Effect Of Risk-reducing Salpingo-oophorectomy Research Articles

The Effect of Risk-Reducing Salpingo-Oophorectomy on Breast Cancer Incidence and Histopathological Features in Women with a BRCA1 or BRCA2 Germline Pathogenic Variant

Risk-reducing salpingo-oophorectomy (RRSO) is advised for female BRCA1/2 germline pathogenic variant (GPV) carriers to reduce tubal/ovarian cancer risk. RRSO may also affect breast cancer (BC) incidence. The aim was to investigate the effect of RRSO on BC incidence and histopathological features in female BRCA1/2 GPV carriers. Prospectively collected clinical data from BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the Dutch Nationwide Pathology Databank (PALGA) in January 2022. Multivariable Cox-proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs), where the pre-RRSO group was considered the reference group and the primary endpoint was the first primary BC. Histopathological features of BCs pre- and post-RRSO were compared using descriptive statistics. In 1312 women, 164 incident primary BCs were observed. RRSO did not decrease BC risk for BRCA1 GPV (HR: 1.48, 95% CI: 0.91-2.39) or BRCA2 GPV (HR: 0.95, 95% CI: 0.43-2.07) carriers. BCs tended to be smaller post-RRSO (median: 12 mm) than pre-RRSO (15 mm, p: 0.08). There were no statistically significant differences in histopathological features. RRSO did not decrease BC risk or affect BC features in BRCA1/2 GPV in this study, although BCs diagnosed post-RRSO tended to be smaller.

Effect of risk-reducing salpingo-oophorectomy on sex steroid hormone serum levels among postmenopausal women: an NRG Oncology/Gynecologic Oncology Group study

Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels. We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes. Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy. Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change,-61.9 post-risk-reducing salpingo-oophorectomy vs+15.2 in controls; P=.02), but no significant differences were seen for the other hormones. Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.

A competing risks model with binary time varying covariates for estimation of breast cancer risks in BRCA1 families.

Mammographic screening and prophylactic surgery such as risk-reducing salpingo oophorectomy can potentially reduce breast cancer risks among mutation carriers of BRCA families. The evaluation of these interventions is usually complicated by the fact that their effects on breast cancer may change over time and by the presence of competing risks. We introduce a correlated competing risks model to model breast and ovarian cancer risks within BRCA1 families that accounts for time-varying covariates. Different parametric forms for the effects of time-varying covariates are proposed for more flexibility and a correlated gamma frailty model is specified to account for the correlated competing events.We also introduce a new ascertainment correction approach that accounts for the selection of families through probands affected with either breast or ovarian cancer, or unaffected. Our simulation studies demonstrate the good performances of our proposed approach in terms of bias and precision of the estimators of model parameters and cause-specific penetrances over different levels of familial correlations. We applied our new approach to 498 BRCA1 mutation carrier families recruited through the Breast Cancer Family Registry. Our results demonstrate the importance of the functional form of the time-varying covariate effect when assessing the role of risk-reducing salpingo oophorectomy on breast cancer. In particular, under the best fitting time-varying covariate model, the overall effect of risk-reducing salpingo oophorectomy on breast cancer risk was statistically significant in women with BRCA1 mutation.

Effect of risk-reducing salpingo-oophorectomy on the quality of life in Korean BRCA mutation carriers

