Risk-reducing Bilateral Salpingo-oophorectomy Research Articles

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.

The Role of Hormonal Replacement Therapy in BRCA Mutated Patients: Lights and Shadows.

All cancers develop as a result of mutations in genes. DNA damage induces genomic instability and subsequently increases susceptibility to tumorigenesis. Women who carry mutations of BRCA 1 and BRCA2 genes have an augmented risk of breast and ovarian cancer and a markedly augmented probability of dying because of cancer compared to the general population. As a result, international guidelines recommend that all BRCA1\2 mutation carriers be offered risk-reducing bilateral salpingo-oophorectomy at an early age to reduce the risk of cancer and decrease the mortality rate of this high-risk population. NCCN guidelines recommend risk-reducing bilateral salpingo-oophorectomy in pre-menopausal women, between 35-40 years in BRCA1 mutation carriers and between 40-45 years in BRCA2 mutation carriers. Unfortunately, the well-documented reduction of cancer risk is counterbalanced by early sterility and premature ovarian failure with an early onset of secondary menopausal syndromes such as neuromotor, cardiovascular, cognitive and urogenital deficiency. Hormonal replacement therapy significantly compensates for hormonal deprivation and counteracts menopausal syndrome morbidity and mortality; however, some data suggest a possible correlation between hormonal medications and cancer risk, especially in BRCA1\2 carriers who undergo long-term regimens. Conversely, short-term treatment before the age of natural menopause does not appear to increase the cancer risk in BRCA1 mutation carriers without a personal history of breast cancer after prophylactic surgery. Few data are available on BRCA2 mutation carriers and more well-designed studies are needed. In conclusion, clinicians should propose short-term hormone replacement therapy to BRCA 1 carriers to counteract hormonal deprivation; personalized counselling should be offered to BRCA2 mutation carriers for a balance between the risks and benefits of the treatment.

Evaluation of bone health in breast cancer patients with germline pathogenic

Patients with breast cancer (BC) have an increased risk of bone loss due to both the cancer itself and the side effects of antineoplastic therapies. This study evaluated the bone health of survivors of BC with germline pathogenic variants (PVs). This is a retrospective cross-sectional study. We identified 165 BC patients in whom PVs in BC susceptibility genes were diagnosed between February 2017 and December 2022 at our breast health center in Acibadem Altunizade Hospital. Only 80 patients underwent dual-energy X-ray absorptiometry (DXA) at the time of diagnosis. The median patient age was 44 years. Of 80 patients, 47% had (n = 38) had BRCA1 and BRCA2, while the remaining 53% (n = 42) had other PVs, which we refer to as non-BRCA. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) was performed in 21 patients with BRCA and 6 patients with non-BRCA PVs patients (p < 0.001). At the 68-months follow up period, a total of 53% had osteopenia, and 11% had osteoporosis. According to the mutation type, among patients with BRCA1 and BRCA2, 47% exhibited osteopenia and 11% had osteoporosis. In non-BRCA, 57% had osteopenia and 12% had osteoporosis (p > 0.05). In this study, we showed that patients with BRCA and non-BRCA mutations have similar rates of osteopenia and osteoporosis. This is particularly important for non-BRCA mutation carriers, because there is insufficient data on this subject.

The risks of cancer in older women with BRCA pathogenic variants: How far have we come?

The purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75years of age with a BRCA1 or BRCA2 pathogenic variant. Participants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50years. Participants completed a baseline questionnaire and follow-up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow-up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan-Meier method. There were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n=186) and ovarian (n=45) were the most frequent cancers observed. For women who had both risk-reducing mastectomy and bilateral salpingo-oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%. Women with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75years and should be counselled appropriately.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2

BackgroundOur study aimed to establish ‘real-world’ performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO).MethodsOur study recruited 875...

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy.

