Risk-reducing Bilateral Salpingo-oophorectomy Research Articles

Abstract GS02-13: Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study

Abstract Background: Oncofertility counseling in BRCA carriers has unique challenges due to a possible negative impact of germline pathogenic/likely pathogenic variants (PVs) on reproductive potential and the indication to undergo risk-reducing bilateral salpingo-oophorectomy. While previous studies demonstrated the safety of pregnancy in women with prior breast cancer (BC) history, limited evidence exists in BRCA carriers specifically. We report the results of the largest study to date investigating likelihood of pregnancy after BC, reproductive and disease outcomes specifically in BRCA carriers. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including young BRCA carriers with history of BC (NCT03673306). Eligible patients were women harboring germline PVs in BRCA1 and/or BRCA2 and diagnosed with stage I-III invasive BC at the age of ≤ 40 years between January 2000 and December 2020. BRCA healthy carriers or patients with BRCA variants of unknown significance, non-invasive BC, lack of follow-up, prior ovarian cancer or other malignancies without history of BC were excluded. Primary endpoints were pregnancy rate and disease-free survival (DFS). Overall survival (OS), BC specific survival (BCSS), pregnancy, fetal and obstetric outcomes were secondary endpoints. To mitigate the impact of guaranteed time bias, two survival analyses were performed: 1) Extended Cox model with occurrence of pregnancy as a time-varying covariate; 2) Case-control analysis by matching 1:3 patients with and without a pregnancy for type of BRCA PV, hormone receptor status, nodal status and year at diagnosis; moreover, each control had to have a disease-free interval longer than the time occurring between BC diagnosis and conception of the matched case. Results: From 78 centers worldwide, 4,732 patients were included, of whom 659 had at least one pregnancy after BC (pregnancy cohort) and 4,073 did not (non-pregnancy cohort). Patients in the pregnancy cohort were significantly more likely to carry BRCA1 PVs, to be younger at BC diagnosis, to have node-negative and hormone receptor-negative (HR-) BC (all p< 0.01). Pregnancy rate at 10 years was 22% (95% CI 21%-24%) overall, 18% (95% CI 16%-21%) and 26% (95% CI 24%-26%) in patients with HR+ and HR- BC, respectively (p< 0.01). Median time from BC diagnosis to conception was 3.5 years (IQR 2.2-5.3 years), significantly longer in patients with HR+ than HR- BC (4.3 vs 3.2 years, p< 0.01). Among 659 patients with a pregnancy after BC, 45 (6.8%) and 63 (9.6%) experienced an induced abortion or a miscarriage, respectively. Of the 517 (78.5%) patients with completed pregnancy, 54 (10.4%) had twins and 406 (78.5%) delivered at term (delivery ≥37 weeks). Among the 571 babies born, 5 (0.9%) had congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in DFS was observed between the pregnancy and non-pregnancy cohorts (unadjusted HR 0.97, 95% CI 0.82-1.15, p=0.74; adjusted HR [aHR] 0.99, 95% CI 0.81-1.20, p=0.90). Patients in the pregnancy cohort showed significantly better BCSS (HR 0.53, 95% CI 0.38-0.74, p< 0.01; aHR 0.59, 95% CI 0.41-0.86, p< 0.01) and OS (HR 0.52, 95% CI 0.38-0.72, p< 0.01; aHR 0.58, 95% CI 0.40-0.85, p< 0.01). Similar results were obtained in the case-control analysis. Subgroup analyses of survival endpoints according to patient, tumor and treatment characteristics will be presented at the conference. Conclusions: In this global study, 1 out of 5 young BRCA carriers conceived within 10 years after a BC diagnosis, higher than rates previously reported in unselected young BC populations. Pregnancy following BC in BRCA carriers did not appear to adversely impact maternal prognosis or fetal outcomes. These findings should be incorporated into oncofertility counseling of young BRCA carriers with BC. Citation Format: Matteo Lambertini, Eva Blondeaux, Elisa Agostinetto, Anne-Sophie Hamy-Petit, Hee Jeong Kim, Camila Chiodi, Rinat Bernstein-Molho, Florentine Hilbers, Katarzyna Pogoda, Estela Carrasco Lopez, Kevin Punie, Jyoti Bajpai, Michail Ignatiadis, Halle Moore, Kelly-Anne Phillips, Angela Toss, Christine Rousset-Jablonski, Fedro Alessandro Peccatori, Tiphaine Renaud, Alberta Ferrari, Shani Paluch-Shimon, Robert Fruscio, Wanda Cui, Stephanie Wong, Claudio Vernieri, Kathryn Ruddy, Maria Vittoria Dieci, Alexios Matikas, Mariya Rozenblit, Cynthia Villareal Garza, Laura De Marchis, Lucia Del Mastro, Fabio Puglisi, Maria Del Pilar Estevez-Diz, Kenny A. Rodriguez-Wallberg, Bela Mrinakova, Sarah Meister, Luca Livraghi, Florian Clatot, Rinat Yerushalmi, Carmine De Angelis, Rodrigo Sánchez-Bayona, Icro Meattini, Natalia Cichowska-Cwalińska, Martine Berlière, Mahmoud Salama, Ugo De Giorgi, Amir Sonnenblick, Hatem Azim, Ann Partridge. Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-13.