This study aimed to compare the quality of life (QOL), psychosocial status, sexual function, and menopausal symptoms between the risk-reducing salpingo-oophorectomy (RRSO) and non-RRSO groups comprising BRCA mutation carriers and to evaluate the effect of timing of RRSO on those aspects. This cross-sectional study recruited BRCA mutation carriers aged ≥35 years between September 2015 and September 2016. Demographic data of carriers were collected. Outcomes were measured using the questionnaires addressing QOL, anxiety, depression, optimism, sexual function, and menopausal symptoms. Of 52 participants, 30 (57.7%) underwent RRSO, whereas 22 (42.3%) did not. In the RRSO group, 16 (53.3%) and 14 (46.7%) women underwent RRSO before and after menopause, respectively. The mean age in the RRSO group was higher than that in the non-RRSO group (49.8 vs. 42.1 years, respectively, p=0.002). The scores for QOL, anxiety, depression, optimism, sexual function, and menopausal symptoms were similar between both groups. In the multivariate analysis, RRSO uptake was associated with worse physical QOL (coefficient,-5.350; 95% confidence interval,-10.593 to-0.108). With respect to the timing of RRSO, only the mental QOL was significantly lower in the postmenopausal RRSO group than in the premenopausal RRSO group (39.2 vs. 43.7, respectively, p=0.043). We could not find any difference in mental QOL, psychosocial status, sexual function, and menopausal symptoms between the RRSO and non-RRSO groups. RRSO uptake only affected worse physical QOL. These results will help physicians counsel BRCA mutation carriers about the effect of RRSO on QOL.

Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

BackgroundThe effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause.MethodsA multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women.ResultsThere was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94–1.61) or BRCA2 (HR = 0.88; 95% CI 0.62–1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40–1.15) and 1.07 (95% CI 0.69–1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26–0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar.ConclusionWe found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

Salpingectomy With Delayed Oophorectomy in BRCA1/2 Mutation Carriers

To estimate BRCA1/2 mutation carriers' cumulative ovarian cancer risks after risk-reducing salpingectomy at various ages with delayed oophorectomy several years later compared with risk-reducing salpingo-oophorectomy. A literature search was performed on cumulative ovarian cancer risks and effects of risk-reducing salpingo-oophorectomy and salpingectomy. Results were used in a modeling study to estimate cumulative ovarian cancer risks for various scenarios of salpingectomy with delayed oophorectomy and risk-reducing salpingo-oophorectomy using Cox proportional hazard models. Estimated cumulative ovarian cancer risks at age 70 years for risk-reducing salpingectomy with delayed oophorectomy are highest for BRCA1 mutation carriers undergoing surgeries at higher age. Maximum increase in point estimates (from 1.8% to 4.1%) occurs in 40-year-old BRCA1 mutation carriers undergoing oophorectomy at age 45 years after nonprotective salpingectomy instead of salpingo-oophorectomy at age 40 years. In the best-case scenario, assuming 65% risk reduction by salpingectomy and 96% by salpingo-oophorectomy, point estimates increase (from 1.8% to 2.6%) or decrease (from 3.4% to 3.3%) depending on age. In the worst-case scenario for BRCA2, point estimates maximally increase from 0.6% to 1.8% in 45-year-old carriers when oophorectomy is performed at age 50 years instead of risk-reducing salpingo-oophorectomy at age 45 years. In the best-case scenario, point estimates increase (from 1.3% to 1.5%) or decrease (from 1.5 to 1.3%). Differences in estimated ovarian cancer risks between risk-reducing salpingo-oophorectomy and salpingectomy with delayed oophorectomy are small, even if salpingectomy is ineffective. Presented estimated ovarian cancer risks can be used in counseling BRCA1/2 mutation carriers, thereby facilitating a personalized and well-informed choice for either strategy.

Erratum to: Quantitative assessment of background parenchymal enhancement in breast MRI predicts response to risk-reducing salpingo-oophorectomy: preliminary evaluation in a cohort of BRCA1/2 mutation carriers

Introduction We present a fully automated method for deriving quantitative measures of background parenchymal enhancement (BPE) from breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perform a preliminary evaluation of these measures to assess the effect of risk-reducing salpingo-oophorectomy (RRSO) in a cohort of breast cancer susceptibility gene 1/2 (BRCA1/2) mutation carriers.

