Risk-reducing Salpingo-oophorectomy Research Articles

Attitudes toward Risk-Reducing Mastectomy and Risk-Reducing Salpingo-oophorectomy among Young, Unmarried, Healthy Women in Korea.

PurposeThis study investigated the attitudes toward risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) as cancer prevention options for BRCA1/2 carriers in healthy, young, unmarried Korean women.Materials and MethodsA nationally representative sample of 600 women, aged 20–39 years, completed a questionnaire on sociodemographic variables, preference for genetic testing, and intention to undergo risk-reducing surgeries after receiving information on the cancer risk of BRCA1/2 mutations and benefits of risk-reducing surgeries.ResultsA total of 54.7% and 57.7% had the intention to undergo RRM and RRSO, respectively, on the assumption that they were BRCA1/2 carriers. Older age and no intention to undergo genetic testing were associated with a reduced likelihood of undergoing RRM (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.14 to 0.61 for age 35–39 years and OR, 0.35; 95% CI, 0.20 to 0.62 for no intention for genetic testing) and RRSO (OR, 0.39; 95% CI, 0.19 to 0.79 for age 35–39 years and OR, 0.30; 95% CI, 0.17 to 0.53 for no intention for genetic testing). Women who chose to be single were likely to undergo risk-reducing surgeries (OR, 1.67; 95% CI, 1.07 to 2.60 for RRM and OR, 1.56; 95% CI, 1.00 to 2.44 for RRSO).ConclusionMore than 50% of healthy, unmarried, young Korean women were inclined to undergo prophylactic surgeries if they were BRCA1/2 mutation carriers. Further studies on decision-making process for cancer prevention in individuals at high risk for cancer need to be conducted.

The effect of hormone therapy on breast density following risk-reducing salpingo-oophorectomy in women with an increased risk for breast and ovarian cancer.

To compare the effect of tibolone to conjugated estrogens with medroxyprogesterone-acetate (CEE + MPA) on breast density, as a predictor for breast cancer risk, in women with a high risk of breast and ovarian cancer. Women aged 30-50 (N = 114) who had undergone risk-reducing salpingo-oophorectomy (RRSO) were randomized to tibolone or CEE + MPA. Breast density decreased 46% after RRSO in untreated women, 39% after treatment with tibolone, and 17% after treatment with CEE + MPA; the decrease in breast density after CEE + MPA was significantly different compared with that of untreated women (P = 0.017). A decline in breast density is seen after premenopausal RRSO despite the use of both CEE + MPA or tibolone, although lower breast density is seen after tibolone use.

Bilateral Salpingo-oophorectomy and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Assessing the Evidence.

Without preventive interventions, women with germline pathogenic variants in BRCA1 or BRCA2 have high lifetime risks for breast cancer and tubo-ovarian cancer. The increased risk for breast cancer starts at a considerably younger age than that for tubo-ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is effective in reducing tubo-ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, but whether it reduces breast cancer risk is less clear. All studies of rrBSO and breast cancer risk are observational in nature and subject to various forms of bias and confounding, thus limiting conclusions that can be drawn about causation. Early studies supported a statistically significant protective association for rrBSO on breast cancer risk, which is reflected by several international guidelines that recommend consideration of premenopausal rrBSO for breast cancer risk reduction. However, these historical studies were hampered by the presence of several important biases, including immortal person-time bias, confounding by indication, informative censoring, and confounding by other risk factors, which may have led to overestimation of any protective benefit. Contemporary studies, specifically designed to reduce some of these biases, have yielded contradictory results. Taken together, there is no clear and consistent evidence for a role of premenopausal rrBSO in reducing breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Rates of risk-reducing salpingo-oophorectomy in patients with CHEK2 mutations in a large healthcare system