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

Adherence to guideline-based preoperative and intraoperative care during risk-reducing bilateral salpingo-oophorectomy among gynecologist-oncologists compared to general gynecologists (335)

<b>Objectives:</b> Risk-reducing Bilateral Salpingoopherectomy (rrBSO) is the only intervention proven to reduce mortality from epithelial ovarian cancer in patients with hereditary breast and ovarian cancer (HBOC)-associated gene mutations. Optimal surgical technique for rrBSO includes five steps outlined in 2005 by the Society of Gynecologic Oncology and the American College of Obstetrics and Gynecology. These five steps include: <i>1)</i> Abdominal survey; <i>2)</i> Peritoneal washings; <i>3)</i> Entering retroperitoneal space and creating pedicle 2cm from the ovary; <i>4)</i> Dividing pedicle at the uterus; and <i>5)</i> Removal in an endoscopic bag. rrBSO can be performed by both general gynecologists (GYN) and gynecologist oncologists (GO). We aimed to evaluate adherence to surgical guidelines for rrBSO when performed by GO compared to GYN and assess the utility of preoperative (preop) CA-125 and pelvic ultrasound as predictors of malignancy identified at the time of rrBSO. <b>Methods:</b> A retrospective review of patients who underwent rrBSO from October 1, 2015, to December 31, 2020, by faculty and privately employed physicians at three high volume academic sites within a healthcare system was performed. The primary outcome was compliance with all five steps of rrBSO as dictated by a surgeon. Secondary outcomes included the presence of a pre-malignant or malignant lesion at the time of rrBSO and association with preoperative imaging or CA-125. Patient demographics and clinical characteristics were collected. Descriptive statistics for continuous variables were calculated. Univariable logistic regression was used to screen variables with a p-value criterion of p < 0.05 for entry into the model selection procedure. Multivariate regression was used to identify differences in practice patterns. <b>Results:</b> A total of 236 patients were included. Among them, 122 (52%) cases were performed by a GO. Among the cases documented by GO, 27 (22%) performed all five steps of the procedure, 65 (53%) performed four steps, 26 (21%) performed three steps, four (3%) performed two steps, and none performed only one step. Among the 114 cases by GYN, four (4%) performed all five steps, 17 (15%) performed four steps, 50 (44%) performed three steps, 40 (35%) performed two steps, and three (3%) performed only one step. Univariable analysis demonstrated no association between demographic variables and procedure compliance. GO were significantly more likely to adhere to all five recommended surgical steps, (OR: 7.816, 95% CI: 2.640-23.138, p=0.0002). In total, five patients (2.12%) had pre-malignant or malignant lesions diagnosed at the time of rrBSO. None of the five patients had documented preop CA-125 or preop imaging, and all five cases occurred in patients undergoing surgery with GYN. <b>Conclusions:</b> Our results show a statistically significant difference in compliance to procedural steps of rrBSO between GYN and GO. This demonstrates a need for institution-wide education and implementation of procedural standards and standardized nomenclature for dictations to ensure provider adherence to rrBSO guidelines. Fig. 1

Guideline concordance for risk-reducing bilateral salpingo- oophorectomy in a cohort of reproductive age women with BRCA1/2 mutations (562)

