Immunohistochemical and molecular pattern of p53 in epithelial ovarian cancers negative for germline BRCA1/2 variants.

Epithelial ovarian cancers (EOC) associated with germline or somatic BRCA pathogenetic variants have a significantly higher rate of TP53aberrations. The majority of TP53 mutations are detectable by immunohistochemistry and several studies demonstrated that an abnormal p53 pattern characterized high-grade EOCs. An abnormal p53 immunohistochemical staining in fallopian tube (serous tubal intraepithelial carcinoma (STIC) and "p53 signature" is considered as a precancerous lesion of high-grade EOCs and it is often found in fallopian tube tissues of BRCA germline mutated patients suggesting that STIC is an early lesion and the TP53 mutation is an early driver event of BRCA mutated high-grade EOCs. No relevant data are present in literature about the involvement of p53 abnormal pattern in EOC carcinogenesis of patients negative for germline BRCA variants. We describe TP53 mutation results in relationship to the immunohistochemical pattern of p53 expression in a series of EOCs negative for BRCA1 and BRCA2 germline mutations. In addition, we also investigated STIC presence and "p53 signature" in fallopian tube sampling of these EOCs. Our results demonstrate that TP53 alterations are frequent and early events in sporadic EOCs including also low-grade carcinomas. Also in this series, STIC is associated with an abnormal p53 pattern in fallopian tubes of high-grade EOCs. In summary, TP53 aberrations are the most frequent and early molecular events in EOC carcinogenesis independently from BRCA mutation status.

Prognostic Value of the Immunohistochemical Expression of RAD51 and BRCA2 in Gastric Adenocarcinoma.

Current scientific literature lacks data on the prognostic value of the expression of RAD51 and BRCA2 in gastric adenocarcinoma. Therefore, we aimed to evaluate those and other homologous recombination-related proteins (ATM, ATR, BRCA1, CHK2, γH2AX, p53) in gastric cancer, assessing their correlation with clinical prognosis. Paraffin-embedded samples were obtained from surgical specimens collected in total or subtotal gastrectomy procedures. Between 2008 and 2017, 121 patients with advanced gastric adenocarcinoma underwent surgical resection and were included in this study. Negativity for nuclear RAD51 correlated with vascular invasion, lymph node metastasis, larger tumor size, and lower overall survival and disease-free survival in univariate analysis. However, nuclear RAD51-negative cases presented better response rates to adjuvant therapy than the positive ones. Nuclear ATR negativity correlated with larger tumor size and a higher histological grade. Positivity for ATM was associated with more prolonged disease-free survival. Positivity for nuclear BRCA2 correlated with lower overall survival and diffuse histological type, whereas its high expression was associated with vascular invasion. Nevertheless, tumors positive for nuclear BRCA2 were more frequently low grade in the intestinal histological type. Our findings indicate that RAD51 and BRCA2 are valuable immunohistochemical prognostic markers in gastric adenocarcinoma.

Assessing frequency and clinical outcomes of BRCA mutated ovarian cancer in Saudi women.

PURPOSE: BRCA gene mutations (BRCAm) have an impact on patients' characteristics and clinical outcomes of ovarian cancer (OC). The frequency and patterns of BRCAm vary among countries and ethnicities. There are limited data from Saudi Arabia (SA); thus, this study aims to determine the frequency, pattern, and impact on patient characteristics and outcomes of BRCAm OC compared to wild-type BRCA (BRCAw) in Saudi women. METHODS: This retrospective study evaluated women diagnosed with non-mucinous OC, fallopian tube, or peritoneal carcinoma who had BRCA status tested in an accredited lab between January 2016 and December 2017. The associations between various parameters and BRCAm were estimated using logistic regression. Statistical analysis performed with SPSS (Version 27). RESULT: Sixty-one women with a median age of 52 at diagnosis were analyzed. Germline BRCA mutations were found in 41% of cases (25/61). The most common deleterious germline BRCA1 mutation was c.1140dupG (39%). Most women (72%) had no family history of cancers and 82% had advanced stage. Regardless of BRCA mutations, an optimal overall response rate (ORR) to first-line treatment has been achieved although most cases relapsed (84%) and the majority were platinum-sensitive relapse (85%). Higher ORR to subsequent lines and better survival were obtained in women with BRCA-mutation. CONCLUSION: The prevalence of BRCAm of OC was higher in Saudi women compared to regional and most of the international figures. The better clinical outcomes of BRCAm women agreed with the reported evidence. Further studies on BRCA mutations of OC and genetic counseling are highly recommended. TRIAL REGISTRATION: Trial approved by the Institutional Review Board of King Faisal Specialist Hospital and Research Center (RAC # 2171137) and conducted at King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11,211, Saudi Arabia.

