-RRSO group. However, other characteristics such as parity, comorbidity, menopausal and educational status, prior abdominopelvic surgery, type of mutated gene ( BRCA1 or BRCA2 ), personal history of cancer other than breast/ovarian cancers, and family history of cancers were similar between the two groups. Overall, 101 (86.3%) of the study population had been diagnosed with breast cancer before the genetic test was performed, and this proportion did not differ between the RRSO and non-RRSO groups ( p >0.999) ( Table 1 ). However, the age at breast cancer diagnosis was significantly older in the RRSO group than in the non-RRSO group (mean, 46.3 years vs. 41.7 years, p =0.027). Regarding history of breast cancer, significantly more patients in the RRSO group had been diagnosed with bilateral breast cancer ( p =0.031), while no differences in the proportions of young-age breast cancer (diagnosed before the age of 40 years) ( p =0.084) and recurrent breast cancer cases ( p =0.546) were observed between the two groups. In the RRSO group, the median time interval between the BRCA1/2 gene test and RRSO was 10.0 months. During the observation period, 11 of the 71 (15.5%) breast cancer patients experienced disease recurrence, while one of the 11 (9.1%) non-breast cancer patients developed de novo breast cancer ( Table 2 ). The mean age at the time of RRSO was 48.8 years and 52.9 years for the BRCA1 and BRCA2 mutation carriers, respectively ( Supplementary Table 1 , only online). In accordance with the current practice guidelines, 5 six out of 42 BRCA1 -mutated women and six out of 40 BRCA2 -mutated women received RRSO between the ages of 35 and 40 years and between the ages of 40 and 45 years, respectively. None of these 12 patients were diagnosed with ovarian/tubal cancers. Surgical details of the RRSO group are also presented in Supplementary Table 1 (only online). Of 82 women, 58 (70.7%) received RRSO only, while 8 (9.8%) received RRSO plus hysterectomy. The reasons for hysterectomy were uterine myoma (n=4), adenomyosis (n=1), endometrial hyperplasia (n=1), endometrial polyp (n=1), and cervical intraepithelial neoplasia 3 (n=1). One postmenopausal woman opted to received hysterectomy without any cause. Breast cancer surgery was conducted on the same day of RRSO in 11 (13.4%) patients, of which one also received simultaneous risk-reducing mastectomy (RRM). Among the rest, 3 (3.7%), 1 (1.2%), and 1 (1.25%) received RRM, myomectomy, and breast augmentation surgery, respectively, concomitantly with RRSO. In terms of the surgical approach for RRSO, laparoscopic surgery was the dominant method that accounted for 95.1% of the cases, while open surgery was conducted in 4.9%. The final pathologic diagnosis was reported with no abnormality in 46.3% of the salpingo-oophorectomy specimens ( Supplementary Table 2 , only online). Approximately, one-third of patients (31.7%) were diagnosed with paratubal cysts, and other benign lesions were identified in 18 (22.0%) patients. Three (3.7%) patients were incidentally diagnosed with ovarian/tubal cancers; HGSCs were identified in their single ovary (n=1), both ovaries (n=1), and single tube (n=1). All patients underwent subsequent laparoscopic staging operations. Regarding the observation periods of these three incidental ovaria/tubal cancer patients, one received RRSO 1.9 months after BRCA1/2 gene testing, and the other two took 14.3 months and 69.0 months. In the non-RRSO group, the median observation period was 96.6 months, during which 13 of the 30 (43.3%) breast cancer patients experienced disease recurrence, while none of the five non-breast cancer patients developed de novo breast cancer. Following BRCA1/2 gene testing, one patient was diagnosed with cervical cancer at 26.3 months and another developed primary peritoneal cancer at 103.8 months ( Table 2 ). The follow-up of the study population focusing on the development of breast and gynecologic cancers after BRCA1/2 gene testing are shown in Fig. 2 . In addition, details of three incidental ovarian/tubal cancer cases in the RRSO group and newly developed primary peritoneal cancer and cervical cancer cases are shown in Table 3 . Lastly, we re-assigned the study population to the RRSO strategy and surveillance strategy groups, based on the women's age at the time of the BRCA1/2 gene test and time interval between the test and actual date of RRSO (12 months). After excluding 14 women aged <35 years, we identified that 44 of the 103 women received RRSO within 12 months after genetic testing; therefore, the intentional uptake rate of RRSO was 42.7%. Multivariate analysis was conducted to identify the factors affecting the BRCA1/2 mutation carrier's decision on taking RRSO strategy rather than surveillance. Results showed that age ≥50 years (aOR, 5.060; 95% CI, 1.639–15.623; p =0.005) and employed status (aOR, 3.402; 95% CI, 1.104–10.484; p =0.033) were positive factors towards RRSO strategy ( Table 4 ).