<b>Objectives:</b> Current guidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women diagnosed with <i>BRCA1</i> mutations by ages 35-40 and <i>BRCA2</i> mutations by ages 40-45. Our study aimed to examine guideline concordance for RRSO in a cohort of women with <i>BRCA1</i> and <i>BRCA2</i> mutations. <b>Methods:</b> We performed a retrospective cohort study of women aged 18-45 diagnosed with pathogenic <i>BRCA1</i> or <i>BRCA2</i> mutations seen by gynecologic oncologists at a single academic center between 2015 and 2019 and were eligible for RRSO per national guidelines. Our primary outcome was guideline concordance, defined as <i>1)</i> electing RRSO by age 35 for women with <i>BRCA1</i> and by age 40 for women with <i>BRCA2,</i> or <i>2)</i> if the patient was diagnosed after age 35 with <i>BRCA1</i> or after age 40 with <i>BRCA2,</i> electing RRSO within one year of diagnosis. Patients were monitored for electing RRSO by July 1^st, 2021. We excluded those previously diagnosed with gynecologic malignancies and those whose current age was less than 35 for <i>BRCA1</i> and less than 40 for <i>BRCA2</i>. We examined patient differences in guideline concordance using Fisher's exact and Pearson's Chisquare tests. We then identified relevant patient factors associated with guideline concordance using univariate log-binomial regression. <b>Results:</b> Of 62 total patients, 41 had a diagnosis of a suspected pathogenic or pathogenic <i>BRCA1</i> mutation (median age at diagnosis 34 y), and 21 had a diagnosis of suspected pathogenic or pathogenic <i>BRCA2</i> mutation (median age at diagnosis 41 y). Overall, 23% of patients (<i>n</i>=14/62) were guideline-concordant, or 27% of <i>BRCA1</i> patients (<i>n</i>=11/41) and 14% of <i>BRCA2</i> patients (<i>n</i>=3/21). In the descriptive analysis, guideline concordance was more common in non-White women compared to White women (<i>n</i>=7/18 vs <i>n</i>=7/44, p=0.09) and single women compared to partnered women (<i>n</i>=4/8 vs <i>n</i>=10/54, p=0.07). More women with a family history of both breast and ovarian cancer were guideline-concordant than women with a family history of breast cancer only (<i>n</i>=9/27 vs <i>n</i>=5/30, p=0.14). However, women with a personal history of breast cancer were less commonly guideline-concordant than women without a personal history (<i>n</i>=3/19 vs <i>n</i>=11/43, p=0.5). In univariate analysis, factors significantly associated with guideline concordance were non-White compared to White race (RR: 2.4, 95% CI: 1.00-5.97) and being single compared to being partnered (RR: 2.7, 95% CI: 1.11-6.58). There were no significant associations with guideline concordance by patient BMI, having children, having private insurance, income, type of <i>BRCA</i> diagnosis, past diagnosis of breast cancer, or family history of breast or ovarian cancer. Table 1 <b>Conclusions:</b> A minority of reproductive-age <i>BRCA1/2</i> patients met guideline concordance for electing RRSO. Being guideline-concordant was associated with non-White and single status. Further studies are needed to verify and identify disparities in meeting guideline- recommended timing of RRSO for the <i>BRCA1/BRCA2</i> population.

Ovarian cancer risk-reduction and screening in BRCA 1/2 mutation carriers (383)

<b>Objectives:</b> To determine the utilization of risk-reducing strategies and screening protocols for ovarian cancer in female <i>BRCA1/2</i> carriers. <b>Methods:</b> A multi-center, cross-sectional survey was conducted among <i>BRCA1/2</i> mutation carriers unaffected by cancer. The questionnaire was administered electronically via email using REDCap with two reminder emails. There were 2-23 fixed-response questions, including questions on genetic testing and risk-reducing decisions. Data were analyzed with Fisher's exact test. <b>Results:</b> The survey was completed by 105 female <i>BRCA</i> mutation carriers (34% response rate). <i>BRCA</i> subtypes included 54.3% <i>BRCA 2,</i> 41.0% <i>BRCA 1</i> and 2.9% of both. The age at which patients underwent genetic testing varied, with 21.0% within the age range of 18-24 years (yr), 24.8% within 25-34 yr, 30.5% 35-44 yr, 17.1% were 45-54 yr and 6.7% were >55 years. The majority of ordering providers were genetic counselors (57.1%), with fewer tests ordered by OBGYNs (18.1%), primary care providers (4.8%), gynecologic oncologists (4.8%), and breast surgeons (3.8%). Approximately half (55.8%) of respondents reported having been offered increased screening for possible early detection of ovarian cancer. Of the 79 women who performed their genetic testing before 45 years, 41.8% underwent increased ovarian cancer screening with either transvaginal ultrasound alone (21.2%), CA-125 alone (12.1%), or combined (63.6%). There were no differences seen in screening utilization based on <i>BRCA</i> mutation type <i>(BRCA1</i> 40.0% vs <i>BRCA2</i> 42.5%; p=0.93). Nearly all respondents (97.1%) reported that a provider had discussed risk-reducing surgeries. Sixty women underwent a risk-reducing bilateral salpingo-oophorectomy, which was recommended in similar proportions by gynecologic oncologists (58.3%), OBGYNs (48.3%), and genetic counselors (46.7%). Overall, 43.3% of respondents reported that a healthcare provider recommended taking combined oral contraceptive pills to reduce their risk of ovarian cancer, and of these women, 86.7% chose to use them. Combined oral contraceptive pills were offered at higher rates among women who were younger at age of genetic testing (18-24 yr: 86%, 25-34 yr: 62%, 35-44 yr: 23%; p<0.0001) as well as women with <i>BRCA1</i> mutations <i>(BRCA1:</i> 60%, <i>BRCA2:</i> 43%; p=0.048). <b>Conclusions:</b> In our cohort of female <i>BRCA</i> mutation carriers, ovarian cancer screening was offered to only half of the women. While the majority had discussed surgical options, less than half of women received recommendations to use medication-based risk-reduction. Further investigation is needed to identify barriers to utilization of ovarian cancer screening and nonsurgical risk-reduction among this high-risk population.

