Current Situation and Future Directions of Risk-reducing          Salpingo-oophorectomy

Kenta Masuda; Yusuke Kobayashi; Tomoko Seki; Tomoko Yoshihama; Kohei Nakamura; Yumiko Goto; Mamiko Yamada; Aiko Nagayama; Sayaka Uchida; Ikumi Ono; Kumiko Misu; Megumi Yokota; Wataru Yamagami

doi:10.2302/kjm.2024-0024-RE

Abstract

High-grade serous carcinoma (HGSC), the most aggressive subtype of epithelial ovarian cancer, is strongly associated with hereditary breast and ovarian cancer (HBOC) syndrome and is primarily linked to germline BRCA1/2 pathogenic variants (PVs). The cumulative risks of ovarian cancer by the age of 70 years are 40% and 18% for carriers of BRCA1 and BRCA2 PVs, respectively. Risk-reducing salpingo-oophorectomy (RRSO) is a recommended preventive strategy that reduces the risk of ovarian cancer by more than 80% and may improve overall survival. However, surgical menopause after RRSO poses several challenges, including infertility and hormonal deficiency. Although the use of hormone replacement therapy may alleviate symptoms, it requires careful consideration of breast cancer risk. Emerging strategies, such as prophylactic salpingectomy with delayed oophorectomy, are being investigated to balance cancer prevention and patient quality of life. Further research is required to refine personalized prevention and management approaches for HBOC-associated ovarian cancer.

Introduction

Hereditary breast and ovarian cancer (HBOC) is associated with increased risks of breast, ovarian (including fallopian tube and primary peritoneal cancers), pancreatic, and prostate cancer. Individuals with ovarian cancer have a high risk of developing high-grade serous carcinoma (HGSC), the most common malignant subtype of epithelial ovarian cancer. Pathogenic variants (PVs) in the germline BRCA1/2 (gBRCA1/2) genes significantly increase the risk of ovarian cancer, with a lifetime risk of up to 40% for women with gBRCA1 PV and 18% for women with gBRCA2 PV.¹

Prevention strategies, including risk-reducing salpingo-oophorectomy (RRSO), effectively reduce cancer risk and improve survival. However, the issues associated with these strategies include surgical menopause and impacts on patient quality of life. Recent clinical trials have evaluated the potential of alternative approaches, including prophylactic salpingectomy with delayed oophorectomy (PSDO). The present review examined the characteristics of HBOC in ovarian cancer, the effectiveness of RRSO, and future directions.

HBOC in Ovarian Cancer

Epithelial ovarian cancer has four main histological subtypes: serous (low-grade and high-grade), endometrioid, mucinous, and clear cell. HGSC is characterized by TP53 mutations and is the most common and aggressive subtype. This subtype is most likely to be HBOC and originates in the fallopian tube or ovarian epithelium. In contrast, low-grade serous, mucinous, clear cell, and endometrioid carcinomas are thought to arise from inclusion cysts or implantation of the ovarian epithelium as well as KRAS, BRAF, or PTEN mutations.²

The reported frequency of HBOC in ovarian, fallopian tube, and primary peritoneal cancer (hereafter, ovarian cancer) worldwide is 13%–15%.³^,⁴ In Japan, the overall prevalence of gBRCA1/2 PVs in 634 patients diagnosed with ovarian cancer was 14.7% (93/634), of which gBRCA1 PVs were more common than gBRCA2 PVs (9.9% vs 4.7%). When limited to stage III–IV ovarian cancer, the prevalence of gBRCA1 and gBRCA2 PVs increased to 16.4% and 7.7%, respectively.⁵ In another multicenter study, HBOC was diagnosed in 21.5% of 205 Japanese patients with stage III–IV ovarian cancer, with gBRCA1 and gBRCA2 PVs detected in 14.1% and 7.3% of cases, respectively.⁶

Penetrance of Ovarian Cancer in HBOC

Women with gBRCA1/2 PV are at high risk of ovarian cancer. The results of a meta-analysis indicated an average cumulative risk of ovarian cancer at 70 years of age of 40% [95% confidence interval (CI), 35%–46%] for gBRCA1 PVs and 18% (95% CI, 13%–23%) for gBRCA2 PVs.¹ In a large prospective cohort study of 6036 gBRCA1 and 3820 gBRCA2 women carrying PVs, the cumulative risks of ovarian cancer by the age of 80 years were 44% (95% CI, 36%–53%) and 17% (95% CI, 11%–25%) for those with gBRCA1 and gBRCA2 PVs, respectively.⁷