Serous Tubal Intraepithelial Carcinoma in a Japanese Woman with a Deleterious BRCA1 Mutation

Risk-reducing salpingo-oophorectomy for reducing future cancer risk in women with hereditary breast and ovarian cancer syndrome is rarely performed in Japan; therefore, the cancer preventive effect of risk-reducing salpingo-oophorectomy for hereditary breast and ovarian cancer syndrome among the Japanese population remains unclear. Here, we report the first case of serous tubal intraepithelial carcinoma identified through a risk-reducing salpingo-oophorectomy in a Japanese woman with hereditary breast and ovarian cancer syndrome and who had a deleterious germline mutation of E1214X in BRCA1, but not a BRCA2 mutation. A pre-operative examination revealed multiple uterine leiomyomas but no adnexal mass. Robotic-assisted bilateral salpingo-oophorectomy together with hysterectomy was performed. A pathological examination identified serous tubal intraepithelial carcinoma in the right fallopian tube with no dissemination. Serous tubal intraepithelial carcinoma is implicated as an origin of invasive cancer of the fallopian tube with peritoneal dissemination; prophylactic salpingo-oophorectomy is currently the only method to identify this occult cancer. Our case demonstrated that risk-reducing salpingo-oophorectomy can detect occult cancers, including serous tubal intraepithelial carcinoma, thereby preventing future cancer development in the Japanese hereditary breast and ovarian cancer syndrome population.

Fatigue and Quality of Life After Risk-Reducing Salpingo-Oophorectomy in Women at Increased Risk for Hereditary Breast-Ovarian Cancer

Risk-reducing salpingo-oophorectomy (RRSO) is the safest intervention for prevention of ovarian cancer in women at increased risk for hereditary breast-ovarian cancer. Little is known about other effects of RRSO. The objective of this study was to investigate quality of life (QoL) and fatigue in a sample of women who had RRSO for increased cancer risk and to compare the findings with those of age-matched controls from the general population (NORM). In a cross-sectional follow-up mailed questionnaire design, 301 (67%) of 450 invited Norwegian women with RRSO attended. The questionnaire contained measures of QoL, fatigue, anxiety/depression, and body image, and questions about demography, lifestyle, and morbidity. The findings were compared with those of the NORM. For RRSO women, mean age at survey was 53.7 years (SD, 9.2), mean age at RRSO was 48.4 years (SD 8.4), and median follow-up time was 5.0 years (range, 1-15 years). No clinically significant differences were observed between RRSO and NORM for any of the QoL or fatigue dimensions. In subgroup analyses of the RRSO group, no clinically significant differences in QoL and fatigue were observed between those who had surgery before or after age 50 years, or between BRCA1/2 carriers and women with unknown mutation statuses. Women who had cancer (32%), however, showed clinically significant lower levels of QoL and more fatigue than women without cancer. Women who had RRSO showed similar levels of QoL and fatigue as NORM. Women who had cancer before RRSO had lower levels of QoL and more fatigue.

Prevention of primary and contralateral breast cancer by risk reducing salpingo-oophorectomy in high risk women with a BRCA1/2 mutation or familial predisposition.