Creating Breast and Gynecologic Cancer Guidelines for Transgender Patients With BRCA Mutations.

More than 1.5 million individuals in the United States identify as transgender. Transgender individuals have lower rates of health care utilization and higher rates of health care discrimination than cisgender patients. With a growing interest in providing comprehensive and compassionate care to the transgender community, there has been a concurrent increase in research on transgender health. However, lack of long-term data limits understanding the effects of hormone therapy on cancer risk factors in this population. This is particularly relevant for patients with hormonally mediated cancers and those at elevated risk from hereditary breast and ovarian cancer syndromes. Few cancer-screening and management guidelines currently exist for this population. Specific practices guided by the nuances of gender identity and gender-affirming care are essential to improve clinical management and to avoid further alienating a population that is already marginalized from the health care system. This commentary summarizes screening, management, and surveillance strategies devised for cisgender patients to offer corresponding recommendations tailored for transgender BRCA mutation carriers. In doing so, it highlights critical unanswered questions pertaining to the care of these patients. To address these questions, we must prioritize this population and adopt more inclusive frameworks in medicine and research.

Tumor BRCA testing in ovarian cancer and EQA scheme: our experience of a critical evaluation.

Next generation sequencing (NGS) is a widespread molecular biology method integrated into clinical practice to detect genetic variants, for diagnostic and prognostic purposes. The scheduled external quality assessments (EQA) is integral part of clinical molecular laboratory quality assurance. The EQA provides an efficient system to compare analytic test performances among different laboratories, which is essential to evaluate consistency of molecular test. EQA failures demands targeted corrective action plans. In this context, the complexity of the NGS techniques requires careful and continuous quality control procedures. We report a tumor BRCA1/2 (tBRCA) testing benchmark discrepancy provided by the European Molecular Genetics Quality Network in our laboratory during a round of EQA for somatic mutation testing of BRCA genes in relation to ovarian cancer. The critical analysis emerging from the tBRCA EQA is presented. We underline that harmonization processes are still required for the EQA in the molecular biology field, especially if applied to the evaluation of methods characterized by high complexity.

Vaginal NOTES approach for risk-reducing salpingo-oophorectomy in BRCA mutation carriers: A video demonstration.

Risk-reducing bilateral salpingo-oophorectomy (BSO) is an important option to prevent the development of ovarian and fallopian tube cancers in women with a BRCA1/2 mutation. Conventional laparoscopy is the current preferred technique since it is associated with less morbidity compared to laparotomy. Transvaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) is a new minimally invasive technique that allows access to the peritoneal cavity through the vagina without skin incisions. The vNOTES technique for risk-reducing BSO is presented herein. This article includes a narrated, step-by-step video demonstration of the entire procedure. Risk-reducing BSO using the vNOTES approach is a feasible technique that appears to be simple, safe, and reproducible. This technique has the potential to improve patients' surgical experience and provide good long-term functional and cosmetics outcomes. This technique needs to be further evaluated and compared to the conventional laparoscopic approach.

