Risk-reducing Salpingo-oophorectomy Research Articles

Breast cancer risk and hormone replacement therapy among BRCA carriers after risk-reducing salpingo-oophorectomy

IntroductionBRCA1/BRCA2 mutation carriers often undergo risk-reducing salpingo-oophorectomy (RRSO) before natural menopause, raising the issue of hormonal replacement treatment (HRT) use. There is conflicting evidence on the effect of HRT on breast cancer (BC) risk, and there are limited data on risk based on age at exposure. In the general population, HRT users have an increased BC risk (hazard ratio = 1.34). We assessed the impact of short-term HRT use on BC risk among healthy BRCA1/2 mutation carriers, with emphasis on age at exposure to HRT. MethodsA retrospective cohort of 306 consecutive healthy BRCA1/2 mutation carriers who had undergone RRSO was followed up for a mean of 7.26 years. We compared BC incidence over time in carriers who received HRT with that in those who did not receive. ResultsThirty-six of the carriers were diagnosed with BC, 20 of 148 patients (13.5%) in the HRT group compared with 16 of 155 (10.3%) in the non-HRT group (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 0.7–2.7). In women who were aged 45 years or younger at RRSO, HRT did not affect BC rates. However, in those older than 45 years at RRSO, BC rates were significantly higher in HRT users than in non-users (OR = 3.43, p < 0.05, 95% CI = 1.2–9.8). ConclusionsIn BRCA1/BRCA2 carriers in this study, short-term post-RRSO HRT use was associated with a threefold risk of BC in carriers older than 45 years. These results suggest that risk may be related to time of exposure to HRT around the natural age of menopause, even among BRCA1/2 carriers. Further studies are needed for validation and to guide future recommendations.

A prospective controlled study of sexual function and sexually related personal distress up to 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy.

Premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) may impair sexual function, but the nature and degree of impairment and impact of estrogen therapy on sexual function and sexually related personal distress after RRBSO are uncertain. Prospective observational study of 73 premenopausal women at elevated risk of ovarian cancer planning RRBSO and 68 premenopausal controls at population risk of ovarian cancer. Participants completed the Female Sexual Function Index and the Female Sexual Distress Scale-Revised. Change from baseline in sexual function following RRBSO was compared with controls at 12 months according to estrogen therapy use. Baseline sexual function domains did not differ between controls and those who underwent RRBSO and subsequently initiated (56.2%) or did not initiate (43.8%) estrogen therapy. At 12 months, sexual desire and satisfaction were unchanged in the RRBSO group compared with controls. After RRBSO, nonestrogen therapy users demonstrated significant impairment in sexual arousal (β-coefficient (95% confidence interval) -2.53 (-4.86 to -0.19), P < 0.03), lubrication (-3.40 (-5.84 to -0.96), P < 0.006), orgasm (-1.64 (-3.23 to -0.06), P < 0.04), and pain (-2.70 (-4.59 to 0.82), P < 0.005) compared with controls. Although sexually related personal distress may have been more likely after RRBSO, irrespective of estrogen therapy use, there was insufficient data to formally test this effect. The findings suggest premenopausal RRBSO adversely affects several aspects of sexual function which may be mitigated by the use of estrogen therapy. Further research is needed to understand the effects of RRBSO on sexual function and sexually related personal distress, and the potential for estrogen therapy to mitigate against any adverse effects.

Outcomes of incidentally detected ovarian cancers diagnosed at time of risk-reducing salpingo-oophorectomy in BRCA mutation carriers