Factors associated with concurrent vs. sequentially combined surgery for patients undergoing risk-reducing bilateral salpingo- oophorectomy (434)

Factors associated with concurrent vs. sequentially combined surgery for patients undergoing risk-reducing bilateral salpingo- oophorectomy (434)

Jinekolojik Onkoloji Pratiğimizde Risk Azaltıcı Cerrahi Yönetimi Gerektiren Genetik Değişiklikler

Kanser, fonksiyonu hücre büyümesi ve DNA’nın bütünlüğünü koruma olan genlerdeki mutasyonlar sonucu gelişir. Mutasyonlar, germ hücrelerinde(germline)(GLM) ve diğer hücrelerde (somatik)(SM) olabilir. Kanserlerin %5-10’undan germline mutasyonlar sorumludur. Erken dönemde GLM’ların tespit edilmesi; risk altındaki bireylerin belirlenmesi, takibinin yapılması ve risk azaltıcı koruyucu stratejilerin geliştirilmesi açısından önemlidir. Ayrıca son zamanlarda tümör dokusunda SM’ların tespiti, hedefe yönelik ve adjuvan tedaviyi düzenlemede rehber olmaktadır. Over ve meme kanserlerinin yaklaşık %10-30’u ailesel kümelenme göstermekle birlikte vakaların sadece %5-10’u kalıtsaldır. Özellikle, kalıtsal over kanserlerinin yaklaşık %65-85’ini DNA onarım kusurlarına neden olan BRCA1/2 genlerinde GLM’lar sonucu oluşmaktadır. BRCA1/2 genlerinde patojenik mutasyonu olan bireyler için risk azaltıcı mastektomi (RRM) meme kanseri riskini %90-95 oranında azaltırken, salpingo-ooferektomi (RRSO) ile meme ( %50), over ve fallop tüpü kanseri insidansı da ( %70-96) azalmaktadır. Ayrıca RRSO, kansere özgü genel mortaliteyi azaltmakla ve over kanserini önlemede en etkili seçenek olarak kabul edilmektedir. BRCA1/2 dışında homolog rekombinasyon yolu DNA tamirinde rol oynayan RAD51C, RAD51D ve BRIP1 genlerdeki patojenik mutasyonlar over kanserinde rol oynamaktadır. RAD51C, RAD51D ve BRIP1, genlerinin patojenik mutasyon taşıyıcılarında rehberler, RRSO’i önermektedir. Lynch sendromu (LS), kolorektal ve endometriyal kanser gelişme riskinde artış ile karakterize otozomal dominant bir hastalıktır. LS’da endometrium ve over kanseri risk artışı en fazla olan MLH1, MSH2 ve MSH6 genlerinde patojenik mutasyon taşıyıcılarında fertilitesini tamamladıktan sonra risk azaltıcı cerrahi olarak histerektomi ve RRSO önerilmektedir. Bu derlemede amacımız, jinekolojik onkoloji pratiğimizde son zamanlarda kullanımı gittikçe artan risk azaltıcı profilaktik cerrahi uygulamaları gerektiren genetik hastalıkları son rehberler eşliğinde özetlemektir.