Objectives: CHEK2 mutations are associated with increased risk of breast, colon, and prostate cancer but not ovarian cancer. Our study investigated if women with CHEK2 mutations underwent risk reducing salpingo-oophorectomies (RRSO), despite no known risk of ovarian cancer associated with CHEK2, and if personal or family history of ovarian cancer was related to uptake of salpingo-oophorectomy. Methods: Retrospective cohort study was conducted from 2015-2018 in a large integrated healthcare system. Eligible patients were female, at least 18 years old and identified as CHEK2 mutation carriers. Those with concurrent non-CHEK2 pathogenic gene mutations were excluded. Surgical indications, personal history, family history up to third degree relatives, and mutation type were collected retrospectively. Primary outcome was RRSO rates among women with pathogenic CHEK2 mutation. Secondary outcomes included association of personal and family cancer history in patients with salpingo-oophorectomy. Results: Of 11,640 men and women who had genetic testing, 150 (1.3%) were identified with pathogenic CHEK2 mutation. 37 patients were excluded because they had more than one gene mutation, and 11 men in the remaining cohort were excluded, resulting in 102 women with a pathogenic CHEK2 mutation in the final cohort. A total of eighteen (18%) patients underwent uni- or bilateral salpingo-oophorectomy (BSO) for any reason, and six (6%) were for risk-reduction. Mean age at time of surgery was 53.0 years for all patients who underwent salpingo-oophorectomy and 54.4 years for those who underwent RRSO. Four (4%) patients total had personal history of ovarian cancer. 24 (24%) patients had family history of ovarian cancer. Four (67%) of the six patients who underwent RRSO had family history of ovarian cancer (p=0.03). Of the two patients without family history: one chose to have BSO for risk-reducing purposes as opposed to follow up for a unilateral benign ovarian cyst after being counseled that there was no increased risk of ovarian cancer and the other chose BSO for hormonal management of breast cancer but also cited risk reduction of ovarian cancer as an indication. Conclusions: Although, personal history of ovarian cancer is uncommon, family history of ovarian cancer is present in almost one quarter of CHEK2 mutation carriers. Most women with CHEK2 mutations did not have RRSO and the majority of those who chose RRSO had family history of ovarian cancer. This suggests that women and providers correctly assessed risk of ovarian cancer related to CHEK2, with few electing for RRSO because of increased perceived risk.

Presentation of ovarian cancer in women with BRCA mutations

<h3>Objectives:</h3> Investigate the clinical presentation and diagnosis of ovarian cancer in women with <i>BRCA</i> mutations. <h3>Methods:</h3> Retrospective cohort study of all women in an integrated healthcare system with pathogenic mutations identified between 1/1/2003-12/31/2018 who were diagnosed with ovarian cancer (OC). Primary outcome was stage of OC; secondary outcomes included method of diagnosis in women with genetic testing before OC diagnosis, interval to diagnosis, and age at genetic testing and ovarian cancer diagnosis. <h3>Results:</h3> Of the 299 women with OC and a <i>BRCA</i> mutation, 41 women were diagnosed with OC after <i>BRCA</i> testing, with 26 (63%) diagnosed on risk-reducing salpingo-oophorectomy (RRSO), 4 (10%) diagnosed by abnormal surveillance testing, and 11 (27%) diagnosed with symptoms. Median age at OC diagnosis was 55, 54, and 58 years for the RRSO, surveillance and symptom groups respectively. Women with a known <i>BRCA</i> mutation status at the time of their OC diagnosis were more likely to have earlier stage OC compared to those who underwent genetic testing after their OC diagnosis (54% vs 15%, <i>p</i><0.001). <h3>Conclusions:</h3> In women with a known <i>BRCA</i> mutation, most OC is diagnosed in older women and at the time of RRSO. Women with a known <i>BRCA</i> mutation at the time of their OC diagnosis were more likely to have earlier stage disease compared to those who underwent genetic testing after their OC diagnosis. The late age at genetic testing of these patients, as well as the earlier stage disease seen in those with a known <i>BRCA</i> mutation, highlights the need for earlier genetic testing and RRSO. Cancers diagnosed on RRSO are more likely to be early stage. Few cancers are detected by surveillance.

Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

PurposePALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited. MethodsA workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors. ResultsPALB2 heterozygotes should be offered BRCA1/2-equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1/2. ConclusionThis guidance is similar to those for BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis.