ObjectivePrior data suggested that women with incidentally detected occult invasive ovarian cancer (OIOC) at the time of risk-reducing salpingo-oophorectomy (RRSO) for BRCA mutation may have poorer prognoses than would be expected based on disease stage. We sought to evaluate prevalence and outcomes of patients with OIOC in a tertiary referral center. MethodsPatients with BRCA mutation undergoing RRSO from 01/2005 to 05/2017 were identified, and their records reviewed. Women with incidentally detected OIOC were included; those with clinical features raising preoperative suspicion for malignancy were excluded. Results548 patients with BRCA mutation who underwent RRSO were identified. 26 (4.7%) had an OIOC (median age 55 years; range 42–75); 15(58%) patients, BRCA1; 9(34%), BRCA2; 2(8%) had a mutation in both genes. All OIOCs were high-grade serous: 10 (38%) Stage I; 8 (31%) Stage II; 8(31%) Stage III. 24(92%) patients received adjuvant platinum/taxane therapy. Of Stage III patients, 4 (50%) were identified intraoperatively; the remaining 4 (50%) had microscopic nodal disease on final pathology only. At median follow-up of 67.3 months (28–166) no Stage I patients have recurred; 2 Stage II and 6 Stage III patients recurred. 5-year progression-free survival (PFS) was 72% (95%CI, 50.2–85.7%); median PFS for the cohort was 129 months (95%CI, 75.3-not estimable). 5-year disease-specific survival (DSS) was 96% (95%CI, 76–99%); median DSS not reached. ConclusionConsistent with prior reports, almost 5% of patients had an OIOC at RRSO. The majority with early-stage disease had excellent PFS and DSS outcomes, as would be expected based on disease stage.

Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants

Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear. To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants. This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020. Risk-reducing salpingo-oophorectomy. In all analyses, the primary end point was the time to a first primary breast cancer. A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO. Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.

The needs of Southeast Asian BRCA mutation carriers considering risk-reducing salpingo-oophorectomy: a qualitative study.

The decision to have risk-reducing salpingo-oophorectomy (RRSO) by BRCA mutation carriers to reduce the risk of ovarian cancer is difficult. The choice involves trade-offs in terms of its risks and benefits. To date, understanding the decision-making needs of RRSO among Southeast Asian BRCA mutation carriers is limited. This study aimed to explore the decision-making needs of Malaysian BRCA mutation carriers as an exemplar for the Southeast Asian community. In-depth interviews and clinic observations were conducted with 31 BRCA mutation carriers and analysed thematically. The core theme identified was 'Coping with complex information and alleviating uncertainties' with the following subthemes: (1) the need for an adjustment period, (2) information support, (3) social support and, (4) religious support. We found that women required time to accept their BRCA mutation status before they were ready to make a risk-reducing choice; that understanding complex genetic information and multiple risk management options can be an overwhelming experience; and obtaining further information and a second opinion were challenging. Many described the need for experiential information from other peer-carriers who had undergone RRSO. Support from their spouse and family members was thought to be essential for them to feel reassured with their decision. Many relied on religion to positively cope with cancer risk and cancer worry; Muslim BRCA carriers sought religious guidance through prayers and Islamic fatwas to feel more certain about their RRSO decision. These findings underscore the importance of the provision of resources and support that includes input from peers, husband, family members and religion to underpin the decision-making needs of Malaysian BRCA mutation carriers considering RRSO.

Abstract PS7-70: Uptake of screening and risk reducing recommendations among women with hereditary breast and ovarian cancer syndrome evaluated at a large urban comprehensive cancer center