Hereditary ovarian cancer risk reduction: a retrospective evaluation of patient perspectives and service provision at a regional hereditary gynaecologic cancer clinic 2006–2016

BackgroundGermline pathogenic variants in BRCA1/2 have been established in hereditary breast and ovarian cancer (HBOC) syndrome and result in significantly elevated lifetime risk of ovarian cancer. Risk reduction interventions are presently the only effective means of improving survival and specialized counselling clinics have been established as an effective means of aiding this population in navigating complex decisions surrounding these interventions. This study sought to evaluate patient perceptions of a specialized counselling clinic for patients with HBOC Syndrome and referral patterns to this clinic.MethodsWe completed a retrospective review of 200 patients with HBOC in Nova Scotia, Canada seen through Maritime Medical Genetics Services between 2006 and 2016. Data were collected on referral pattern to the Hereditary Gynaecologic Risk Reduction Clinic (HGRRC), demographics, health history, and uptake of risk-reducing interventions. Participants were invited to complete a questionnaire about their experience.Results156/200(78%) women were referred to HGRCC and 135/156 (85.9%) of those referred attended their appointment. 124/200 (62%) were over age 40 at the time of testing. The mean time from referral to HGRCC appointment was 134.68 days (SD 85.78). 85/135 (63%) underwent risk-reducing bilateral salpingo-oophorectomy following their HGRCC appointment. The questionnaire was completed by 94/188 (50.3%) women. Most participants found information received from genetics clinics (81/94; 91%) and genetic counsellors (87/94; 95%) most helpful in making choices around risk-reduction strategies. 83/94 (88%) participants felt they had sufficient information to make an informed decision.ConclusionThe majority of women with HBOC in Nova Scotia during the study period were referred to and counselled through HGRRC. Genetic counselling was found most valuable in risk-reduction decision making, which highlights the importance of a multidisciplinary team. Patients viewed this clinic as an effective care model to support informed choice about risk-reducing intervention.

Abstract 806: Interrogating chromosomal instability in the earliest steps of ovarian cancer development

Abstract Ovarian Cancer is the deadliest gynecologic malignancy. Despite recent advances in cancer diagnostics, it is a cancer that is often detected late. After treatment with debulking surgery and chemotherapy, 80% of patients have tumor relapse. 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 the origins of HGSC is likely within secretory cells of the fimbriae in the fallopian tube. This is based on numerous lines of correlative evidence including the identification of abnormal regions in the fallopian tube called serous tubal intraepithelial cancer (STIC) in 10-15% of patients undergoing RRSO, and the presence of STIC in 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 understand the early genomic and signaling events in the development of HGSC, we are interrogating FFPE 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 disease with STIC. We have performed a pilot experiment of 20 patient samples of different genetic backgrounds. Intriguingly, cGAS signaling was observed only rarely in the STICs indicating low rates of CIN in STICs, however we note that even in early invasive disease, we observe cGAS positivity. Moreover, we observe robust CD8+ T cell localization to early invasive disease. 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 with early immune recognition that is lost in invasive disease. We propose a model of ovarian cancer development where fallopian tube secretory transition from a p53 WT SCOUT to p53 mutant state STIL acquire a proliferative capacity forming a STIC and then develop CIN transitioning to invasive disease. Citation Format: Duaa Hassan Al-Rawi, Herman Chui, Sorhab Shah, Samuel Bakhoum. Interrogating chromosomal instability in the earliest steps of ovarian cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 806.

Hysterectomy as a risk-reducing procedure in BRCA1 and BRCA2 women.