Guideline adherence for risk-reducing salpingo-oophorectomy among diverse women with BRCA mutations at an urban public hospital

<h3>Objectives:</h3> Rates of referral to genetic counseling are low for women of color and lower socioeconomic status, and these women are underrepresented in studies examining decisional factors related to uptake of risk-reducing bilateral salpingo-oophorectomy (rrBSO) in patients with pathogenic <i>BRCA1</i> or <i>BRCA2</i> mutations. To address this gap in the literature, our objective is to report adherence to evidence-based guidelines for rrBSO recommendation and uptake among <i>BRCA1</i> and <i>BRCA2</i> mutation carriers at an urban, public academic center whose population is racially and socioeconomically diverse, and to identify any association of sociodemographic variables with rrBSO uptake. <h3>Methods:</h3> This is an IRB-approved retrospective cohort study of <i>BRCA1</i> and <i>BRCA2</i> mutation carriers eligible for rrBSO by NCCN guidelines presenting from January 1, 2008 to December 31, 2019. Demographic and clinical data were collected from electronic medical records. Zip codes and census data were used as surrogate determinants for neighborhood exposure to poverty, unemployment, food security and violent crime. Differences between groups were determined by Chi-square analyses and associations determined by logistic regression modeling. <h3>Results:</h3> The study population was made up of 167 eligible patients, 39% of whom were Black (n=65), 35% Caucasian (n=59), 19% Hispanic (n=32), and 7% self-identified as ‘other' race. Less than 5% of patients reported known Ashkenazi Jewish heritage. Approximately half carried either <i>BRCA1</i> (51%, n=86) or <i>BRCA2</i> (46%, n=77) mutations (unspecified <i>BRCA</i> mutation, n=4). Over 95% (n=159) received the recommendation for age-appropriate rrBSO, and 52% (n=87) underwent the surgery. Women who had rrBSO were older, with 56% being 50 years or older at the time of the study (n=49), compared to 35% in the group who had not undergone the surgery (n=28, p=0.0058). There were no other differences between groups (Table 1). Black race (OR 3.70, 95% CI 1.02 - 13.46) was associated with uptake of rrBSO, as were lower rates of unemployment (continuous OR 1.18, 95% CI 1.03 - 1.35), and documented recommendation for rrBSO (OR 56.01, 95% CI 3.42 - 917.43). There was no significant association between rrBSO uptake and mutation type, age, parity, insurance type, level of education, neighborhood poverty, food security or violent crime, personal history of breast cancer, or family history of ovarian or other <i>BRCA-</i>related cancers. <h3>Conclusions:</h3> This study demonstrates that the majority of <i>BRCA1</i> and <i>BRCA2</i> carriers at an urban, public hospital received the recommendation for age-appropriate rrBSO. Black race and lower unemployment were associated rrBSO uptake. Genetic counseling was associated with adherence to evidence-based guidelines for the recommendation, as well as patients' odds of having the surgery. Future qualitative studies will report decisional factors in this diverse population.

What happens after menopause? (WHAM): A prospective controlled study of vasomotor symptoms and menopause-related quality of life 12 months after premenopausal risk-reducing salpingo-oophorectomy

ObjectiveTo measure menopausal symptoms and quality of life up to 12 months after risk-reducing salpingo-oophorectomy (RRSO) and to measure the effects of hormone therapy. MethodsProspective observational study of 95 premenopausal women planning RRSO and a comparison group of 99 who retained their ovaries. Vasomotor symptoms and menopausal-related quality of life (QoL) were measured by the Menopause-Specific QoL Intervention scale at baseline, 3, 6 and 12 months. Chi-square tests measured differences in prevalence of vasomotor symptoms between RRSO vs the comparison group and by hormone therapy use. Change in QoL were examined with multilevel modelling. ResultsThree months after RRSO hot flush prevalence increased from 5.3% to 56.2% and night sweats from 20.2% to 47.2%. Symptoms did not worsen between 3 and 12 months and remained unchanged in the comparison group (p<0.001). After RRSO, 60% commenced hormone therapy. However, 40% of hormone therapy uses continued to experience vasomotor symptoms. After RRSO, 80% of non-hormone therapy users reported vasomotor symptoms. Regardless of hormone therapy use, 86% categorized their vasomotor symptoms as “mild” after RRSO. Following RRSO, Menopause-related QoL deteriorated but was stable in the comparison group (adjusted coefficient = 0.75, 95%CI = 0.55-0.95). After RRSO, QoL was better in hormone therapy users vs non-users (adjusted coefficient = 0.49, 95%CI = 0.20-0.78). ConclusionsVasomotor symptoms increase by 3 months after RRSO but do not worsen over the next 12 months. Hormone Therapy reduces but does not resolve vasomotor symptoms and may improve QoL, but not to pre-oophorectomy levels.

Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location.

Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.

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.

Risk of cardiovascular disease among women carrying BRCA mutations after risk-reducing bilateral salpingo-oophorectomy: A population-based study

ObjectiveExamine the risk of cardiovascular disease (CVD) following risk reducing bilateral salpingo-oophorectomy (RRBSO) among women with BRCA mutations. MethodsIn this retrospective population-based study in British Columbia, Canada, between 1996 and 2017, we compared the risk of CVD among women with known BRCA mutations who underwent RRBSO before the age of 50 (n = 360) with two groups of age-matched women without known BRCA mutations: 1) women who underwent bilateral oophorectomy (BO) for benign conditions (n = 3600); and, 2) women with intact ovaries who had hysterectomy or salpingectomy (n = 3600). Our primary outcome was CVD (a composite (any of) myocardial infarction, heart failure, and/or cerebrovascular disease). Secondary outcomes included a diagnostic code for predisposing conditions (hypertension, dyslipidemia, and/or diabetes mellitus), and use of cardioprotective medications (statins and/or beta-blockers). ResultsWe report no significant increased risk for CVD between women with BRCA mutations and women who underwent BO (aHR = 1.08, 95%CI: 0.72–1.62), but women with BRCA mutations were less likely to be diagnosed with predisposing conditions (aHR = 0.69, 95%CI: 0.55–0.85). Compared to women without BRCA mutations with intact ovaries who underwent hysterectomy or salpingectomy, women with BRCA mutations had significantly increased risk for CVD (aHR = 1.82, 95%CI: 1.18–2.79) and were less likely to be diagnosed with predisposing conditions (aHR = 0.78, 95%CI: 0.62–0.97) and to fill cardioprotective medications (aHR = 0.88, 95%CI: 0.64–1.22). ConclusionOur results suggest an opportunity for improved prevention of CVD in women with BRCA mutations after prophylactic oophorectomy. Despite the observed lower prevalence of predisposing conditions for CVD and lesser use of cardioprotective medications, this population did not have a lower rate of CVD.

Uptake and timing of risk-reducing salpingo-oophorectomy among patients with BRCA1 and BRCA2 mutations