Abstract Background: Carriers of pathogenic variants in BRCA1 and BRCA2 have an elevated lifetime risk of breast, ovarian and other cancers. Current NCCN guidelines recommend specific screening for early cancer detection and risk reducing surgeries. Previous studies investigating the choices women make following the identification of pathogenic germline BRCA1 or BRCA2 variants reveal racial disparities in uptake of recommendations with black patients having lower rates of risk-reducing surgical procedures. We report on screening and prevention practices among 128 women identified with a pathogenic BRCA1 or BRCA2 variant at a large, urban comprehensive cancer center in Detroit, Michigan to evaluate racial differences in compliance with screening and prevention practices and to identify potential barriers to guideline-recommended care. Methods: The study population included women evaluated for genetic counseling and testing at the Karmanos Cancer Institute (KCI) from January 1, 2000 through December 31, 2017, who tested positive for a pathogenic variant in BRCA1 or BRCA2. A 54-item mail or telephone-based questionnaire was used to measure sociodemographics, medical history, cancer screening and risk reducing surgery, and cancer worries and fears. The primary and secondary outcomes were rate of risk reducing salpingo-oophorectomy (RRSO) and risk reducing mastectomy (RRM). Univariable logistic regression analyses were performed to identify potential predictors of RRSO and RRM, including race, personal cancer history, age at survey, time interval since BRCA1 or BRCA2 diagnosis, education, income, marital status and family history of a pathologic BRCA variant. P values less than 0.05 were considered statistically significant. Results: Of 374 women with pathogenic BRCA1 or BRCA2 variants during the study period, 129 (35%) completed the study survey (75 written, 54 telephone) with one ineligible. Of the 128 BRCA1 or BRCA2 carriers, 94 (73%) and 76 (59%) underwent RRSO and RRM, respectively and 13 (38%) and 10 (19%) planned to complete those procedures in the future. The rate of RRSO was 72% for white and 71% for black carriers. Black women tended to be less likely to have RRM compared to white women, but this difference did not reach statistical significance (OR 0.5 [95% CI 0.17 - 1.43], p = 0.193). Women who had RRM were 3 times more likely to have RRSO (and vice versa) (OR = 3.28, p = 0.004). With each increasing year of age at the time of genetic counseling, the odds of RRSO increased by 6% (OR = 1.06, p = &amp;lt;0.001). The odds of having had RRM increased with the time interval between genetic diagnosis and the survey by 9% (OR = 1.09, p = 0.043) for each elapsed year. The occurrence of new breast or ovarian cancer since genetic testing had no impact on RRSO, however participants who developed a new ovarian cancer had higher odds of having RRM (OR = 2.63, p = 0.01). There was no association between rate of RRSO or RRM with education level, annual household income, marital status or family history of pathologic BRCA variant. Conclusion: There was no racial difference in the rate of RRSO or RRM between white and black carriers of pathogenic BRCA1 or BRCA2 variants. Further multivariable models will assess predictors of risk reducing surgeries and will include assessment of screening practices as well as cancer worries and fears. Citation Format: Maria Levitin, Hadeel Assad, Hyejeong Jang, Wei Chen, Nancie Petrucelli, Michael Simon. Uptake of screening and risk reducing recommendations among women with hereditary breast and ovarian cancer syndrome evaluated at a large urban comprehensive cancer center [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-70.

Abstract PS8-25: Genetic cancer risk assessment and its impact on the uptake of cancer risk reduction strategies: The experience of a Mexican center