Abstract PO1-08-04: Universal Germline Genetic Testing for Breast Cancer: Implementation in a Rural Practice and Impact on Shared Decision Making

Abstract Background: Prior work from our group has shown a high rate of familial breast cancer (BC) among rural BC patients (pts), with 33% reporting > 1 first-degree family members with BC and 55% meeting NCCN germline genetic testing (GGT) criteria (Shelton CH et al. NC Med. J; 2022). In 2018, we increased GGT to include all BC pts and observed: 1) many pts were out-of-criteria per NCCN guidelines but had actionable pathogenic germline variants (PGVs) and 2) knowledge of GGT factored significantly into shared decision making by providers and patients, including for positive and negative results. Beginning in 2019, concurrent with the recommendation from the American Society of Breast Surgeons, we expanded this model of universal GGT to an IRB-approved study to measure the impact of prospective testing on shared decision-making. Herein we report the real-world implementation of universal GGT for patients with BC and genetics-informed treatment decision-making in a rural community practice. Methods: From 2019-2022 all BC pts at a small, rural community hospital were offered GGT. Demographics, clinical features, and GGT results were collected along with clinician-reported clinical recommendations for treatment based on GGT results. Descriptive statistics and two-tailed Fisher’s exact test were employed and significance was set at p< 0.05. Results: 210 BC pts were offered GGT and 192 (91%) underwent testing [97% female, 95% non-Hispanic White, mean age at diagnosis of 62, 75% Stage I], with all but 7 pts completing GGT before primary treatment decisions. 104 (54%) of patients were in-criteria (IC) and 88 (46%) out-of-criteria (OOC) with NCCN GGT guidelines. PGVs were identified in 25 pts (13%) and 15 genes, most commonly BRCA1/2 (5 pts), PALB2 (3), monoallelic MUTYH (3) and ATM, BARD1, CHEK2 (2 pts each). PGV frequencies were 15% in IC and 11% in OOC patients (p=0.495). 46 (24%) pts had only a variant of uncertain significance (VUS) results. 70% of patients had > 1 clinical management change based on their GGT results. Changes in breast surgery, uptake of risk-reducing bilateral salpingo-oophorectomy, surveillance and clinical follow-up were significantly higher in patients with PGV compared to those with VUS/negative results (p < 0.0001). Compared to those with negative results, patients with PGVs in BRCA1 and BRCA2 were significantly more likely to undergo bilateral mastectomy (BLM) while those with PGVs in other genes or with VUS were not significantly more likely to elect for BLM than those with negative results. Clinicians reported that return of GGT reinforced their recommendation for 73/138 (53%) of patients who underwent breast-conserving therapy. GGT results aided in radiation therapy strategy for 54% of pts, most often resulting in dose de-escalation (accelerated fractionation) for negative/VUS pts (Table). Conclusions: Universal GGT for patients with BC was successfully implemented in a rural community practice with >90% uptake. Treatment was enhanced in those with clinically actionable PGVs and de-escalated in those without PGVs. Universal GGT for patients with BC is feasible to implement as the standard of practice within rural populations, enabling optimization of clinical care to patients’ genetic profile and may reduce unnecessary healthcare resource utilization. Universal Germline Genetic Testing for Breast Cancer: Implementation in a Rural Practice and Impact on Shared Decision Making Changes in Radiation Therapy Strategy based on GGT Citation Format: Charles Shelton, Sarah Nielsen, Antonio Ruiz, Lauren Shelton, Karen Freas, Sarah Poll, Brandie Heald, Daniel Pineda-Alvarez, Edward Esplin, Rachel Ellsworth, Hannah Montgomery. Universal Germline Genetic Testing for Breast Cancer: Implementation in a Rural Practice and Impact on Shared Decision Making [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-04.