In women with BRCA mutations, risk-reducing bilateral salpingo-oophorectomy has been shown to decrease gynecologic cancer-specific and overall mortality. The National Comprehensive Cancer Network recommends that patients with BRCA mutations undergo risk-reducing bilateral salpingo-oophorectomy between the ages of 35 and 40 years for BRCA1 mutation carriers and between the ages of 40 and 45 years for BRCA2 mutation carriers or after childbearing is complete. Currently, uptake and timing of risk-reducing bilateral salpingo-oophorectomy and reasons for delays in risk-reducing bilateral salpingo-oophorectomy are not well understood. We sought to evaluate uptake and timing of risk-reducing bilateral salpingo-oophorectomy among women with BRCA1 and BRCA2 mutations concerning the National Comprehensive Cancer Network guidelines and reasons for delays in risk-reducing bilateral salpingo-oophorectomy. In this retrospective chart review, we identified women with BRCA1 and BRCA2 mutations who discussed risk-reducing bilateral salpingo-oophorectomy with a provider between 2012 and 2021. Uptake of risk-reducing bilateral salpingo-oophorectomy was documented, and patients were classified as having timely or delay in risk-reducing bilateral salpingo-oophorectomy based on the National Comprehensive Cancer Network guidelines. For those with delay in risk-reducing bilateral salpingo-oophorectomy, reasons cited for delay were collected. Comparative statistical analyses were performed to evaluate characteristics of those with timely vs delayed risk-reducing bilateral salpingo-oophorectomy. A multivariable logistic regression model was used to evaluate the associations among factors related to timing of risk-reducing bilateral salpingo-oophorectomy. We identified 638 BRCA1 and BRCA2 mutation carriers seen between 2012 and 2021. Of these patients, 306 (48.0%) had undergone risk-reducing bilateral salpingo-oophorectomy and 332 (52.0%) had not. When evaluating the timing of risk-reducing bilateral salpingo-oophorectomy, 136 (21.3%) underwent timely risk-reducing bilateral salpingo-oophorectomy, 239 (37.5%) had delays in risk-reducing bilateral salpingo-oophorectomy, and 263 (41.2%) had not undergone risk-reducing bilateral salpingo-oophorectomy but were younger than the National Comprehensive Cancer Network age guidelines; therefore, they were neither timely nor delayed. Patients with delay in risk-reducing bilateral salpingo-oophorectomy were significantly older at the time of genetic testing than those with timely risk-reducing bilateral salpingo-oophorectomy (mean, 49.8 vs 36.3 years; P<.001). Of the 306 patients who underwent risk-reducing bilateral salpingo-oophorectomy, those with delayed risk-reducing bilateral salpingo-oophorectomy had a significantly shorter interval between BRCA identification and risk-reducing bilateral salpingo-oophorectomy than those with timely risk-reducing bilateral salpingo-oophorectomy (median, 8.7 vs 17.6 months; P<.001). Patients with delay in risk-reducing bilateral salpingo-oophorectomy were more likely to have a personal history of cancer than those with timely risk-reducing bilateral salpingo-oophorectomy (49.8% vs 37.5%; P=.028). Of the 239 women with delay in risk-reducing bilateral salpingo-oophorectomy, 188 (78.7%) had delayed BRCA mutation identification, 29 (12.1%) had menopausal concerns, 17 (7.1%) had ongoing cancer treatment, 12 (5.0%) had coordination with breast surgery, 20 (8.4%) had miscellaneous reasons, and 19 (7.9%) had no reason documented. In the multivariate model, older age at BRCA diagnosis (odds ratio, 0.73; 95% confidence interval, 0.68-0.78; P<.001) was significantly associated with delayed risk-reducing bilateral salpingo-oophorectomy timing; those with BRCA2 mutation type were 7.54 times as likely to have timely risk-reducing bilateral salpingo-oophorectomy than BRCA1 mutation carriers (odds ratio, 7.54; 95% confidence, 3.70-16.42; P<.001). Nearly 38% of BRCA1 and BRCA2 mutation carriers undergo or have yet to undergo risk-reducing bilateral salpingo-oophorectomy over the recommended National Comprehensive Cancer Network age. The most common reason for the delay in risk-reducing bilateral salpingo-oophorectomy was delayed identification of BRCA mutation, noted in 79% of patients with delayed risk-reducing bilateral salpingo-oophorectomy. Timely genetic testing for eligible patients can increase appropriately timed risk-reducing bilateral salpingo-oophorectomy for the prevention of ovarian cancer and reduction of mortality in BRCA mutation carriers.

What happens after menopause? (WHAM): A prospective controlled study of sleep quality up to 12 months after premenopausal risk-reducing salpingo-oophorectomy

ObjectiveSleep difficulties impair function and increase the risk of depression at menopause and premenopausal oophorectomy may further worsen sleep. However, prospective data are limited, and it remains uncertain whether Hormone Therapy (HT) improves sleep. This prospective observational study measured sleep quality before and up to 12 months after risk-reducing salpingo-oophorectomy (RRSO) compared to a similar age comparison group who retained their ovaries. MethodsNinety-five premenopausal women undergoing RRSO and 99 comparisons were evaluated over a 12-month period using the Pittsburgh Sleep Quality Index (PSQI). ResultsAlmost half reported poor sleep quality at baseline. Overall sleep quality was not affected by RRSO until 12 months (p = 0.007). However, sleep disturbance increased by 3 months and remained significantly elevated at 12 months (p < 0.001). Trajectory analysis demonstrated that 41% had increased sleep disturbance after RRSO which persisted in 17.9%. Risk factors for sleep disturbance included severe vasomotor symptoms, obesity and smoking. Around 60% initiated HT after RRSO. Sleep quality was significantly better in HT users vs non users (p = 0.020) but HT did not restore sleep quality to baseline levels. ConclusionsOverall sleep quality is not affected by RRSO, but new onset sleep disturbance is common, particularly in those with severe vasomotor symptoms. Clinicians should be alert to new-onset sleep disturbance and the potential for HT to improve sleep quality.