Abstract Background: The implementation of genetic cancer risk assessment (GCRA) in resource-constrained settings is limited due to multiple factors, including insufficient access to preventive strategies. In our center, GCRA was formally established in 2014, and access to genetic testing is provided to underserved patients through a research collaboration with City of Hope's CCGCRN. The aim of this study is to determine the proportion of patients with germline mutations that underwent risk-reducing surgeries (RRS) and followed recommended breast cancer (BC) screening strategies. Methods: Patients that received GCRA in a center located in Monterrey, Mexico who met NCCN criteria for testing for BC predisposition genes were eligible. Information on mutation status, performance of RRS and BC screening strategies was prospectively collected. The patients were grouped by type of healthcare (i.e. private vs public), with differences explored using Fisher's exact or Mann Whitney U tests, as appropriate. Results: Between 2014 and 2019, a total of 437 probands and 139 of their relatives underwent GCRA. Of these, 23% and 37% were identified as mutation carriers, respectively: BRCA1/2 (72.5%), PALB2 (6.4%), CHEK2 (6.4%) and others (14.7%). The median time elapsed from disclosure of genetic test results to collection of data was 16 months. The median age was 41 years, with no statistical difference according to type of healthcare. Based on NCCN guidelines, 151 RRS were recommended according to mutational status and age, of which 52 (34%) were performed: 28 risk-reducing mastectomies (RRM) and 24 risk-reducing salpingo-oophorectomies (RRSO). A substantial proportion of these were funded by non-governmental organizations, while the rest were covered by public health insurance (as adjuvant treatment), private health insurance or the patient herself. Regarding BC screening, after excluding 78 patients because of active BC treatment, bilateral mastectomy or male sex, 92% of eligible patients followed NCCN recommendations. No differences in the performance of RRS or BC screening strategies were found according to type of healthcare delivery. Conclusion: In this cohort, an adequate adherence to recommended screening strategies was observed but only one-third of recommended RRS were performed. Notably, type of healthcare was not a determining factor for the adherence to NCCN's recommended prevention strategies, suggesting that economical barriers might not be the main limiting factor. Efforts to elucidate if sociocultural barriers limit adherence to RRS are being conducted in order to enhance standard of care at Mexican centers with GCRA programs. Characteristics according to healthcare coverage.Private insurancePublic insurancep valueMutational status- Probands: carriers/tested32/117 (27%)67/320 (21%)NS- Relatives: carriers/tested10/42 (24%)42/97 (43%)0.036RRS- RRM performed/recommended9/24 (38%)19/65 (29%)NS- RRSO performed/recommended6/18 (33%)18/44 (41%)NS- RRS covered by NGOs0 (0%)11/37 (30%)0.022Current BC screening modality- Mammogram (MMG) ± US9 (41%)33 (65%)0.033- MRI ± MMG ± US9 (41%)6 (12%)- None3 (14%)1 (2%)- Unknown1 (5%)11 (22%)Follow BC screening recommendations- Yes19 (90%)37 (93%)NS- No2 (10%)3 (8%) Citation Format: Dione Aguilar, Alejandro Aranda-Gutierrez, Ana S Ferrigno, Jeffrey N Weitzel, Kathleen N Blazer, Danielle Castillo, Josef Herzog, Rosa Mejia, Nancy L Sada-Villarreal, Servando Cardona, Mauricio Canavati-Marcos, Margarita Garza-Montemayor, Cynthia Villarreal-Garza. Genetic cancer risk assessment and its impact on the uptake of cancer risk reduction strategies: The experience of a Mexican center [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-25.