10611 Background: BRCA1/2 pathogenic variants (PV) are associated with an increased lifetime risk of developing several malignancies, particularly breast (BC) and ovarian (OC) cancers. The association between BRCA1/2 and endometrial cancer (EC) is controversial. Therefore, adding hysterectomy (HT) to risk-reducing (RR) bilateral salpingo-oophorectomy (BSO) is of uncertain benefit. In our multidisciplinary group this decision is personalized and takes in account other gynaecological pathologies or, for BC survivors, tamoxifen treatment. Objectives of this study are to assess the risk of EC on BRCA1/2 families registered in our program and to discuss the role of prophylactic HT in BRCA1/2 carriers. Methods: Pathologic confirmed EC cases were extracted from the prospective follow up cohort of 949 women diagnosed with a BRCA1/ 2 PV through the hereditary breast, ovarian and prostate program at our centre. Data was collected from the medical records. Results: Of the 949 women, 345 (36.3%) were diagnosed with a BRCA1 PV, 603 (63.5%) with a BRCA2 PV and 1 (0.1%) with PV in both genes. Of all women, 648 (68.3%) had a previous cancer diagnosis while 291 (30.7%) were in primary risk management. Excluding non-melanoma skin cancer, EC was the fourth most frequent neoplasia: BC (553, 85.3%), ovarian, fallopian and peritoneal cancer (117, 18.1%), thyroid cancer (15, 2.3%) and EC (8, 1.2%). BSO with HT was performed in 372 (39.1%) women: RR in 259 (69.6%; BRCA1 36.7%, BRCA2 63.3%, history of cancer 75.7%, no history of cancer 24.3%) and therapeutic in 113 (30.4%; ovarian/fallopian cancer 92.0%, uterine cancer 8.0%). BSO alone was performed in 174 (18.3%), being RR in 170 (97.7%; BRCA1 34.7%, BRCA2 65.3%, history of cancer 72.9%, no history of cancer 27.1%). HT alone was performed in 3 (benign disease). Regarding family phenotype, we found another 2 cases of EC in possible BRCA carriers. For these 10 cases of EC, median age of diagnosis was 58.5 years (42-75), 7 in BRCA1 and 3 in BRCA2 patients (pts). Pathology: endometrioid (5), serous (1), mixed (2, 1 endometrioid and serous and 1 endometrioid, squamous cell and seromucous) and carcinosarcoma (2). Six (out of 10) pts had previous BC: 4 BRCA1 (2 triple negative, 2 luminal-like) and 2 BRCA2 (2 luminal-like), 4 of them had previous tamoxifen use (2 BRCA1, 2 BRCA2). In 1 case the diagnosis of EC occurred after RR BSO ( BRCA1, no tamoxifen use) and another during the RR surgery ( BRCA2, tamoxifen use). There was no significant association of EC with BRCA1 or BRCA2 (two-sided p= 0.149). EC was the cause of dead in 5 pts (50%), all BRCA1. Conclusions: EC was the fourth most frequently cancer registered in our cohort of BRCA1/2 women. BRCA1 women, representing around 1/3 of all cohort, had 70% of all EC diagnoses. This apparent excess of BRCA1 EC diagnoses was not statistically significant. Tamoxifen may be a confounding factor. While an association was not confirmed at this time, our data also reinforces the need to discuss HT with our BRCA1/2 pts.

Heart toxicity effects (HTE) of anthracyclines-containing regimens (ACRs) in patients with breast cancer (BC) carrying mutational signature of homologous recombination deficiency (HRD).