Association of Salpingectomy With Delayed Oophorectomy Versus Salpingo-oophorectomy With Quality of Life in BRCA1/2 Pathogenic Variant Carriers

Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P < .001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P < .001) compared with RRS. Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy. ClinicalTrials.gov Identifier: NCT02321228.

Patterns and Prevalence of BRCA1 and BRCA2 Germline Mutations Among Patients with Triple-Negative Breast Cancer: Regional Perspectives.

BackgroundAmong all subtypes, patients with triple-negative (TN) breast cancer is known for their poor outcome and their higher risk of harboring BRCA1 or BRCA2 pathogenic mutations. Identification of such mutations has clinical impact on breast and ovarian cancer prevention and treatment decisions. We here report on patterns and prevalence of BRCA1 and BRCA2 mutations among Arab patients diagnosed with TN subtype.Patients and MethodsPatients with TN-breast cancer (n=197) were enrolled regardless of their age or family history. Following a detailed genetic counseling, BRCA1/2 testing was performed at reference labs. BRCA1 and BRCA2 variants were classified as negative, pathogenic/likely pathogenic (positive) and variants of uncertain significance (VUS).ResultsMedian age of enrolled patients was 42 (range, 19–74) years and 27 (13.7%) were non-Jordanian Arabs. Among the study group, 50 (25.4%) were tested positive for BRCA1 (n=36, 18.3%) or BRCA2 (n=14, 7.1%), while 14 (7.1%) others had VUS. Compared to older ones, mutation rates were higher among patients <40 years (32.9%, P= 0.034), those with close relatives with breast, ovarian, pancreatic or prostate cancer (37.8%, P=0.002) and those with two or more breast cancers (41.4%, P=0.032). Among eligible patients, 23 (63.9%) patients underwent prophylactic mastectomy, while 19 (52.8%) patients had risk-reducing salpingo-oophorectomy. None of the patients with VUS underwent any prophylactic surgery.ConclusionArab patients with TN-breast cancer have relatively high BRCA1 or BRCA2 mutation rates. Young age at diagnosis and personal and family history of breast cancer further increase this risk.

BRCA Genetic Test and Risk-Reducing Salpingo-Oophorectomy for Hereditary Breast and Ovarian Cancer: State-of-the-Art.

Simple SummaryThe BRCA genetic test and HRD (homologous recombination deficiency) test are used as a companion diagnosis before starting PARP (poly ADP-ribose polymerase) inhibitor treatment. In clinical practice, gynecologists treating ovarian cancer are faced with decisions such as whether to recommend germline BRCA (gBRCA) test to all ovarian cancer patients and whether to do the gBRCA test first or HRD test first. Regarding the judgment result of the HRD test, the cutoff value differs depending on the clinical trial, and the prevalence of gBRCA pathogenic variant rate is different in each histological type and country. RRSO (risk reducing salpingo-oophorectomy) may have possibly reduced the risk of breast cancer for BRCA2 pathogenic variant carriers but not for BRCA1 carriers.In the field of gynecology, the approval of the PARP inhibitors (PARPi) has been changing the treatment of ovarian cancer patients. The BRCA genetic test and the HRD test are being used as a companion diagnosis before starting PARPi treatment. BRACAnalysis CDx® and Myriad myChoice® HRD test are widely used as a BRCA genetic test and HRD test, respectively. In addition, FoundationOne®CDx is sometimes used as a tumor BRCA test and HRD test. In clinical practice, gynecologists treating ovarian cancer are faced with making decisions such as whether to recommend the gBRCA test to all ovarian cancer patients, whether to perform the gBRCA test first or HRD test first, and so on. Regarding the judgment result of the HRD test, the cutoff value differs depending on the clinical trial, and the prevalence of gBRCA pathogenic variant rate is different in each histological type and country. A prospective cohort study showed that RRSO reduced all-cause mortality in both pre- and postmenopausal women; however, RRSO significantly reduced the risk of breast cancer for BRCA2 pathogenic variant carriers, but not for BRCA1 pathogenic variant carriers. Moreover, salpingectomy alone is said to not decrease the risk of developing ovarian or breast cancer, so further discussion is evidently required. We discuss the current situation and problems in doing BRCA genetic test and RRSO in this review article.