In this retrospective cohort study, we presented our real-world experience on the 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. 8 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. 9 Women who are employed also tended to choose RRSO strategy over surveillance, possibly since it is more difficult for them to take regular screening tests compared to unemployed women. Previous studies have shown that the type of mutated BRCA gene, family history of cancer, and personal history of breast cancer were important factors for BRCA1/2 mutation carriers to undergo RRSO. 10 11 12 However, we observed inconsistent results, which might originate from the uniqueness of our study population; all BRCA1/2 mutation carriers had either or both personal history of breast cancer and family history of breast or ovarian cancer. Especially, the proportions of the mutation carriers who had been diagnosed with breast cancer before genetic testing and those who had at least one family member of breast cancer were exceptionally high (86.3% and 65.8%, respectively). Such a unique study population, reflecting the reality of a tertiary institutional hospital in Korea, might result in no association between personal and familial cancer histories and the uptake rate of RRSO. The total uptake rate of RRSO in this study was at the upper end of the range described in previous studies, which was reported to be 50%–70% with inter-center and inter-country variations. 12 13 14 These variations are due to differences in the characteristics of the study population, sociocultural atmosphere, follow-up period, follow-up strategy, counseling 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 began 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. Also, only about 20% of the patients underwent RRSO at the age suggested by the guidelines. 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 having no abnormal findings on preoperative evaluation. They were reluctant to receive RRSO at the ages of 30–40s, probably in their premenopausal state. In literature, the occult ovarian/tubal cancer rate in BRCA1/2 mutation carriers undergoing RRSO has been reported to be 0.6%–17%. 15 16 17 18 19 Therefore, it is recommended that BRCA1/2 mutation carriers, especially those who completed childbearing, undergo RRSO soon after genetic testing to prevent the development of ovarian/tubal cancer and microscopic cancer progression. Nevertheless, neglecting cancer screening after RRSO should be avoided, as the risks of developing primary peritoneal cancer and breast cancer still remain. 20 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. 21 22 RRESDO is a two-stage surgical alternative to RRSO. In a pilot study, early salpingectomy was performed for premenopausal women immediately after the detection of a BRCA1/2 gene mutation. Then, delayed oophorectomy was recommended for patients aged 40 years with the BRCA1 gene mutation and those aged 45 years with the BRCA2 gene mutation. 23 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. 24 For BRCA1/2 mutation carriers who are reluctant to undergo RRSO, the Korean Society of Gynecologic Oncology recommends transvaginal sonography or serum CA-125 tests every 4 months. 7 Although such intense screening might offer a better chance for early detection of ovarian cancer, robust scientific evidence on this issue is still 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, there was a significant difference in the follow-up period between the RRSO and non-RRSO groups (median, 10.0 months vs. 96.6 months; p <0.001). As our institution is a tertiary hospital, most patients who underwent RRSO without any diagnostic abnormalities were referred out to the local OB/GYN clinics for further surveillance. Fourth, we could not investigate whether or not the counselor-related factors affected the uptake rate of RRSO, owing to a relatively higher number of faculty who participated in the counseling than the small study population. Moreover, due to the retrospective design of this study, we were unable to know the women's exact reasons for accepting or refusing RRSO and the quality of each counseling provided by the counselors. Lastly, the trend of undergoing RRSO with time was not analyzed. Further prospective cohort studies in a larger population are warranted. 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, women might refrain from the delayed implementation of RRSO after the confirmation of germline BRCA1/2 mutations. Further prospective studies investigating long term health consequences of RRSO and alternative strategies to RRSO are warranted for the premenopausal BRCA1/2 mutated women.