Pathogenic BRCA Variants in the Ashkenazi Jewish Population: A Retrospective Study [ID 2683559

INTRODUCTION: Pathogenic variants in BRCA genes (BRCA-PV) increase risk for cancers. Established guidelines for BRCA-PV risk reduction include surveillance, chemoprevention, and surgery. Ashkenazi Jews (AJ) have increased prevalence of BRCA-PVs versus the general population: 1/40 versus 1/160. Population testing of AJs, testing based on ancestry alone, identifies more BRCA-PV carriers than testing based on family history. METHODS: Charts of 683 AJ patients tested in a gynecology office for BRCA-PVs between January 1, 2017, and June 30, 2020, were retrospectively reviewed for BRCA-PV status, history, and clinical management. Findings were compared to 2017 National Comprehensive Cancer Network (NCCN) guidelines, current at time of testing. Patients were appropriately counseled for clinical management. RESULTS: Six hundred eighty-three AJs, mean age 51.0±13.5 years, were tested for BRCA-PVs: 14 tested positive (2%), mean age 41.6±14.16; 13/14 (93%) were female. Of patients with PV, 6 (43%) patients did not qualify for screening based on 2017 guidelines. Of positive female patients, 7 (54%) chose risk-reducing bilateral salpingo-oophorectomy (rrBSO), 4 (31%) chose mastectomy, 3 (21%) chose in vitro fertilization with wild-type embryos. One patient was found to have invasive serous tubal cancer at rrBSO; another with ER− breast cancer with first screening MRI. CONCLUSION: Our study confirms increased BRCA-PV prevalence amongst AJs. Over half of individuals tested did not meet 2017 NCCN criteria, including two positive patients diagnosed with cancer—indicating that 2017 criteria did not capture at-risk individuals. Updated guidelines recommending BRCA-PV testing of AJs must be implemented to identify actionable PVs and initiate cancer prevention strategies.

Abstract 1069: Interrogating the role of the cGAS/STING pathway fallopian tube transformation

Abstract Ovarian Cancer is the deadliest gynecologic malignancy. Despite recent advances in cancer diagnostics, it is a cancer that is often detected late and the vast majority of patients are diagnosed at Stage III and Stage IV. After treatment with debulking surgery and chemotherapy, 80% of patients have tumor relapse with increasing resistance. Early detection efforts have been largely unsuccessful and the only effective prevention strategy in high risk patients is surgical removal of the fallopian tube and ovaries. Careful pathologic studies of prophylactic risk reducing bilateral salpingo-oophorectomy (RRSO) has demonstrated that HGSC originates in the fallopian tube. Within the fallopian tube, secretory cells within the fimbriae are believed to be the origin of HGSC based on numerous lines of correlative evidence including the identification of histologically and molecularly abnormal regions in the fallopian tube called serous tubal intraepithelial cancer (STIC) in 3-5% of patients undergoing RRSO, and the presence of STIC in approximately half of patients undergoing debulking surgeries for HGSC. Finally, p53 mutations have been found to be identical in STIC and in the concurrent invasive disease indicating that HGSC and the STIC likely arise from the same clone. TCGA analysis has demonstrated that HCSC is a disease characterized by genomic and chromosomal instability harboring copy number alteration, including amplifications, deletions and more complex chromosomal rearrangements which impact multiple genes and pathways. Aberrantly segregating chromosomes that lag behind the spindle apparatus fail to become part of the primary nucleus (PN) and are instead enclosed by a self-assembled nuclear membrane, creating a structure called the micronucleus (MN). Spontaneous breakdown of the MN causes cytoplasmic DNA sensing and activation of the cGAS-STING pathway, an important innate cellular defense mechanism to foreign cytoplasmic DNA. To better understand the early genomic and signaling events in the development of HGSC, we are interrogating tissue from our archives from MSKCC patients who have undergone RRSO, hormone ablation surgeries or surgical debulking and were found to have benign fallopian tube, STIC lesions or invasive HGSC with STIC. We have performed a pilot experiment of 20 patient samples of different germline genetic backgrounds. Intriguingly, cGAS signaling was observed only rarely in the STICs indicating low rates of CIN in STICs we have evaluated, however we note that even in early invasive disease, we observe cGAS positivity. Taken together, these data are consistent with a model where CIN and subsequent cGAS/STING pathway activation drives the transition from pre-invasive to invasive disease. Citation Format: Duaa Hassan Al-Rawi, Danguole Norkunaite, Samuel Bakhoum, Sohrab Shah. Interrogating the role of the cGAS/STING pathway fallopian tube transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1069.

Abstract IA015: Is salpingectomy as effective as bilateral salpingo-oophorectomy in preventing ovarian, fallopian tube, and peritoneal cancer? Let’s prove it!