Risk-reducing salpingo-oophorectomy and breast cancer incidence among BRCA-mutation carriers.

10548 Background: Uncertainty exists with regard to the role of bilateral salpingo-oophorectomy in altering the risk of breast cancer in BRCA-mutation carriers. Methods: Included were 1645 healthy Jewish Israeli BRCA1/2 -mutation carriers from a single center without prophylactic mastectomy. Carriers with and without risk-reducing bilateral salpingo-oophorectomy (RRBSO) were matched according to BRCA-mutation type (BRCA1 vs. BRCA2) and year of birth (±1 year). Hormonal and reproductive variables were compared and incidence of breast cancer recorded. Association between RRBSO and breast cancer was studied. Results: Seventy-seven and 50 matched-pairs had BRCA1 and BRCA2 mutation respectively. Fifty-two carriers had breast cancer, 21 in RRBSO-group and 31 in no- RRBSO group, with no statistically significant difference. When analysing each mutation group separately, stratified by age at surgery, no association between RRBSO and breast cancer incidence was found among BRCA1-mutation carriers. However, in BRCA2 mutation carriers, RRBSO was associated with a statistically significant decreased overall incidence of breast cancer, HR = 0.2 (confidence interval 0.44-0.913, p = 0.038). Breast cancer incidence was lower after 5, 10,15 and 20 years in BRCA2-mutation carriers with RRBSO compared to no-RRBSO. Age at menarche, age at surgery, parity and oral contraceptive use were not significant risk factors for breast cancer. Hormone replacement therapy was used by 62 mutation carriers, 52 in the RRBSO group and 10 in the no-RRBSO group, and its use did not alter breast cancer risk (p = 0.463). Conclusions: According to our findings, RRBSO is associated with a reduced risk of breast cancer only in BRCA2 mutation carriers, regardless of HRT use.

Genetic assessment of hereditary breast and ovarian cancer in the Harris Health System: A five-year, single-center experience.

10587 Background: Identifying patients with hereditary breast cancer is critical since lifetime breast cancer risk is as high as 85% for those with germline BRCA1/2 mutations and preventive interventions can reduce that risk. However, genetic assessments and counseling are often underutilized among racial/ethnic minority populations. Reducing this genetic testing gap is important since hereditary breast/ovarian cancer syndromes occur among racial/ethnic minorities at least as frequently as non-Ashkenazi Jewish, non-Hispanic White populations. More information on variants in these populations is also needed to better define their genetic susceptibility. Methods: We conducted a retrospective study of adult patients evaluated for genetic testing for hereditary breast/ovarian cancer by a genetic counselor between October 1, 2009 and September 30, 2014 in Harris Health System which is a large, county health system composed mostly of underserved and minority patients. Data from 2015-2019 is currently being extracted and we are reporting the first 5 years of data. Descriptive statistics were used to summarize patient data. Results: 659 patients underwent genetic counseling (10.5% non-Hispanic White, 24.4% Black, 56.9% Hispanic, 5.9% Asian, and 2.3% other). Five patients had Ashkenazi Jewish ancestry. The majority of patients completed testing (87.4%) with 72.7% receiving financial assistance. Among those who did not complete testing, only 12.0% declined, while 66.3% did not meet guideline-based criteria or were recommended to have an affected relative tested. Multigene panel testing was not available until April 2014, so most underwent BRCA sequencing (75.0%) and/or a BRCA large rearrangement test (61.0%). 36.1% received multigene panel testing, 4.6% single site analysis, and 4.4% p53 sequencing. Deleterious mutations occurred in 98 (14.9%) patients: BRCA1 (n = 60), BRCA2 (n = 25), PALB2 (n = 7), ATM (n = 3), and other (n = 3). The distribution of races/ethnicities among those with deleterious mutations was similar to the overall population (7.1% non-Hispanic White, 18.4% Black, 69.4% Hispanic, 3.1% Asian, and 2.0% other). 80.6% of those with deleterious mutations had breast cancer. High rates of bilateral mastectomies were performed in patients with deleterious mutations: BRCA1 60%, BRCA2 55%, PALB2 57.1%, and ATM 33%. Risk-reducing salpingectomy or salpingo-oophorectomy was performed in 56.7% BRCA1, 60% BRCA2, 28.5% PALB2, and 33.3% other mutation carriers. Conclusions: We demonstrate that with the support of financial assistance programs, most patients who receive genetic counseling will accept genetic testing in a socioeconomically underserved, racially/ethnically diverse population. Identification of high-risk patients in these groups is critical since pathogenic variants in this population were common and more than half underwent risk-reducing procedures.