This retrospective cohort study was approved by the Institutional Review Board of Seoul National University Hospital (SNUH No. H-2011-040-1170), and was conducted in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived. Between September 2005 and August 2020, a total of 824 women underwent germline BRCA1/2 gene testing at our institution. We included women aged 20 years or older who had a pathogenic or a likely pathogenic variant on either the BRCA1 or the BRCA2 gene. We excluded women with the following conditions: 1) diagnosed with peritoneal, ovarian, or tubal cancers, or received bilateral salpingo-oophorectomy before the time of the genetic test; 2) had not been referred to the OB/GYN clinic; or 3) were lost to follow-up checks after visiting the OB/GYN clinic once. Overall, 117 BRCA1/2 mutation carriers who met the inclusion criteria were included in our analysis ( Fig. 1 ). They were divided into two groups based on whether they received RRSO after BRCA1/2 gene testing or not. Thereafter, we compared the baseline characteristics of the RRSO and non-RRSO (surveillance only) groups. We reviewed the women's medical records and pathologic reports, retrospectively, and collected their clinicopathologic data, including age at BRCA1/2 gene testing, menopausal status, parity, marital status, educational status, occupational status, comorbidity, prior abdominopelvic surgery, and personal history of breast and other cancers. Family history of breast, ovarian, and other cancers were also collected up to the women's second-degree relatives. Germline BRCA1/2 gene testing methods at SNUH were described in our previous study. 6 As of February 2016, the method changed from direct sequencing (Sanger sequencing) to next-generation sequencing (NGS) of BRCA1/2 genes. Pathogenic or like-pathogenic variants found in NGS were confirmed by direct sequencing. All BRCA1/2 mutation carriers included in this study visited the OB/GYN clinic and underwent comprehensive counseling with 13 faculty from the Department of Obstetrics and Gynecology; nine were gynecologic oncology faculty, and four were non-gynecologic oncology faculty. They provided the following information to the BRCA1/2 mutated women per the contemporary clinical practice guidelines 5 7 : 1) lifetime risk of breast and ovarian cancers; 2) screening methods; 3) methods of prophylactic surgery, complications, and the extent of risks decreased by surgery; 4) other alternative options; and 5) the need for family screening. Based on the women's marital status, marriage plan, and whether they completed childbearing, the adequate age of RRSO was also discussed. For the breast cancer survivors and breast cancer patients on active treatment, their attending breast surgeons and medical oncologists provided additional counseling in breast cancer. In the non-RRSO group, patients received regular examinations with transvaginal ultrasonography, serum CA-125, or both every 6–12 months. In the RRSO group, the patients also received regular examinations until the date of RRSO, and their detailed surgical information and pathological results were collected. Observation period was defined as intervals between the BRCA1/2 gene test and date of gynecologic cancer diagnosis or last visit in the non-RRSO group, while it was defined as intervals between the BRCA gene test and date of RRSO in the RRSO group. First, we calculated the total uptake rate of RRSO in BRCA1/2 mutation carriers. Next, regarding the BRCA1/2 mutation carriers aged ≥35 years at the time of genetic testing and receiving RRSO within 12 months as having intentions to receive RRSO, we assigned them to the RRSO strategy group. In contrast, the remaining participants were assigned to the surveillance strategy group. We calculated the intentional uptake rate of RRSO, which was the proportion of patients receiving RRSO within a year among BRCA1/2 mutated patients aged ≥35 years. We compared the women's clinicopathologic characteristics between the two groups using Student's t- or Mann-Whitney U-tests for continuous variables and Pearson's chi-squared or Fisher's exact tests for categorical variables. In multivariate analysis, a logistic regression model was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI) for each variable. All statistical analyses were performed using SPSS statistical software (version 25.0; IBM Corp., Armonk, NY, USA). A p value<0.05 was considered statistically significant.