Abstract IA015: Is salpingectomy as effective as bilateral salpingo-oophorectomy in preventing ovarian, fallopian tube, and peritoneal cancer? Let’s prove it!

The Concept behind the Suitability of Menstrual Blood-Derived Stem Cells for the Management of Vaginal Atrophy among BRCA Mutation Carriers after RRSO.

Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended for breast cancer gene 1 (BRCA1) and 2 (BRCA2) mutation carriers. A major consequence of RRSO is surgical menopause associated with severe menopausal symptoms, mostly genitourinary complaints. Due to the inherent breast cancer risk, estrogen-based therapies are generally avoided in these patients. So far, the non-hormonal approaches available are not efficient to successfully treat the disabling vaginal atrophy-related symptoms. In regenerative medicine, mesenchymal stem cells (MSC) are the most frequently used cell type due to their remarkable and regenerative characteristics. Therapies based on MSC have revealed positive outcomes regarding symptoms and signs associated with vaginal atrophy by promoting angiogenesis, vaginal restoration, and the proliferation of vaginal mucosa cells. Menstrual blood-derived stem cells (MenSC) are a novel source of MSC, with promising therapeutic potential directly linked to their high proliferative rates; low immunogenicity; non-invasive, easy, and periodic acquisition; and almost no associated ethical issues. In this review, we update the current knowledge and research regarding the potential value of previously preserved MenSC in the therapy of vaginal atrophy among BRCA mutation carriers subjected to RRSO.

Concurrent uterine surgery and uptake of hormone therapy in patients undergoing bilateral salpingo-oophorectomy for risk-reducing or therapeutic indications

ObjectiveThis study aimed to analyze factors associated with concurrent uterine surgery in patients undergoing bilateral salpingo-oophorectomy (BSO) for risk reducing or therapeutic purposes. Additionally, trends in surgical choice and uptake of post-operative hormone therapy (HT) were examined. MethodsA 10-year retrospective study was conducted on patients who underwent risk-reducing or therapeutic BSO at one institution. Multinomial regression analysis of patient and case characteristics was performed evaluating associations with surgery type (BSO, BSO and hysterectomy, or BSO and endometrial sampling). Trends in surgery type and uptake of HT post operatively are described. ResultsAmong the study sample of 643 patients, 140 (22%) patients underwent therapeutic BSO for a history of hormone receptor (HR) positive breast cancer, while the remainder underwent risk-reducing BSO due to a pathogenic variant and/or family history. Pathogenic variants included BRCA1 (141, 40%) BRCA2 (173, 49%), and Lynch syndrome genes (15, 4%). Regression analysis revealed significant associations between concurrent hysterectomy and Black race (RR = 3.55, CI = 1.51–8.38, p = 0.004), history of HR positive breast cancer (RR = 1.88, CI = 1.03–3.42, p = 0.04), and surgeon (Surgeon 1, RR = 2.43, CI = 1.36–4.35, p = 0.003). Among eligible patients under age 51, 36% initiated HT. Over the study period, concurrent hysterectomy rates declined while endometrial sampling increased. ConclusionsRates of hysterectomy declined over the study period and slightly more than one-third of eligible patients utilized post-operative HT. Further research on concurrent uterine surgery is needed to establish standardized treatment recommendations in the risk-reducing and therapeutic BSO population. Additionally, education regarding the benefits of postoperative HT in eligible patients is warranted.

Combined Bilateral Salpingo-oophorectomy and Cesarean Delivery in BRCA1/2 Alteration Carriers : A Case Series.

The cumulative lifetime risk of ovarian cancer is 16-68% and 11-30% in female BRCA1 and BRCA2 gene alteration carriers, respectively. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only proven way to reduce ovarian cancer mortality. We report a series of patients who underwent risk-reducing surgery at the time of planned obstetric-indicated cesarean delivery. This is a case series of four women carrying a pathogenic germline BRCA1 or BRCA2 gene alteration who underwent RRSO at the time of cesarean delivery between March 1, 2018, and March 31, 2022. All women were referred during pregnancy to the University College London Hospitals Familial Cancer Clinic for consideration of RRSO at the time of obstetric-indicated cesarean delivery. Women were considered eligible for RRSO if they had a proven pathogenic germline alteration, would have completed childbearing after the cesarean delivery, and were older than age 35 or 40 years with BRCA1 or BRCA2 alterations, respectively. Operating time, blood loss, transfusion requirements, length of hospital stay, complications, and ability to breastfeed were assessed and, where possible, compared with the institutional means for similar patients who underwent cesarean delivery only, to determine whether RRSO was associated with increased morbidity. Women were contacted 11-59 months postprocedure to assess satisfaction. The mean blood loss was 687 mL (range 400-1,000 mL), mean operating time was 68 minutes, mean length of hospital stay was 3 days, and mean change in hemoglobin was -1 g/dL. No patient required a transfusion, had internal organ damage, returned to the operating room, or was readmitted. One of two women with intact breast tissue successfully breastfed, and the other chose to bottle feed. The mean contemporaneous institutional blood loss for cesarean delivery was not significantly different at 681 mL for singleton pregnancies and 872 mL for twin pregnancies. All four women reported a high level of satisfaction with the combined procedure. Our results show that RRSO can be performed at the time of cesarean delivery with high patient satisfaction. This approach can be offered to appropriately counseled individuals, with the benefit of avoiding the need for two separate procedures, with potentially reduced patient morbidity and health care costs.