Furthermore, differences in ovarian and breast cancer risk have been reported based on the location of gBRCA1/2 variants. Specifically, when gBRCA1/2 variants are located in the ovarian cancer cluster region (OCCR), the risk of ovarian cancer is elevated relative to the risk of breast cancer.⁸ In Japanese individuals, an analysis using the JOHBOC database reported a higher prevalence ratio of ovarian cancer than breast cancer for gBRCA1 Q934X and gBRCA2 R2318X variants located in the OCCR.⁹ Currently, the Japan Gynecologic Oncology Group (JGOG) is conducting a cohort study (JGOG3024) that aims to elucidate the association between gBRCA1/2 variants, cancer development, clinicopathological features, and risk factors. Further accumulation of data on Japanese individuals is expected in the future.

The Origin of High-grade Serous Carcinoma (HGSC)

Several reports of serous tubal intraepithelial carcinoma (STIC) in the fallopian tube removed by risk-reducing surgery in patients with gBRCA1/2 PV suggest that HGSC may originate from the fimbria of the fallopian tube.¹⁰^,¹¹^,¹² The theory that many HGSCs, which account for most ovarian cancers in gBRCA1/2 PVs, originate from the fallopian tubes is now generally accepted. However, a subgroup of patients with HGSC do not have any obvious precursor lesions in the fallopian tubes; therefore, further research is needed to understand how these cancers develop.¹³

In the second edition of the General Rules for Clinical and Pathological Management of Ovarian Tumors, Fallopian Tube Cancer, and Primary Peritoneal Cancer 2022, the primary site of HGSC is diagnosed as fallopian tube cancer if an STIC is identified in the fallopian tube. STIC is now diagnosed as stage IA fallopian tube cancer.¹⁴However, at present, clinical management strategies for precursor lesions such as STIC and p53 signatures have not been established, and further evidence will be required in the future.

Screening for Ovarian Cancer

No evidence suggests that screening for ovarian cancer reduces cancer-related mortality rates. Several studies have examined the significance of ovarian cancer screening. The UK Familial Ovarian Cancer Screening Study (UK FOCSS) phase II study included 4348 women with an estimated lifetime risk of ovarian cancer of 10% or greater who did not opt for RRSO and underwent examinations including measurement of serum cancer antigen 125 (CA125) using the risk of ovarian cancer algorithm (ROCA) and transvaginal ultrasound (TVUS). Overall, 13 cases of ovarian cancer were screened, 5 of which (38.5%) were diagnosed at early stages (stages I–II).¹⁵ Another study evaluated serum CA125 levels using ROCA and performed TVUS in 3692 women with a strong family history of breast or ovarian cancer or gBRCA1/2 PVs. Three of six (50%) identified ovarian cancers were in the early stages. This method has a higher sensitivity for early stage disease than CA125 every 6 months or annually, but a lower positive predictive value (PPV).¹⁶ Considering their high sensitivity and possible significance in stage shifts, these surveillance methods may be an option for carriers of gBRCA1/2 PVs who do not opt for RRSO; however, the significance of these strategies in improving survival remains unclear.

Risk-reducing Salpingo-oophorectomy (RRSO)

Because screening methods have not yet been established to improve the survival rates of patients with ovarian cancer, guidelines recommend RRSO for carriers of gBRCA1/2 PVs. Considering the ages of onset, RRSO should be performed between the ages of 35 and 40 years for women with gBRCA1 PVs and between the ages of 40 and 45 years for those with gBRCA2 PVs unless age at diagnosis in the family warrants earlier age for prophylactic surgery.¹⁷^,¹⁸

In Japan, the average age of onset for ovarian cancer in women with gBRCA1 and gBRCA2 PVs was reported as 51.3 and 58.3 years, respectively, showing the relevance of the recommended ages for RRSO. However, because some families have cases of ovarian cancer occurring at ages younger than the recommended ages, it is important to consider the youngest age of onset of ovarian cancer in the family.¹⁹