Abstract PD10-06: Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study

Abstract Background: Young breast cancer patients (pts) carrying a germline BRCA mutation (mBRCA) have similar outcomes as non-carriers. However, there is currently lack of evidence regarding the impact of mBRCA type and hormone receptor status on clinical behavior and outcomes of mBRCA breast cancer. We aim to address these questions in the largest dataset to date of young mBRCA breast cancer pts. Methods: This was an international, multicenter, hospital-based, retrospective cohort study. Women harboring deleterious germline mBRCA1 or mBRCA2 that received a diagnosis of stage I-III invasive early breast cancer at age ≤40 years between January 2000 and December 2012 were included. Baseline pts, tumor, and treatment characteristics, pattern and risk over time of disease-free survival (DFS) events, and survival outcomes (DFS, distant recurrence-free interval [DRFI] and overall survival [OS]) were compared between mBRCA1 and mBRCA2 pts overall and by hormone receptor status. Multivariate Cox proportional hazard models were used to compare hazard rates (HRs). Results: 1,236 young mBRCA breast cancer pts were included. Among 808 and 428 pts with mBRCA1 or mBRCA2, respectively, 191 (23.6%) and 356 (83.2%) had hormone receptor-positive tumors while 617 (76.4%) and 72 (16.8%) hormone receptor-negative disease (p&amp;lt;0.001). Compared to mBRCA2 breast cancer pts, those with mBRCA1 were younger, more likely to have reported Jewish ancestry, had more grade 3 tumors, less nodal involvement, lobular histology and HER2 positivity, and received more frequently chemotherapy (all p&amp;lt;0.001). More mBRCA1 pts with hormone receptor-positive tumors did not receive adjuvant endocrine therapy (14.7% vs. 4.2%, p&amp;lt;0.001). No difference between mBRCA1 and mBRCA2 pts was observed in risk-reducing mastectomy (43.9% vs. 46.0%; p=0.371) or salpingo-oophorectomy (48.3% vs. 48.8%; p=1.0). Median follow-up was 7.9 years (range 5.6-10.6 years). Second primary breast cancers (17.0% vs. 12.2%, p=0.025) and non-breast primary malignancies (4.3% vs. 1.9%, p=0.033) were more frequent among mBRCA1 pts compared to mBRCA2 pts, while distant recurrences were less frequent (10.4% vs. 15.4%, p=0.013). 8-year DFS was 62.8% and 65.9% for mBRCA1 and mBRCA2 pts, respectively (adjusted HR 0.76; 95% CI 0.60-0.96). The worse DFS in mBRCA1 was observed regardless of hormone receptor status (pinteraction=0.848): hormone receptor-positive (adjusted HR 0.77; 95% CI 0.58-1.03) and hormone receptor-negative (adjusted HR 0.73; 95% CI 0.48-1.13). No differences in DRFI and OS were observed between mBRCA1 and mBRCA2 pts. Compared to pts with hormone receptor-negative disease, those with hormone receptor-positive breast cancer had higher chances of developing distant (± loco-regional) recurrences (16.1% vs. 9.0%; p&amp;lt;0.001) and less frequent second primary malignancies (BC: 12.1% vs. 17.9%, p=0.005; non-BC: 2.8% vs. 4.0%, p=0.216). No differences in DFS and OS were observed between pts with hormone receptor-positive or negative breast cancer. However, there was a trend towards worse DRFI in women with hormone receptor-positive breast cancer as compared to those with hormone receptor-negative disease (8-year DRFI: 83.4% vs. 90.1%; adjusted HR 1.39; 95% CI 0.94-2.05). Conclusions: In this large unique dataset, young mBRCA1 breast cancer pts had worse DFS than those with mBRCA2 mostly due to higher rates of second primary malignancies. Hormone receptor positivity had no positive prognostic value in young mBRCA breast cancer pts with a trend towards worse DRFI in those with hormone receptor-negative disease. These results provide important information for counseling young mBRCA breast cancer pts regarding treatment, prevention and follow-up care strategies. Citation Format: Matteo Lambertini, Marcello Ceppi, Anne-Sophie Hamy, Olivier Caron, Philip D. Poorvu, Estela Carrasco, Albert Grinshpun, Kevin Punie, Christine Rousset-Jablonski, Alberta Ferrari, Shani Paluch-Shimon, Angela Toss, Claire Senechal, Fabio Puglisi, Katarzyna Pogoda, Jose Alejandro Pérez-Fidalgo, Laura De Marchis, Riccardo Ponzone, Luca Livraghi, Maria Del Pilar Estevez-Diz, Cynthia Villarreal-Garza, Maria Vittoria Dieci, Florian Clatot, Francois P. Duhoux, Rossella Graffeo, Luis Teixeira, Octavi Córdoba, Amir Sonnenblick, Arlindo R. Ferreira, Ann H. Partridge, Antonio Di Meglio, Claire Saule, Fedro A. Peccatori, Marco Bruzzone, Lucia Del Mastro, Lieveke Ameye, Judith Balmaña, Hatem A. Azim, Jr. Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-06.

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

ObjectiveRisk-reducing bilateral salpingo-oophorectomy (RRBSO) substantially reduces ovarian cancer risk in women with pathogenic gene variants and is generally recommended by age 34–45 years. Natural menopause is a vulnerable period for mood disturbance, but the risk of depression and anxiety in the first 12 months after RRBSO and potential modifying effect of hormone therapy are uncertain. MethodsProspective controlled observational study of 95 premenopausal women planning RRBSO and a Comparison group of 99 premenopausal women who retained their ovaries,- 95% of whom were at population level risk of ovarian cancer. Clinically significant symptoms of depression and anxiety were measured using standardised instruments at baseline, 3, 6 and 12 months. Chi-square tests and adjusted logistic regression models compared differences between groups. ResultsBaseline symptoms and previous depression or anxiety did not differ between groups. At 3 months after RRBSO clinically significant depressive symptoms were doubled (14.5% vs 27.1%, p = 0.010), which persisted at 12 months. Depressive symptoms were stable in comparisons. At 3 months after RRBSO, clinically significant anxiety symptoms almost trebled (6.1% vs 17.7%, p = 0.014) before plateauing at 6 months and returning to baseline at 12 months. Compared to comparisons, RRBSO participants were at 3.0-fold increased risk of chronic depressive symptoms (Wald 95% CI 1.27–7.26), 2.3-fold increased risk of incident depression (95% Wald CI 1.08–5.13) and 2.0-fold increase of incident anxiety (Wald 95% CI 0.78–5.00). Depression and anxiety were slightly more common in Hormone Therapy users after RRBSO vs non-users. ConclusionsRRBSO leads to a rapid increase in clinically significant depressive and anxiety symptoms despite Hormone Therapy use.