Disturbed sleep is associated with reduced verbal episodic memory and entorhinal cortex volume in younger middle-aged women with risk-reducing early ovarian removal.

Women with early ovarian removal (<48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored. We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed. Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume. Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women.

Executive Summary of the Ovarian Cancer Evidence Review Conference

ABSTRACT Ovarian cancer has the 17th highest incidence among all cancers in the United States; however, it is the deadliest gynecologic cancer and the fifth most common cause of cancer-related death in women in the United States. The Centers for Disease Control and Prevention funded the American College of Obstetricians and Gynecologists (ACOG) to create educational materials for clinicians on the early diagnosis and prevention of gynecologic cancers. This article is an evidence summary based on ACOG's extensive literature review on the early diagnosis and prevention of ovarian cancer. An expert panel was recruited from the Society for Academic Specialists in General Obstetrics and Gynecology and the Society of Gynecologic Oncology to review and summarize evidence from articles published between January 2000 and October 2021. Topics used to frame the literature review included the epidemiology of ovarian cancer, risk factors, prevention and risk reduction, screening strategies and early detection, health disparities, diagnosis and care coordination by primary care providers, and special considerations. The Ovarian Cancer Evidence Review Conference occurred in February 2022 where the expert panel and stakeholder professional and patient advocacy organizations discussed their findings and drafted summaries to develop educational materials. Review of the epidemiology revealed that in 2022 there were 19,880 new cases of ovarian cancer, 12,810 women died of ovarian cancer, 5-year survival is 49.7% and correlates strongly with stage at diagnosis, and fewer than 10% of women with stage 1 disease will have recurrence. Risk factors for ovarian cancer include older age, inactivity, nulliparity, early menarche, late menopause, postmenopausal hormone therapy, genetic mutations such as BRCA1 and BRCA2, and endometriosis. Risk-reducing bilateral salpingo-oophorectomy reduces incidence of ovarian cancer by 80% in BRCA1 and BRCA2 carriers (95% confidence interval, 0.12–0.39) and is recommended by ACOG for women at increased risk of ovarian cancer. Contraception, physical activity, and lactation may help reduce the risk of ovarian cancer. The most common methods studied for screening include transvaginal ultrasonography, bimanual palpation, and measuring tumor marker CA-125. The Risk of Ovarian Cancer Algorithm uses CA-125 and transvaginal ultrasound to estimate the risk of ovarian cancer based on age and change in CA-125; however, it is still being studied, and no established screening method exists for asymptomatic women. Several organizations including ACOG support identifying women at high risk and subsequent genetic counseling. Symptoms of ovarian cancer are nonspecific and include abdominal distention and pain, and while workup should include ultrasonography and CA-125 measurement, no high-quality studies have compared imaging, biomarkers, risk algorithms, or multimodal risk assessment tools for the primary evaluation of patients with high-risk symptoms. Regarding disparities, Black women consistently had worse outcomes compared with their White counterparts, and little evidence regarding other racial and ethnic groups or gender minorities was identified. Finally, care coordination is critical, and ACOG recommends a low bar for referral to a gynecologic oncologist for patients with suspicion of ovarian cancer, which has been shown to increase survival and offer other advantages. This evidence review identifies many research gaps and opportunities for ovarian cancer and provides a high-level educational summary of current best practices in the risk stratification, diagnosis, and prevention of ovarian cancer.