Effects of RRSO

RRSO is expected to reduce the risk of the development of ovarian and breast cancers and to prolong overall survival (OS) in women with gBRCA1/2 PVs. Various meta-analyses have reported the risk-reducing effect of RRSO on the development of ovarian cancer to be greater than 80%.²⁰^,²¹^,²² A meta-analysis in 2018 showed that RRSO reduced the risk of the development of ovarian cancer, with a hazard ratio (HR) of 0.06 (95% CI, 0.02–0.17) among 2534 women with gBRCA1/2 PVs who participated in three prospective cohort studies (observation period: 0.5–27 years).

Consensus is lacking regarding the effectiveness of RRSO in reducing the risk of breast cancer. In their meta-analysis, Gaba et al.²³ reported that the risks of primary [relative risk (RR): 0.84 (95% CI, 0.59–1.21)] and contralateral [RR: 0.95 (95% CI, 0.65–1.39)] breast cancers were not reduced. In contrast, a meta-analysis by Wang et al.²⁴ reported reduced risks of breast cancer in both pathogenic variants of gBRCA1 [HR: 0.63 (95% CI, 0.49–0.81)] and gBRCA2 [HR: 0.51 (95% CI, 0.34–0.75)]. In addition to these meta-analyses, the effectiveness of RRSO in reducing the risk of developing breast cancer has also been investigated; however, the conclusions have been inconsistent. The risk of developing a new breast cancer is thought to be reduced by RRSO, at least in patients younger than 45 years of age. Regarding OS, a meta-analysis showed that RRSO was associated with longer OS when compared with no RRSO [HR: 0.32 (95% CI, 0.19–0.54)].²²

The risk of primary peritoneal cancer remains even after undergoing RRSO. According to a recent international, multicenter, and longitudinal study by Narod et al.,²⁵ among 6310 gBRCA1/2 PV carriers who underwent RRSO, the cumulative risk of primary peritoneal cancer over 20 years post-RRSO was 2.7% for gBRCA1 carriers and 0.9% for gBRCA2 carriers. Notably, primary peritoneal cancer did not occur in gBRCA1 carriers who underwent RRSO by age 35 or in gBRCA2 carriers who underwent RRSO by age 45.²⁵ These findings support the importance of having RRSO performed at the appropriate age.

Disadvantages of RRSO

In women who wish to have children, RRSO results in permanent infertility unless eggs or embryos are cryopreserved. In addition, surgical menopause caused by RRSO may result in hormonal changes, which can have detrimental effects on bone, cardiovascular, and psychosocial health.¹⁷ Therefore, these risks and possible methods of addressing them must be discussed.

Hormone Replacement Therapy after RRSO

Hormone replacement therapy (HRT) is an effective strategy to compensate for hormone deficiency and alleviate menopausal symptoms after RRSO. HRT may improve all symptoms associated with surgical menopause, including vasomotor symptoms, mood changes, sleep disorders, and sexual dysfunction.²⁶ Short-term HRT in women with gBRCA1/2 PVs does not appear to increase the risk of breast cancer.²⁷^,²⁸^,²⁹ In terms of breast cancer risk, HRT with estrogen alone may be preferable to combined estrogen and progestin therapy.²⁶ However, HRT is contraindicated in patients with a history of breast cancer because it increases the incidence of recurrence, metastasis, and contralateral breast cancer.³⁰ Moreover, 24%–30% and 65%–79% of breast cancers with gBRCA1 and gBRCA2 PVs, respectively, are estrogen-receptor (ER)-positive.³¹ The safety of HRT for triple-negative breast cancer (TNBC) is an issue that needs to be examined in the future.³²

Prophylactic Salpingectomy with DelayedOophorectomy

Salpingectomy reduces the risk of HGSC. In premenopausal women with gBRCA1/2 PVs who are not yet ready to undergo RRSO, PSDO, in which the first salpingectomy procedure is followed by oophorectomy a few years later, has been attempted. Steenbeek et al.³³ compared 154 cases of RRSO and 394 cases of risk-reducing salpingectomy (RRS) with delayed oophorectomy among 577 patients (297 with gBRCA1 PVs and 280 with gBRCA2 PVs) and found that the menopause-related quality of life was better in the RRS group than the RRSO group. Although the quality of life of the RRSO group showed improvement when HRT was administered, it was less than that in the RRS group.³³