Surgical decision making in premenopausal BRCA carriers considering risk-reducing early salpingectomy or salpingo-oophorectomy: a qualitative study

BackgroundAcceptance of the role of the fallopian tube in ‘ovarian’ carcinogenesis and the detrimental sequelae of surgical menopause in premenopausal women following risk-reducing salpingo-oophorectomy (RRSO) has resulted in risk-reducing early-salpingectomy...

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.

Satisfaction with prophylactic risk-reducing salpingo-oophorectomy in BRCA mutation carriers is very high and little dependent on the participants' characteristics at surgery: a prospective study.

BRCA carriers are recommended to undergo prophylactic risk-reducing salpingo-oophorectomy (RRSO). Possible adverse health impacts of RRSO, particularly when done before natural menopause, can reduce the long-term satisfaction with this risk-reducing strategy. The aim of this study was to prospectively evaluate the level of satisfaction of women undergoing RRSO, also in relation to some specific characteristics at RRSO. A prospective cohort study was performed in the Modena Family Cancer Clinic of the University Hospital of Modena (Italy). All BRCA1/2 confirmed mutation carriers who decided to undergo RRSO were recruited between 2016 and 2019. Fifty-five women (29 BRCA1 and 26 BRCA2) (mean age: 50.4 ± 7.7 years [range 35-79]) were included with a mean follow-up after RRSO of 660.9 days (1.8 years) (range 35-1,688 days) (median: 549 days). No intraepithelial (Serous Tubal Intraepithelial Carcinoma)/invasive cancers were found (0%) at RRSO. No vasomotor symptoms at 1 month after surgery were reported by 11/22 (50%) premenopausal women at RRSO. All women (100%) with new "RRSO-caused" vasomotor symptoms with no previous breast cancer initiated postmenopausal hormone therapy. At the final follow-up the satisfaction rate (0-100 visual analog scale points) of the participants was 96.4 ± 8.6 points (range 62-100). To the question "Would you undergo RRSO again if it was proposed today? (0-100 visual analog scale points)" the answer was 99.4 ± 3.2 points (range 79-100). These scores were in general very high and did not change in the different groups according to pre/postmenopausal status at RRSO, cancer survivors versus healthy women at RRSO, BRCA status, hormone therapy users/nonusers after RRSO, "RRSO-caused" symptoms versus not RRSO-caused (P > 0.05). Findings from this prospective study suggest that satisfaction with RRSO is very high and little dependent on the participants' characteristics at surgery. Women at high risk for ovarian cancer are very satisfied with their choice of risk-reduction strategy.

Breast Cancer Patients at Increased Risk of Developing Type II Endometrial Cancer: Relative and Absolute Risk Estimation and Implications for Counseling.