10519 Background: BRCA1/2 genes ( BRCA) play a prominent role in the Homologous Recombination Repair (HRR) pathway. Following the technological progress and deeper knowledge on BRCA-related cancers, the demand for genetic testing is rapidly increasing. Beyond BRCA1/2, other genes are involved in the HRR, including ATM, PALB2, RAD51, and BARD1. Due to the important role in the cellular repair process, deleterious variants in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. The role of BRCA1/2 as predisposing condition to cardiac dysfunction is debated, and the contribution by no- BRCA genes is still unknown. Methods: This is a multicenter, retrospective, study to investigate the risk of heart-insults from anthracyclines on adjuvant setting in BC patients carrying germline pathogenic or likely pathogenic variant (PV) (classes IV and V) in BRCA and no- BRCA HRR pathway genes. We collected genetic and clinical data, and evaluated the left ventricular ejection fraction (LVEF) at cardiac ultrasound, before starting ACR therapy, and at subsequent time points, according to clinical indications. Results: Three hundred and sixty (360) BC patients, aging 22 to 80, were included in this study; 131 patients were carriers of germline PVs in HRR pathway genes: 52 in BRCA1 gene (39.7%), 48 in BRCA2 gene (36.6%), and 31 harbored PVs in no- BRCA HRR pathway genes (23.7%), including PVs in PALB2, CHEK2, ATM, RAD51C, RAD50 and BARD1 genes. In the cohort of 229 patients without PVs, 47 showed variant of uncertain significance (VUS, class III), and 173 had genetic testing not informative. When LVEF between the groups was compared, the difference was not significant for the pre-treatment values. Notably, individuals carrying BRCA or other HRR gene deleterious variants, showed a statistically significant reduction of LVEF &gt; 5% at the second time-point (3 month), compared to the LVEF pre-treatment values (p = 0.001). A marked LVEF reduction was in mutated patients treated with risk-reducing bilateral salpingo-oophorectomy prior to age 40, body mass index &gt; 25, and type-II diabetes mellitus. The latter risk factor was probably related to increased risk developing insulin-resistance reported for BRCA-mutated patients. Conclusions: Our data suggest that PVs in BRCA or other genes involved in HRR pathway, can lead to impaired homologous recombination, thus increasing sensitivity of cardiac cells to DNA damaging chemotherapy in BC patients. In this subgroup of patients, other measurements such as the global longitudinal strain (GLS), and a more in-depth assessment of risk factors, could be proposed to optimize cardiovascular risk-management and to improve long-term survival.

Uptake Rates of Risk-Reducing Surgeries for Women at Increased Risk of Hereditary Breast and Ovarian Cancer Applied to Cost-Effectiveness Analyses: A Scoping Systematic Review.

Simple SummaryFor women who have tested positive for BRCA mutations, the decision to make use of preventive surgical options, such as risk-reducing mastectomy (RRM) or risk-reducing bilateral salpingo-oophorectomy (RRSO), depends on the women’s personal preferences and the cultural/social context. Among others, the cost-effectiveness of RRM and RRSO can be affected by the uptake rate of these preventive surgical options. Uptake rates of surgery should be given more attention in the conceptualization of health economic modeling studies for RRM and RRSO. Prospective multicenter studies are recommended to reflect regional and national variations in women’s preferences for preventive surgery.The cost-effectiveness of genetic screen-and-treat strategies for women at increased risk for breast and ovarian cancer often depends on the women’s willingness to make use of risk-reducing mastectomy (RRM) or salpingo-oophorectomy (RRSO). To explore the uptake rates of RRM and RRSO applied in health economic modeling studies and the impact of uptake rates on the incremental cost-effectiveness ratios (ICER), we conducted a scoping literature review. In addition, using our own model, we conducted a value of information (VOI) analysis. Among the 19 models included in the review, the uptake rates of RRM ranged from 6% to 47% (RRSO: 10% to 88%). Fifty-seven percent of the models applied retrospective data obtained from registries, hospital records, or questionnaires. According to the models’ deterministic sensitivity analyses, there is a clear trend that a lower uptake rate increased the ICER and vice versa. Our VOI analysis showed high decision uncertainty associated with the uptake rates. In the future, uptake rates should be given more attention in the conceptualization of health economic modeling studies. Prospective studies are recommended to reflect regional and national variations in women’s preferences for preventive surgery.

Needleoscopic-assisted risk-reducing bilateral salpingo-oophorectomy in BRCA1/2 mutation carriers: Peri-operative outcomes and psychological impact