Details of the PROTECTOR trial³⁴ and several other ongoing prospective clinical trials are given in Table 1. The Salpingectomy with Delayed Oophorectomy to Prevent Ovarian Cancer (TUBA-WISP II) study is the largest ongoing clinical trial and prospective study investigating whether PSDO is non-inferior to the current standard RRSO. The study design is to remove the fallopian tubes between the ages of 25 and 40 years in women with germline BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D PVs and then perform subsequent oophorectomy up to 5 years after the recommended age for RRSO. The primary outcome is HGSC incidence. This study is expected to enroll 1500 carriers of gBRCA1 and gBRCA2 PVs.

Table 1.The list of clinical trials of risk-reducing salpingectomy with delayed oophorectomy

Clinical trial	Location	Patients/ enrollment	Intervention	Comparison	Primary outcome	Estimated date of primary outcome
Early Salpingectomy (Tubectomy) with Delayed Oophorectomy in BRCA1/2 Gene Mutation Carriers (TUBA) (NCT02321228)	Netherlands	Premenopausal women with a documented BRCA1 and/or BRCA2 germline mutation/ 510	Salpingectomy with delayed oophorectomy	RRSO	Menopause-related quality of life	2025
Early removal of fallopian tubes and delayed removal of ovaries in women at high risk of ovarian cancer (ISRCTN25173360)	UK	Premenopausal women with BRCA1, BRCA2, BRIP1, RAD51C, RAD51D germline mutation/ 1000	Group 1: RRESDO Group 2: RRSO Group 3: No surgery		Sexual function measured using the Sexual Activity Questionnaire and Sexual Quality of Life 3D questionnaire	2028
Prophylactic Salpingectomy with Delayed Oophorectomy (NCT01907789)	USA	Premenopausal women with a documented BRCA1 and/or BRCA2 germline mutation/ 80	Group 1: Ovarian cancer screening Group 2: PSDO Group 3: RRSO		Patient compliance with PSDO	2030
A Study to Compare Two Surgical Procedures in Individuals with BRCA1 Mutations to Assess Reduced Risk of Ovarian Cancer (NCT04251052)	USA, Canada, Korea	Premenopausal women with a documented BRCA1 germline mutation/ 2262	Bilateral salpingectomy with delayed oophorectomy + ovarian cancer screening	RRSO + ovarian cancer screening	Time to development of incident high-grade serous carcinomas	2036
TUBA-WISP II (NCT04294927)	Worldwide	Premenopausal women with BRCA1, BRCA2, RAD51C, RAD51D, or BRIP1 germline mutation/ 3000	Risk-reducing salpingectomy with delayed oophorectomy	RRSO	High-grade serous (ovarian) cancer incidence	2040
Surgery in Preventing Ovarian Cancer in Patients with Genetic Mutations (NCT02760849)	USA	Premenopausal women with BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, BARD1, MSH2, MSH6, MLH1, PMS2, or EPCAM germline mutation/ 374	ISDO	RRSO	Percentage of women with clinically meaningful change in the Female Sexual Function Index	2041

RRSO: risk-reducing salpingo-oophorectomy, PSDO: prophylactic salpingectomy with delayed oophorectomy, RRESDO: risk-reducing early salpingectomy and delayed oophorectomy, ISDO: interval salpingectomy with delayed oophorectomy.

Cancer or Precancer Lesions in RRSO Samples

Occult cancer may be identified in specimens removed by RRSO. A Dutch study of 2557 RRSO cases reported frequencies of HGSC diagnosed as occult cancer of 1.5% (24/1624) in women with gBRCA1 PVs and 0.6% (6/930) in women with gBRCA2 PVs.³⁵ RRSO was performed at mean ages of 43 years (range: 25.3–73.8 years) for those with gBRCA1 PVs and 46.8 years (27.6–77.9 years) for those with gBRCA2 PVs. The risk of occult cancer decreases to 0.4% when RRSO is performed at the recommended age. Moreover, 73% of occult cancers are found in the fallopian tubes.³⁵ Among the 2527 patients not diagnosed with occult cancer, STIC, which is thought to be a precursor lesion, was identified in 8 cases, whereas the p53 signature was present in 19 cases.