Caracterización epidemiológica del cáncer de mama / Epidemiological characterization of cancer breast

Con el objetivo de realizar la caracterización epidemiológica del cáncer de mama de las pacientes que asisten a la consulta externa de ginecología oncológica en el Instituto Guatemalteco de Seguridad Social (IGSS) de enero a marzo de 2,018, se realizó un estudio descriptivo transversal en 155 pacientes que acudieron a la clínica de mama del Hospital de Gineco Obstetricia del IGSS, con una media de edad de 62 años, el adenocarcinoma ductal infiltrante es el tipo histológico más frecuente en nuestra población tanto en edad reproductiva como en menopausia. Como factor protector el 69% dio lactancia materna. La etapa clínica más comúnmente diagnosticada es IIA. El Luminal A, el más frecuentemente diagnosticado por inmunohistoquímica, seguido del Luminal B y HER2neu. Se diagnostican pacientes mayormente en etapas clínicas tempranas (I y II).

In order to carry out the epidemiological characterization of breast cancer in patients attending the outpatient gynecology oncology consultation at the Guatemalan Social Security Institute (IGSS) from January to March 2018, a descriptive cross-sectional study was carried out in 155 patients who attended the breast clinic of the IGSS Obstetrics Gynecology Hospital, with a mean age of 62 years, infiltrating ductal adenocarcinoma is the most frequent histological type in our population both in reproductive age and in menopause. As a protective factor, 69% breastfed. The most diagnosed clinical stage is IIA. Luminal A, the most frequently diagnosed by immunohistochemistry, followed by Luminal B and HER2neu. Patients are diagnosed mostly in early clinical stages (I and II).

Implementing NGS-based BRCA tumour tissue testing in FFPE ovarian carcinoma specimens: hints from a real-life experience within the framework of expert recommendations.

AIMS: Next Generation Sequencing (NGS)-based BRCA tumour tissue testing poses several challenges. As a first step of its implementation within a regional health service network, an in-house validation study was compared with published recommendations. METHODS: Epithelial ovarian cancer (EOC) formalin-fixed paraffin-embedded specimens stored in the archives of the eight regional pathology units were selected from a consecutive series of patients with known BRCA germline status. Two expert pathologists evaluated tumour cell content for manual macrodissection. DNA extraction, library preparation and NGS analyses were performed blinded to the germinal status. Parameters used in the study were confronted with guidelines for the validation of NGS-based oncology panels and for BRCA tumour tissue testing. RESULTS: NGS analyses were successful in 66 of 67 EOC specimens, with good quality metrics and high reproducibility among different runs. In all, 19 BRCA pathogenic variants were identified: 12 were germline and 7 were somatic. A 100% concordance with blood tests was detected for germline variants. A BRCA1 variant showed a controversial classification. In different areas of two early stage EOCs showing somatic variants, intratumour heterogeneity not relevant for test results (variant allele frequency >5%) was observed. Compared with expert recommendations, main limitations of the study were absence of controls with known somatic BRCA status and exclusion from the validation of BRCA copy number variations (CNV). CONCLUSIONS: A close collaboration between pathology and genetics units provides advantages in the implementation of BRCA tumour tissue testing. The development of tools for designing and interpreting complex testing in-house validation could improve process quality.

BRCA gene testing in women with high-grade serous ovarian carcinoma.

The objective of this study was to compare the pick-up rate of pathogenic BRCA variants in those with a high-grade serous ovarian carcinoma (HGSOC) undergoing oncology-led testing with the traditional genetics family history-based testing model. With novel therapies, BRCA status can affect treatment. Welsh oncologists are now testing all women with HGSOC at diagnosis rather than referring to genetics, where family history is required for testing. The records of 332 women who underwent testing via oncology were analysed. The outcome measures were; percentage of women with a pathogenic BRCA variant and the difference in identification of pathogenic BRCA variants between the oncology-led and traditional genetics testing models. Of the 332 women, 25 women (7.5%) tested positive for a pathogenic BRCA variant. This was slightly lower than the detection rate of 9.8% for patients tested via the genetics service over the same period. Testing through genetics, using family history criteria would have identified only 19 (76%) of those with pathogenic variants in the oncology cohort. Since women with a pathogenic BRCA variant can be offered life-extending targeted treatment and a significant proportion of these women would be missed if testing was offered based on family history criteria alone, universal BRCA testing of all women with HGSOC is justified.Impact statement:What is already known on this subject? It is well established that individuals with a strong family history of breast and ovarian cancer are more likely to carry a pathogenic BRCA gene variant. With the use of tools such as the Manchester scoring system women are often invited for testing through clinical genetics services. Until recently there was no clinical impact for those already diagnosed with ovarian cancer.What do the results of this study add? Our study has shown that the diagnosis of high grade serious ovarian carcinoma alone without the need for any family history leads to a similar rate of detection of pathogenic BRCA variants as traditional methods. With the advent of targeted treatments such as olaparib, women with a pathogenic BRCA variant can access different life extending treatment options. With comparable pick-up rates to traditional family history based scoring systems, oncologists can now arrange BRCA gene testing directly.What are the implications of these findings for clinical practice and/or further research? Our study shows universal genetic testing of those with high-grade serious ovarian carcinoma by oncologists allows more women to access life extending treatment in a shorter timeframe compared to the traditional testing model used by clinical genetics services. We hope that other centres, both in the UK and beyond, will adopt this approach.