ObjectiveTo investigate the role of needleoscopic-assisted laparoscopy in terms of surgical impact and psychological outcomes in RR-BSO for BRCA1/2 patients. Study designProspective monocentric trial conducted at the Division of Gynecologic Oncology, “Fondazione Policlinico Universitario A. Gemelli” IRCSS in Rome.Between March 2016 and March 2018, 26 consecutive patients were prospectively enrolled in the study and underwent RR-BSO. Peri-operative surgical variables were collected.The psychological interview was performed at the discharge and during the first post-operative follow-up visit (between 30 and 60 days after surgery). ResultsWe reported a median OT of 18.5 min (range, 15–37), a median EBL of 0 mL (0–20), and no conversion to laparoscopy or laparotomy.The median VAS score was “at rest” of 2, 3, and 1; while under “Valsalva maneuver” was 4, 3, 2, respectively at 2, 4, and 24 h.77% (20/26) of the whole population had a previous diagnosis of breast cancer.All patients expressed great cosmetic satisfaction both at discharge and after 30/60 days, with an 84.6% of score 5 and a 15.4% of score 4.The highest number of “score 5”, concerning the cosmetic outcomes, were clustered in the subgroup of breast cancer survivors with a 95% of score 5 versus 50% of score 5 in patients with no previous breast cancer (p = 0.0073).Similarly, the maximal psychological advantage of the ultra-MIS approach was revealed in the breast cancer survivors (70% of score 5 versus 16% of score 5, p = 0.02). ConclusionsThe use of 2.4 mm instruments raises the possibility of decreasing post-operative incisional pain, reducing hospitalization, and ensuring better cosmetic and psychological outcomes without increasing complications.The full psychosomatic benefit of ultra-MIS within BRCA mutation carriers is revealed in breast cancer survivors, probably due to the comparison with the mutilating and invasive previous breast surgery.

Risk-Reducing Options for High-Grade Serous Gynecologic Malignancy in BRCA1/2.

Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignancy. Breast Cancer Susceptibility Gene 1 (BRCA 1) and Breast Cancer Susceptibility Gene 2 (BRCA 2) germline mutations confer an estimated 20 to 40 times increased risk of OC when compared to the general population. The majority of BRCA-associated OC is identified in the late stage, and no effective screening method has been proven to reduce mortality. Several pharmacologic and surgical options exist for risk-reduction of gynecologic malignancy in BRCA 1/2 mutation carriers. This review summarizes up-to-date research on pharmacologic risk-reducing interventions, including the oral contraceptive pill, acetylsalicylic acid/nonsteroidal anti inflammatory drugs (ASA/NSAID) therapy, and denosumab, and surgical risk-reducing interventions, including risk-reducing bilateral salpingo-oophorectomy, salpingectomy with delayed oophorectomy, and hysterectomy at the time of risk-reducing bilateral salpingo-oophorectomy.

Evaluation of two evidence-based decision aids for female BRCA1/2 mutation carriers in Germany: study protocol for a randomised controlled parallel-group trial

BackgroundWomen with BRCA1/2 mutations have a higher risk of developing breast and ovarian cancer compared to women of the general population. Various preventive options are available to deal with the increased risk of developing cancer. These include intensified breast cancer screening and risk-reducing bilateral mastectomy and salpingo-oophorectomy. The choice of a preventive option can lead to increased decisional conflict. To support these women in their decision-making process, two evidence-based decision aids were developed in an upstream research process and adapted to the German healthcare context. These will be evaluated within a randomised controlled trial (RCT) in terms of their effects on decision-making, women’s level of information and psychological outcome variables.MethodsA sample of 310 women carrying BRCA1/2 mutations (A) without a history of cancer or (B) with a history of unilateral breast cancer who have received post-test genetic counselling will be enrolled. Upon study consent, women will be randomly assigned to either the intervention or the control group. All participants will receive standard care including a physician’s letter summarising the counselling content. After baseline data collection (t0), the intervention group receives the respective decision aid while the control group receives standard care only. The primary outcome variable assessed at a 3-month follow-up (t1) is the change of extent in decisional conflict (measured with the Decisional Conflict Scale). Secondary outcome variables comprise the stage of decision-making, self-reported symptoms of anxiety, depression and stress due to the genetic test result, and knowledge regarding cancer risks and preventive options. At t1, the extent of preparation for decision-making and acceptability of the decision aids will also be examined. Another secondary outcome variable assessed at 6-month follow-up (t2) is the extent of decision regret.DiscussionThese will be the first decision aids available for BRCA1/2 mutation carriers in Germany to be evaluated regarding their effectiveness and acceptability in clinical use within an RCT. Subsequently, they are to be integrated into the care concept of the centres of the German Consortium for Hereditary Breast and Ovarian Cancer and the affiliated breast centres.Trial registration {2a}DRKS DRKS00015823. Retrospectively registered on 14 June 2019