Subjective cognitive changes following premenopausal risk-reducing bilateral salpingo-oophorectomy

Objective Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Cognitive symptoms during natural menopause transition are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, we explored the cognitive experiences of women within 24 months post BSO. Methods This observational cross-sectional sub-study is part of a larger project, the Early Menopause and Cognition Study (EM-COG). We investigated perceived cognitive experiences in Australian women (n = 16) who underwent risk-reducing BSO using qualitative interviews. Thematic analysis was undertaken to identify key themes. Results Fifteen out of 16 participants (93.75%) reported changes to cognition within 24 months post BSO. The key cognitive symptoms reported were brain fog, memory and retrieval difficulties, slower processing speed as well as attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. Conclusion Findings from this study suggest that women experience subjective cognitive changes within 24 months post BSO. This period could be a vulnerable time for women’s cognitive health. While these findings need to be confirmed by a large prospective study, our research indicates that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.

An explainable machine learning ensemble model to predict the risk of ovarian cancer in BRCA-mutated patients undergoing risk-reducing salpingo-oophorectomy.

It has been estimated that 19,880 new cases of ovarian cancer had been diagnosed in 2022. Most epithelial ovarian cancer are sporadic, while in 15%-25% of cases, there is evidence of a familial or inherited component. Approximately 20%-25% of high-grade serous carcinoma cases are caused by germline mutations in the BRCA1 and BRCA2 genes. However, owing to a lack of effective early detection methods, women with BRCA mutations are recommended to undergo bilateral risk-reducing salpingo-oophorectomy (RRSO) after childbearing. Determining the right timing for this procedure is a difficult decision. It is crucial to find a clinical signature to identify high-risk BRCA-mutated patients and determine the appropriate timing for performing RRSO. In this work, clinical data referred to a cohort of 184 patients, of whom 7.6% were affected by adnexal tumors including invasive carcinomas and intraepithelial lesions after RSSO has been analyzed. Thus, we proposed an explainable machine learning (ML) ensemble approach using clinical data commonly collected in clinical practice to early identify BRCA-mutated patients at high risk of ovarian cancer and consequentially establish the correct timing for RRSO. The ensemble model was able to handle imbalanced data achieving an accuracy value of 83.2%, a specificity value of 85.3%, a sensitivity value of 57.1%, a G-mean value of 69.8%, and an AUC value of 71.1%. In agreement with the promising results achieved, the application of suitable ML techniques could play a key role in the definition of a BRCA-mutated patient-centric clinical signature for ovarian cancer risk and consequently personalize the management of these patients. As far as we know, this is the first work addressing this task from an ML perspective.

Adherence to risk-reducing salpingo-oophorectomy guidelines among gynecologic oncologists compared to general gynecologists

Risk-reducing bilateral salpingo-oophorectomy reduces mortality from high-grade serous carcinoma in patients with hereditary breast and ovarian cancer associated gene mutations. Ideal surgical management includes 5 steps outlined in 2005 by the Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists. In addition, it is recommended that pathologic examination include serial sectioning of specimens. In practice, risk-reducing salpingo-oophorectomy is performed by both gynecologic oncologists and general gynecologists. To ensure optimal detection of occult malignancy, standardized adherence to outlined guidelines is necessary. This study aimed to evaluate the adherence to optimal surgical and pathologic examination guidelines and to compare the rate of occult malignancy at the time of surgery between 2 provider types. Institutional review board exemption was obtained. A retrospective review of patients undergoing risk-reducing bilateral salpingo-oophorectomy without hysterectomy from October 1, 2015, to December 31, 2020, at 3 sites within a healthcare system was conducted. The inclusion criteria included age ≥18 years and a documented indication for surgery being a mutation in BRCA1 or BRCA2 or a strong family history of breast and/or ovarian cancer. Compliance with 5 surgical steps and pathologic specimen preparation was based on medical record documentation. Multivariable logistic regression was used to determine differences in adherence between provider groups and surgical and pathologic examination guidelines. A P value of <.025 was considered statistically significant for the 2 primary outcomes after Bonferroni correction was applied to adjust for multiple comparisons. A total of 185 patients were included. Among the 96 cases performed by gynecologic oncologists, 69 (72%) performed all 5 steps of surgery, 22 (23%) performed 4 steps, 5 (5%) performed 3 steps, and none performed 1 or 2 steps. Among the 89 cases performed by general gynecologists, 4 (5%) performed all 5 steps, 33 (37%) performed 4 steps, 38 (43%) performed 3 steps, 13 (15%) performed 2 steps, and 1 (1%) performed 1 step. Gynecologic oncologists were more likely to document adherence to all 5 recommended surgical steps in their surgical dictation (odds ratio, 54.3; 95% confidence interval, 18.1-162.7; P<.0001). Among the 96 cases documented by gynecologic oncologists, 41 (43%) had serial sectioning of all specimens performed, compared with 23 of 89 cases (26%) performed by general gynecologists. No difference in adherence to pathologic guidelines was identified between the 2 provider groups (P=.0489; note: P value of >.025). Overall, 5 patients (2.70%) had occult malignancy diagnosed at the time of risk-reducing surgery, with all surgeries performed by general gynecologists. Our results demonstrated greater compliance with surgical guidelines for risk-reducing bilateral salpingo-oophorectomy in gynecologic oncologists than in general gynecologists. No considerable difference was determined between the 2 provider types in adherence to pathologic guidelines. Our findings demonstrated a need for institution-wide protocol education and implementation of standardized nomenclature to ensure provider adherence to evidence-based guidelines.