Plasma Protein Biomarkers Associated with Higher Ovarian Cancer Risk in BRCA1/2 Carriers.

Ovarian cancer (OC) is the most lethal gynecologic malignancy and in-time diagnosis is limited because of the absence of effective biomarkers. Germline BRCA1/2 genetic alterations are risk factors for hereditary OC; risk-reducing salpingo-oophorectomy (RRSO) is pursued for disease prevention. However, not all healthy carriers develop the disease. Therefore, identifying predictive markers in the BRCA1/2 carrier population could help improve the identification of candidates for preventive RRSO. In this study, plasma samples from 20 OC patients (10 patients with BRCA1/2 wild type (wt) and 10 with the BRCA1/2 variant (var)) and 20 normal subjects (10 subjects with BRCA1/2wt and 10 with BRCA1/2var) were analyzed for potential biomarkers of hereditary OC. We applied a bottom-up proteomics approach, using nano-flow LC-MS to analyze depleted plasma proteome quantitatively, and potential plasma protein markers specific to the BRCA1/2 variant were identified from a comparative statistical analysis of the four groups. We obtained 1505 protein candidates from the 40 subjects, and SPARC and THBS1 were verified by enzyme-linked immunosorbent assay. Plasma SPARC and THBS1 concentrations in healthy BRCA1/2 carriers were found to be lower than in OC patients with BRCA1/2var. If plasma SPARC concentrations increase over 337.35 ng/mL or plasma THBS1 concentrations increase over 65.28 μg/mL in a healthy BRCA1/2 carrier, oophorectomy may be suggested.

What Happens After Menopause? (WHAM): A prospective controlled study of cardiovascular and metabolic risk 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy

ObjectiveTo prospectively measure cardiometabolic risk 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) compared to a similar age comparison group, and the effects of Hormone Therapy (HT) on cardiometabolic risk. MethodsProspective observational study of 95 premenopausal women planning RRBSO and 99 comparisons who retained their ovaries. At baseline and 12 months, blood pressure (BP), Body Mass Index (BMI), waist and hip circumference, fasting total, HDL and LDL cholesterol, triglycerides, high-sensitivity C-reactive protein, glucose and insulin were measured and HOMA-IR was calculated. Chi-square tests, t-tests and adjusted logistic regression models were used to compare groups. ResultsBaseline cardiometabolic phenotypes were similar between groups but more RRBSO participants were overweight/obese with higher waist/hip ratios. By 12 months, BP and cardiometabolic phenotypes were largely unchanged. Paired t-tests showed statistically significant increases in BMI (p = 0.037) and weight (p = 0.042) and larger increases in waist circumference (p < 0.001) and waist-hip ratio (p = 0.009) after RRBSO vs comparisons. However, these were not significant when adjusted for baseline values. After RRBSO 60% initiated Hormone Therapy (HT). Paired t-tests demonstrated that non-HT users had a significantly greater mean increase in waist circumference of 4.3 cm (95% CI 2.0–6.5) compared to 1.3 cm in HT users (95% CI -0.2-2.7, p < 0.001), which remained significant when adjusted for baseline values (p = 0.02). At 12 months, mean waist circumference was 2.94 cm greater in non-HT users compared to HT users. ConclusionsCardiometabolic risk markers are largely unchanged 12 months after RRBSO. Hormone Therapy after RRBSO may prevent against an increase in waist circumference.