Abstract Abstract #504 Introduction: Risk reducing salpingo-oophorectomy (RRSO) has become an important preventive option against ovarian/fallopian tube cancer, while it is also risk reducing regarding breast cancer (BC) in women with a BRCA1 or BRCA2 mutation. Recently a difference in efficacy of RRSO concerning the occurrence of BC has been suggested for BRCA1 and BRCA2 mutation carriers, while no data are available on the protective effect of RRSO in women from a hereditary breast/ovarian cancer (HBOC) family without a proven BRCA mutation. Further, it is not known whether the BC risk reduction after RRSO equally applies to primary (PBC) and contralateral BC (CBC).
 Methods: The occurrence of PBC and CBC was prospectively studied in 639 women ≥ 30 years (330 BRCA1 mutation carriers, 117 BRCA2 mutation carriers, and 192 HBOC women) who were enrolled in a breast/ovarian cancer surveillance program at the Rotterdam Family Cancer Clinic. Women with a history of BC without recurrent disease were eligible if BC treatment did not involve adjuvant systemic therapy. Demographics and follow-up (FU) information up to December 31, 2007, were extracted from the medical records. Ninety-eight BRCA1 mutation carriers, 33 BRCA2 mutation carriers and 15 HBOC women eventually underwent RRSO. Results were analyzed separately for women being at risk for PBC (n=489) and for CBC (n=164). The effect of RRSO on the incidence of BC was analyzed using a Cox proportional hazards model in which RRSO was modeled as a time-dependent covariate.
 Results: During a mean FU of 5.5 years, RRSO was associated with a reduction in BC risk of 48% (HR=0.52; 95% CI, 0.26-1.02; p=0.058) versus 81% (HR=0.19; 95% CI, 0.02-1.95; p=0.161) in BRCA1 and BRCA2 mutation carriers, respectively. In BRCA1 mutation carriers, PBC was reduced by 74% (HR=0.26; 95% CI, 0.08-0.89; p=0.032), and CBC by 29% (HR=0.71; 95% CI, 0.23-2.16; p=0.544). In BRCA2 mutation carriers no cases of PBC occurred after RRSO (HR=0,00; 95% CI, not estimable), while 1 CBC was diagnosed (HR=0.25; 95% CI, 0.01-5.62; p=0.379). In HBOC women no BC cases were observed after RRSO.
 Conclusions: RRSO is associated with a BC risk reduction in both BRCA1 and BRCA2 mutation carriers. The risk reductive effect is more pronounced regarding PBC as compared to CBC in BRCA1 mutation carriers. Although a similar trend is suggested for BRCA2 mutation carriers, larger numbers and longer FU are needed to draw firm conclusions. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 504.

Risk-Reducing Salpingo-Oophorectomy for the Prevention of BRCA1- and BRCA2-Associated Breast and Gynecologic Cancer: A Multicenter, Prospective Study

Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers. A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance. The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.

Multi-center prospective analysis of risk-reducing salpingo-oophorectomy to prevent BRCA-associated breast and ovarian cancer

1003 Background: Our groups previously reported on the efficacy of risk-reducing salpingo-oophorectomy (RRSO) for the prevention of BRCA-associated breast and ovarian cancer. (Kauff ND, et al. NEJM 2002; Rebbeck TR, et al. NEJM 2002) Limitations of those reports included relatively short prospective follow-up and lack of power to analyze the protection of RRSO when participants were stratified by BRCA1 vs. BRCA2. To address these limitations, we have pooled our updated datasets to provide robust estimates of the efficacy of RRSO. Methods: 886 women ≥ 30 years of age, with a deleterious mutation in BRCA1 or BRCA2 and ovaries in-situ at time of genetic test results, were enrolled on prospective follow-up studies at one of eleven centers from 11/1/1994 - 12/1/2004. Women chose to participate in either ovarian surveillance or undergo RRSO. Follow-up information was collected by questionnaire and medical record review. Follow-up time was counted from time of RRSO or from time of genetic test results for women who did not undergo RRSO. After excluding cancers diagnosed within the first 6 months of follow-up, the effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. Results: 559 (63%) participants underwent RRSO a median of 5 months after genetic test results. 12 occult ovarian or fallopian tube cancers were diagnosed at time of RRSO. During a mean 40 months follow-up, RRSO was associated with a 52% reduction in breast cancer risk and a 91% reduction in ovarian cancer risk (see Table ). When the cohort was stratified by mutation status, RRSO was associated with a reduced risk of BRCA1-associated ovarian cancer and BRCA2-associated breast cancer. Conclusions: The results confirm that RRSO is highly protective against BRCA-associated breast and ovarian cancer. These results also generate the hypothesis that the protection conferred by RRSO against specific cancers may differ between carriers of BRCA1 and BRCA2 mutations. [Table: see text] No significant financial relationships to disclose.