Advances in epithelial ovarian cancer.

BACKGROUND: Most epithelial ovarian cancer occurs in older women, with a mean age at diagnosis of 62 years and an overall five­year survival rate in Australia of 43%. Most women are diagnosed with advanced disease of high-grade serous type with 20-30% five-year survival; 70% relapse within three years of initial treatment. There is no available screening test for ovarian cancer. OBJECTIVE: The aim of this article is to highlight current management and future directions for women diagnosed with epithelial ovarian cancer, particularly the high incidence of underlying genetic mutations and new options for treatment. DISCUSSION: Risk-reducing surgery with bilateral salpingo-oophorectomy is recommended for women at high risk of developing ovarian cancer. Ovarian cancer treatment still centres on surgery and chemotherapy, with aggressive cytoreductive techniques and intraperitoneal treatments being evaluated in advanced disease. Molecular targeting agents are revolutionising treatment options, particularly the poly adenosine diphosphate-ribose polymerase inhibitors, and especially for patients with an underlying BRCA mutation. Other molecular targeting agents, such as vascular endothelial growth factor (VEGF) receptor inhibitors and newer approaches using immunotherapy and molecular targeting, aim to individualise treatment and improve survival in the future.

BRCA1 and BRCA2 Gene Mutations and Lung Cancer Sisk: A Meta-Analysis.

Background and objective: BRCA1 and BRCA2 are associated with many cancer types in addition to hereditary breast and ovarian cancers. However, their relation to lung cancer remains to be explored. Materials and Methods: Observation studies were systematically reviewed to explore the association of BRCA1 or BRCA2 with lung cancer. PubMed, MEDLINE [EBSCOhost], and relevant articles published up to 7 January 2020 were searched. Odd ratio (OR), standardized morbidity rate (SMR), and cancer-specific standardized incidence ratios (SIRs) were pooled together as relative risk (RR) estimates (95% confidence interval [CI], 0.66-1.40). Results: Thirteen studies were included for analysis. Results showed that the RR of BRCA2 is 0.76 (95% CI, 0.48-1.19), the overall RR is 0.96 (95% CI, 0.66-1.40), and that of BRCA1 is 0.66 (95% CI, 0.41-1.05), indicating that it was not associated with lung cancer. Conclusion: With the limitation of the retrospective study design and severe heterogeneity, these results inform clinicians and relevant families that BRCA1 and BRCA2 mutation carriers have no increased risk of lung cancer.

Low BRCA2 expression predicts poor prognoses in patients with rectal cancer receiving chemoradiotherapy.