STIC is associated with a high risk of developing peritoneal cancer. In a meta-analysis of 17 studies involving 3121 patients who underwent RRSO, the HR for the risk of developing peritoneal cancer after RRSO when STIC was present was 33.9 (95% CI, 15.6–73.9) relative to when STIC was not present at the time of RRSO. In addition, when STIC was present, the 5-year and 10-year risks of developing peritoneal cancer were 10.5% (95% CI, 6.2%–17.2%) and 27.5% (95% CI, 15.6%–43.9%), respectively, compared with 0.3% (95% CI, 0.2%–0.6%) and 0.9% (95% CI, 0.6%–1.4%) when STIC was not present.³⁶ Another meta-analysis involving 3121 patients who underwent RRSO reported a median time from RRSO to the diagnosis of peritoneal cancer in patients with STIC of 48 months (18–118 months).³⁷ Recent studies have suggested that STIC includes both aggressive and non-aggressive subtypes and that it may be possible to classify them based on DNA aneuploidy and IGFBP2 expression.³⁸^,³⁹

Hysterectomy at the Time of RRSO

The risk of endometrial cancer in women with gBRCA1/2 PV remains unclear; therefore, whether hysterectomy should be performed at the same time as RRSO remains controversial. A cohort study in the USA reported that the risk of endometrial cancer did not increase among 1083 women (median age 45.6 years) who underwent RRSO without hysterectomy compared with the incidence expected from the Surveillance, Epidemiology, and End Results database (odds ratio 1.9, 95% CI, 0.8–3.7). However, a higher risk of developing endometrial serous carcinoma after RRSO in women with gBRCA1 PVs has also been reported.⁴⁰

In patients with no history of breast cancer, HRT is considered after RRSO. In women with a uterus, the use of progesterone, which is associated with the risk of breast cancer, is recommended because estrogen monotherapy significantly increases the risk of endometrial cancer.⁴¹^,⁴² Considering the effect of progesterone on the risk of breast cancer, the availability of estrogen monotherapy after hysterectomy may be another reason to consider hysterectomy. Tamoxifen is often used as a postoperative treatment for breast cancer. However, increased deaths from endometrial cancer have been reported.⁴³^,⁴⁴ For patients who are considering taking tamoxifen, hysterectomy may reduce the risk of endometrial cancer. However, under the current Japanese health insurance system, hysterectomy is only covered in cases with a medical reason for the surgery.

Current Situation of RRSO in Japan

We reported on the implementation of RRSO in 2008, with approval from the ethics committee at our university.⁴⁵ Subsequently, this surgery was only available at some facilities as a treatment that patients had to pay for themselves. In 2020, health insurance began to cover the cost of RRSO for women with gBRCA1/2 PVs and a history of breast cancer, and RRSO became widely available across Japan. However, RRSO for those who have not yet developed breast cancer is not covered by health insurance; therefore, the patient must pay for the procedure, which is a significant financial burden. In addition, patients who want to undergo hysterectomy without a medical reason must pay the costs themselves.

Our hospital established the Center for Hereditary Breast and Ovarian Cancer Syndrome (HBOC Center) in 2021, enabling us to provide medical care across departmental boundaries. Before performing RRSO or risk-reducing mastectomy (RRM), we discuss the case thoroughly at the HBOC Center to determine patient eligibility. Recently, the number of patients undergoing RRSO and RRM at the same time has increased.

Summary and Future Issues

This paper summarizes the characteristics of HBOC in ovarian cancer and the effectiveness of RRSO as a preventive strategy. RRSO significantly reduces the risk of ovarian cancer and improves survival; however, it also has challenges, including the impact of surgical menopause on patient health. Although HRT is effective in alleviating menopausal symptoms, the risk of breast cancer needs to be carefully evaluated. Several recent clinical trials investigated the effectiveness of PSDO, which delays oophorectomy after early salpingectomy, as an alternative to RRSO. We hope to see further accumulation of scientific data to support these treatment and prevention strategies and to provide more personalized medicine to improve the quality of life of patients with HBOC.

Conflicts of Interest

The authors have declared that no conflict of interest exists.

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