Hereditary/Familial Ovarian Cancer: Testing Principles and Risk Management

Although BRCA1 and BRCA2 pathogenic or likely pathogenic variants are a well-established cause of hereditary ovarian cancer, recent studies have brought other homologous recombination repair pathway genes into the limelight. The current NCCN Guidelines reflect the most up-to-date, evidence-based data relating to the risk management of patients who are carriers of BRCA1/2 and/or other variants. Risk-reducing bilateral salpingo-oophorectomy is the current standard of care, but a recommendation for salpingectomy alone may be on the horizon.

Risk-Reducing Salpingectomy And Other Strategies For Prevention Of Ovarian And Tubal Carcinoma

Objective: To provide a review of most current evidence and data for risk-reducing strategies used in prevention of ovarian cancer. Methods of study selection: PubMed was used as a search tool for articles with key words focusing on current strategies on prevention of ovarian cancer such as “risk-reducing salpingectomy, “risk-reducing salpingo-oophorectomy, “salpingectomy with delayed oophorectomy”. General consensus and society guidelines from leading organizations such as Society of Gynecologic Oncology, American Cancer Society, and American College of Obstetricians and Gynecologists were reviewed and summarized in this review article with supporting evidence and research studies on most current riskreduction strategies for prevention of ovarian and tubal carcinoma. Result: There is growing evidence that high-grade serous ovarian carcinoma arises in the fallopian tube in the form of serous tubal intraepithelial carcinoma (STIC). Therefore, opportunistic salpingectomy has been increasingly offered at the time of routine benign gynecologic surgery. Risk-reducing bilateral salpingo-oophorectomy has been shown to reduce risk of ovarian cancer up to 90% and offered to women with high hereditary predisposition for ovarian cancer. Riskreducing salpingectomy with delayed oophorectomy (SDO) has been suggested in younger women to balance the effects of infertility and surgically induced menopause resulting from oophorectomy. Conclusion: Combined oral Contraceptive COCs confer long-term protection against ovarian cancer with reported 20% reduction for every 5 years of use, which have been cited as a confounding factor in most of the published studies. Women who used HRT (estrogen alone or combined estrogen and progesterone) carry 20% higher risk of ovarian cancer compared to never-users. The associated increased risk of cervical and breast cancer with COCs/HTR use, have recently let women prefer the RRSO over COCs for prevention of ovarian cancer. Bilateral risk reducing Salpingo-oophorectomy (RRSO) at the age of 40–45 in BRCA1 and 45–50 in BRCA2 mutation carriers is recommended to be the primary approach for risk reduction of ovarian cancer. There is well-supported evidence of lowering the risk of ovarian cancer in high-risk population by 90%. The American college of obstetrics and gynecology committee opinion, recommended opportunistic salpingectomy for the primary prevention of ovarian cancer in a woman already undergoing pelvic surgery for another indication. Bilateral salpingectomy at the time of cesarean delivery is recommended to replace the tubal ligation as the method of choice for sterilization performed with cesarean delivery. The novel alternative procedure of Risk-reducing Salpingectomy with delayed risk-reducing oophorectomy (RRSO-RRO) have growing attention as a better alternative to improve the menopause-related morbidity and quality of life.

Patterns of care and outcomes of risk reducing surgery in women with pathogenic variants in non-BRCA and Lynch syndrome ovarian cancer susceptibility genes

ObjectivesGuidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. MethodsWomen with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000–9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Results26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. ConclusionsNo occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.