OBJECTIVE: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is now the standard care for patients with advanced rectal cancer. Because a certain proportion of these patients have poor response to CCRT, the risk stratification of survival outcomes needs to be investigated. DNA repair responses in tumor cells can regulate malignant potential and therapy resistance. In this study, we analyzed the clinical significance of principal DNA repair effectors in patients with rectal cancer. METHODS: We applied data mining for DNA repair pathways in a published transcriptome for rectal cancer cases, and identified that tumors with BRCA2 downregulation correlated with poor response to CCRT. We next examined BRCA2 expression by using immunohistochemistry staining in tumor tissues of 172 patients with rectal cancer. The correlation between BRCA2 expression levels and clinical variables was further analyzed in this rectal cancer cohort. RESULTS: Among clinical and pathological factors, low BRCA2-expression was significantly correlated with higher pre-treatment (Tx) tumor status (P = .013), post-Tx tumor (P < .001) and nodal status (P = .044), vascular invasion (P = .008), and poor tumor regression grades (P < .001). In analyses of survival outcomes, patients with low BRCA2-expression were associated with shorter local recurrence-free survival (LRFS; P = .0005) and disease-specific survival (P = .0269). Multivariate analyses confirmed the independent prognostic value of low BRCA2-expression for shorter LRFS (P = .045, hazard ratio = 4.695). CONCLUSION: Low BRCA2-expression is a significant predictor for tumors in advanced stages, poor response to CCRT, and shorter survivals in patients with rectal cancer. Poly (adenosine diphosphate-ribose) polymerase inhibitors targeting DNA repair response in cells have demonstrated clinical efficacy in BRCA2-mutated patients with cancer. Further studies evaluating the efficacy of CCRT combined with these inhibitors in low BRCA2-expressing rectal cancers are encouraged.

Germline BRCA Mutation Rates in Latina Women Presenting for Gynecologic Oncology Care.

OBJECTIVE: Germline BRCA mutation rates in the Latina population are yet to be well described. We aimed to quantitate the rates of referral for genetic testing in qualifying women and testing completion rates in a population of women presenting for gynecologic oncology care. Results were then stratified by ethnic/racial background. METHODS: Charts of new patients evaluated at a comprehensive cancer center in Southern California were reviewed. Patients qualifying for genetic testing in accordance with NCCN Guidelines version 1.2017 for breast and/or ovarian cancer genetic assessment were identified. The actual rates of prescriptions for genetic testing placed, testing completion rates, test results, as well as patients' family history were abstracted. Data were analyzed with chi-square tests. RESULTS: Five hundred and seventy-two of 2,053 patients met testing criteria, and 256/572 (45%) were prescribed testing in accordance with the guidelines. By ethnicity, testing was prescribed in 44% of Non-Hispanic White (NHW), 44% of Latina, 46% of African-American, and 60% of Asian (p = 0.6) patients. Testing was completed in 65% of NHW, 66% of Latina, 65% of African-American, and 67% of Asian patients (p = 0.97). Completion rates were low overall: 28% of those who met testing criteria were tested (p = 0.85). Pathogenic BRCA mutations were found in 29% of NHW and 21% of Latina, 45% of African-American, and 20% of Asian patients (p = 0.4). CONCLUSIONS: There was no difference by ethnicity in rates of testing prescription, completion, or presence of BRCA mutations. Overall, testing rates were suboptimal. BRCA mutations were found in large percentage of Latinas (21%). Further studies are underway to identify barriers to testing prescriptions and completion for Latina women.

The association between the methylation frequency of BRCA1/2 gene promoter and occurrence and prognosis of breast carcinoma: A meta-analysis.

OBJECTIVES: Breast cancer susceptibility gene 1/2 (BRCA1/2) is a promising tumor marker in many types of cancer. However, the methylation frequency of BRCA1/2 gene with occurrence risk and survival benefit of patients with breast carcinoma remains controversy. The aim of the present study was to assess the relationship between BRCA1/2 gene promoter methylation and the occurrence and prognosis in breast carcinoma based on a meta-analysis, meanwhile, this article explored the differential expression levels of BRCA1/2 gene promoter methylation in peripheral blood and tumor tissues of breast cancer patients. METHODS: Electronic databases (PubMed, Medline, Cochrane Library, and CNKI) were searched up to June 2019. The number of BRCA1/2 promoter methylation-positive and -negative patients in breast carcinoma patients were measured, and hazard ratio (HR) with 95% confidence interval (CI) for the association between BRCA1/2 gene promoter methylation and the prognosis of breast carcinoma patients. Primary end points were presence of breast cancer, overall survival (OS), disease-free survival (DFS). Statistical analysis was performed with STATA 12.0. RESULTS AND CONCLUSIONS: Fifty-eight articles including 19,084 individuals met full eligibility criteria. We observed that the frequency of BRCA1 gene promoter methylation was higher in breast cancer tissues compared with normal tissues, and the prognostic analysis suggested that BRCA1 gene promoter methylation was significantly associated with poor overall survival and poor disease-free survival. This study also verified that there was no statistically significant difference in the methylation frequency of BRCA1 gene promoter between peripheral blood and tumor tissues in breast cancer patients, which suggests that the detection of BRCA1 promoter methylation in peripheral blood may be a non-invasive and rapid way to monitor the occurrence breast cancer.