IntroductionBreast cancer (BC) is a recognized risk factor for endometrial cancer (EC). Emerging literature indicates that it confers a higher risk of type II EC (T2EC) than type I EC (T1EC). Although some surgeons offer a prophylactic hysterectomy to BC patients referred for risk-reducing bilateral salpingo-oophorectomy, insufficient evidence prevents this from being the standard practice. We aimed to quantify their absolute risk and relative risk (RR) of developing both EC subtypes and identify a higher-risk group that could be considered for prophylactic hysterectomy.MethodologyThis retrospective service evaluation compared patients diagnosed with BC between 2008 and 2014, who subsequently developed EC within 10 years to those who did not. Absolute risk and RR were calculated using the numbers of regional BC and EC cases within this group, alongside 2009 UK female population and EC incidence statistics. Binary logistic regression generated adjusted odds ratios (ORs) for patient- and disease-specific variables.ResultsA total of 45 BC patients developed EC, 24 had T1EC and 21 had T2EC. Their RR of developing EC was greater than that of the general population (RR: 12.44, p < 0.0001). Notably, this was higher for T2EC (RR: 33.96, p < 0.001) than T1EC (RR: 8.63, p < 0.0001). Nonetheless, the absolute risk remained low. Tamoxifen exposure was significantly more prevalent among T2EC patients (adjusted OR: 79.61, p = 0.003). Increased age at BC diagnosis was associated with T1EC (adjusted OR: 1.10, p = 0.043) and T2EC (adjusted OR: 1.13, p = 0.03). Neither smoking status nor family history of BC was significantly associated with any outcome.ConclusionWomen with BC were more likely to develop T2EC than T1EC, and although the absolute risk was low, the cumulative risk was substantial enough to warrant vigilance. Tamoxifen exposure was significantly predictive of EC, particularly T2EC, and might facilitate risk estimation. Older women at BC diagnosis who receive tamoxifen treatment should be screened and closely monitored for EC. However, given the limitations of normal screening methods for the detection of T2EC, counseling for a prophylactic hysterectomy should also be considered. Clarification of the menopausal status will help make more meaningful recommendations.

Long-Term Morbidity and Health After Early Menopause Due to Oophorectomy in Women at Increased Risk of Ovarian Cancer: Protocol for a Nationwide Cross-Sectional Study With Prospective Follow-Up (HARMOny Study).

BackgroundBRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited.ObjectiveThe aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer.MethodsWe will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery.ResultsThis study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study.ConclusionsKnowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO.Trial RegistrationClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793.International Registered Report Identifier (IRRID)DERR1-10.2196/24414

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

PurposeThis study investigated the uptake rate of risk-reducing salpingo-oophorectomy (RRSO) and surgical outcomes of germline BRCA1/2 mutation carriers at Seoul National University Hospital (SNUH).Materials and MethodsWe examined the records of 824 women who underwent germline BRCA1/2 gene testing at SNUH between 2005 and 2020. Among them, we identified women with a pathogenic mutation on either the BRCA1 or the BRCA2 gene, and excluded ovarian cancer patients. Characteristics of participants who underwent RRSO (RRSO group) were compared to those who did not (non-RRSO group). Surgical outcomes and pathologic results were investigated in the RRSO group.ResultsThere were 117 BRCA1/2 mutation carriers included in the analysis. The uptake rate of RRSO was 70.1% (82/117). Older age (mean: 48.8 years vs. 42.1 years; p=0.002) and higher employment rate (65.9% vs. 14.3%; p<0.001) were observed in the RRSO group compared to the non-RRSO group. However, no differences in other factors, such as personal and family history of breast cancer, were observed between the two groups. In the RRSO group, the median time interval between the genetic test and RRSO was 10.0 months, and there were three (3.7%) incidental cases of high-grade serous carcinoma. However, one patient in the non-RRSO group developed primary peritoneal cancer after 103.8 months of surveillance.ConclusionThe uptake rate of RRSO in BRCA1/2 mutation carriers was about 70%. Considering incidental cancer cases in women without abnormal findings on preoperative evaluation, BRCA1/2-mutated women might refrain from the delayed implementation of RRSO after the genetic test.

Commentary on Provider Adherence to Surgical Guidelines for Risk Reducing Salpingo-Oophorectomy

BRCA mutation carriers have a significantly increased lifetime risk of ovarian cancer compared to the general population. Risk-Reducing Salpingo-Oophorectomy (RRSO) is the primary evidence-based treatment to decrease that risk. The National Comprehensive Care Network (NCCN) and American College of Obstetricians and Gynecologists (ACOG) endorse a set of surgical guidelines to be completed at the time of RRSO. In the study “Provider Adherence to Surgical Guidelines for Risk Reducing Salpingo-oophorectomy”, we found that only two-thirds of all surgical providers were fully adherent to these guidelines. Gynecologic oncologists were more likely to follow surgical guidelines compared to general Obstetrician Gynecologists, and more likely to diagnose occult neoplasia despite similar patient populations. Here we discuss the reason for the surgical protocol, the clinical implications of noncompliance, and practical ways that providers can ensure full adherence to the protocol.