BRCA carriers after risk-reducing bilateral salpingo-oophorectomy: menopausal hormone therapy knowledge gaps, and the impact of physicians’ recommendations

Objective Female carriers of BRCA1/2 gene mutations are at an increased lifetime risk for breast and ovarian cancers. They are recommended to undergo risk-reducing surgery, including bilateral salpingo-oophorectomy (RR-BSO), upon completion of childbearing. RR-BSO surgery decreases morbidity and mortality but results in early menopause. Menopausal hormone therapy (MHT) is under-utilized despite being shown as safe for carriers. We aim to evaluate the factors associated with decision-making regarding MHT use following RR-BSO in healthy BRCA mutation carriers. Methods Female carriers aged <50 years who underwent RR-BSO and were followed in a multidisciplinary clinic completed online multiple-choice and free-text questionnaires. Results A total of 142 women met the inclusion criteria and filled the questionnaire: 83 were MHT users and 59 were non-users. MHT users underwent RR-BSO earlier than non-users (40.82 ± 3.91 vs. 42.88 ± 4.34; p < 0.0001). MHT usage was positively associated with MHT explanation (odds ratio 4.318, 95% confidence interval [CI] [1.341–13.902], p = 0.014), and knowledge regarding the safety of MHT and its effects on general health (odds ratio 2.001, 95% CI [1.443–2.774], p < 0.0001). MHT users and non-users retrospectively evaluated their comprehension of RR-BSO consequences as significantly lower than before surgery (p < 0.001). Conclusion Post-RR-BSO outcomes, including the effects on women’s quality of life and its possible mitigation through MHT use, need to be addressed pre surgery by healthcare providers.

The Psychosocial Impact of the Decision to Undergo Risk-Reducing Salpingo-Oophorectomy Surgery in BRCA Mutation Carriers and the Role of Physician-Patient Communication.

Risk-reducing bilateral salpingo-oophorectomy (RRSO) is an effective prophylactic surgery provided to premenopausal women carrying BRCA1 or BRCA2 mutations and presenting an increased risk of developing breast or ovarian cancer. This procedure is related to physiological, sexual, and psychosocial distress, which altogether increase uncertainty and complexity in the clinical decision-making process and post-surgery adaptation. Physician-patient communication (PPC) has been pointed out as a determinant factor in the decision-making to undergo RRSO, and the subsequent adjustment of women. However, studies examining the psychosocial impact of the decision-making process have been scarce and often lack clear theoretical frameworks. While the role of PPC in such processes has been highlighted in a few qualitative studies, there is a paucity of quantitative research addressing this question. Therefore, this narrative review, conducted using a multidisciplinary approach, was planned to: (1) present an updated medical background for RRSO; (2) analyze the psychosocial impact of the decision-making process within a theoretical framework of the Health Belief Model; and (3) discuss the role of PPC in such a decision-making process and in post-surgery. The collected research also enabled the recommendation of some additions to the existing clinical guidelines and the outlining of future research directions.

Long-Term Non-Cancer Risks in People with BRCA Mutations following Risk-Reducing Bilateral Salpingo-Oophorectomy and the Role of Hormone Replacement Therapy: A Review.

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the gold standard preventative option for BRCA mutation carriers at high risk for ovarian and breast cancer. However, when performed at the recommended ages of 35-45 years, RRBSO induces immediate premature surgical menopause, along with the accompanying adverse psychosocial, cardiovascular, bone, and cognitive health consequences. While these health consequences have been thoroughly studied in the general population, little is known about the long-term health outcomes in the BRCA population. Hormone replacement therapy (HRT) until the average age of natural menopause can help mitigate these health risks, yet the initiation of HRT is a complex decision among BRCA carriers due to concern of increasing the already high risk of breast cancer in these people. This review summarizes the current research on long-term non-cancer risks in BRCA carriers following RRBSO-induced premature surgical menopause, and highlights the existing evidence in support of HRT use in this population.

Hormone replacement therapy in BRCA mutation carriers: how shall we do no harm?

Women with a BRCA mutation have an increased risk of developing breast and ovarian cancer. Bilateral salpingo-oophorectomy is the only effective strategy to reduce this risk. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended between the ages of 35 and 40 for women carriers of BRCA1 and between the ages of 40 and 45 for women carriers of BRCA1 and BRCA2 mutations. Most women undergo this procedure prior to their natural menopause subsequently developing an anticipated lack of hormones. This condition affects the quality of life and longevity, while it is more pronounced in women carrying a BRCA1 mutation compared to BRCA2 because they are likely to have surgery earlier. Hormone replacement therapy (HRT) is the only strategy able to significantly compensate for the loss of ovarian hormone production and counteract menopausal symptoms. There is strong evidence that short-term HRT use does not increase the risk of breast cancer among women with a BRCA1 mutation. Few data are available on BRCA2 mutation carriers. Therefore, BRCA mutation carriers require careful counseling about the outcomes of their RRSO, including menopausal symptoms and/or the fear associated with HRT use.