Risk-Reducing Salpingo-Oophorectomy: A Series of 90 BRCA1 and BRCA2 Mutation Carriers and Literature Review

Risk-Reducing Salpingo-Oophorectomy: A Series of 90 BRCA1 and BRCA2 Mutation Carriers and Literature Review

The psychosexual effects of risk reducing bilateral salpingo-oophorectomy in female BRCA1/2 mutation carriers: A systematic review of qualitative studies.

Background: For women with BRCA1/2 mutations risk-reducing bilateral salpingo-oophorectomy (RRBSO) to reduce the risk of primary ovarian cancer is often performed, however the surgery results in immediate onset of surgical menopause. The aim of this research was to explore the psychosexual impacts of risk reducing bilateral salpingo oophorectomy in the published qualitative literature.

Cost Effectiveness of Whole Population BRCA Genetic Screening for Cancer Prevention in Israel.

With the growing technical ease and reduction in genetic screening costs, whole population BRCA screening may be a feasible option. Our objective was to investigate the cost effectiveness of whole population screening for BRCA mutations in Israel, for varying degrees of BRCA carrier state. Lifetime costs of whole female population screening for BRCA mutation carrier state versus nonscreening were compared using a Markovian process decision analysis model. Model parameters including ovarian and breast cancer risks were obtained from previously published data. Screening and other treatment-related costs were received from the Israeli Ministry of Health pricing list according to specified codes. Quality-adjusted life years were used for cost-effectiveness analysis. Sensitivity analysis was conducted to evaluate model uncertainties, specifically varying degrees of BRCA prevalence. Results show that whole population BRCA screening in Israel is cost effective across a wide range of BRCA prevalence rates with an incremental cost-effectiveness ratio of 81,493 new Israeli Shekels for a BRCA prevalence of 2.5%, increasing to 250,000 new Israeli Shekels for a 0.75% prevalence rate, per quality-adjusted life year gained. Discount rate and population BRCA prevalence and rate of risk reduction salpingo-oophorectomy are the most influential parameters in the model. Whole population screening for BRCA mutations should be offered as part of general health screening strategies by national medical insurance providers, even for non-Ashkenazi Jews. Our algorithm can be applied for other countries, adjusting local costs of screening and treatment. PREVENTION RELEVANCE: Whole population BRCA mutation screening in Israel is cost effective across a wide prevalence rate and should be offered as part of general health screening strategies by national medical insurance providers for cancer prevention.

Short-term impact of surgically induced menopause on cognitive function and wellbeing in women at high risk for ovarian cancer following risk-reducing bilateral salpingo-oophorectomy.

Risk-reducing bilateral salpingo-oophorectomy (RRSO) is an effective strategy to prevent pelvic serous carcinoma for women at high risk of developing ovarian cancer; however, it results in premature menopause. Data is lacking to adequately counsel these women about potential effects of premature menopause on cognition and quality of life. A prospective study in premenopausal women at high risk of ovarian cancer to determine changes in cognition over time after RRSO and the impact of hormone therapy (HT) on cognition. Participants were surveyed before and after surgery using the Functional Assessment of Cancer Therapy-Cognitive questionnaire and questions regarding domains of wellbeing at 6, 12 and 18 months. Data was tested for changes across time using mixed model regression and logistic regression. Fifty-seven women were included. Sixty-three percent of participants used HT. At 6 months postoperatively, perceived cognitive impairment declined by 5.5 points overall (4.4 in non-HT users and 6 in HT users), P = 0.003. The other domains of cognition assessed did not change significantly over time and the use of HT did not impact scores. Sleep disruption was common in this cohort and was not mitigated by HT. Self-reported depression improved after RRSO (P = 0.004). Women at high risk of ovarian cancer who choose RRSO may experience declines in cognition within the first 6 months of surgical menopause. HT may cause small declines in perceived cognitive impairment at 6 months after RRSO. Women can expect more sleep disruption after menopause, which is not mitigated by HT.