[Hereditary breast and ovarian cancer syndrome: Diagnosis and therapeutic implications]. / Syndrome héréditaire de prédisposition au cancer du sein et de l'ovaire : diagnostic et implications thérapeutiques.

Patients who carry the BReast Cancer 1 or 2 (BRCA) gene mutations have an underlying hereditary predisposition for breast and ovarian cancers. These deleterious genetic mutations are the most common ones implicated in hereditary breast and ovarian cancers. Oncogenetic counselling plays a key role in identifying patient for BRCA testing and for mutation identification. BRCA1/2 carriers have to be followed up regularly and may justify breast and/or adnexal prophylactic surgery, according to the French National Cancer Institute guidelines (INCa). Poly- (DNA-riboses) polymerases inhibitors, notably olaparib, have a major role in the management of epithelial ovarian cancer in patients with BRCA mutation and many studies are ongoing to expand their indications in a near future.

"How do we rally around the one who was positive?" Familial uncertainty management in the context of men managing BRCA-related cancer risks.

RATIONALE: Men with BRCA-related cancer risks face increased disease risk as well as the prospect of passing on their risk to children. OBJECTIVE: This study investigates men's communicative appraisal and management of uncertainty related to BRCA-related cancer risks and decision-making. METHODS: Guided by uncertainty management theory (UMT), a directed content analysis approach was utilized to analyze interviews with 25 men who either carry a pathogenic BRCA variant or have a 50% chance of carrying a variant but have not yet been tested. RESULTS: Participants appraised their individual uncertainty as irrelevant or dangerous but appraised their familial uncertainty as dangerous. Men appraising their uncertainty as a danger exhibited more proactive information seeking healthcare behaviors-such as genetic testing and following recommended screenings-than men who appraised their uncertainty as irrelevant. Participants appraised familial uncertainty as a danger and were engaged in information management with family members, as well as encouraging family members to engage in proactive healthcare decision-making. CONCLUSIONS: Men with BRCA-related cancer risks lack understanding about their risks and how to manage them. Increased attention should be paid to the development of interventions tailored specifically to men. Further, interventions focusing on strategically developing proactive family communication behaviors would also be beneficial to men and their families.

Breast cancer.

Breast cancer is the most frequent malignancy in women worldwide and is curable in ~70-80% of patients with early-stage, non-metastatic disease. Advanced breast cancer with distant organ metastases is considered incurable with currently available therapies. On the molecular level, breast cancer is a heterogeneous disease; molecular features include activation of human epidermal growth factor receptor 2 (HER2, encoded by ERBB2), activation of hormone receptors (oestrogen receptor and progesterone receptor) and/or BRCA mutations. Treatment strategies differ according to molecular subtype. Management of breast cancer is multidisciplinary; it includes locoregional (surgery and radiation therapy) and systemic therapy approaches. Systemic therapies include endocrine therapy for hormone receptor-positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, bone stabilizing agents, poly(ADP-ribose) polymerase inhibitors for BRCA mutation carriers and, quite recently, immunotherapy. Future therapeutic concepts in breast cancer aim at individualization of therapy as well as at treatment de-escalation and escalation based on tumour biology and early therapy response. Next to further treatment innovations, equal worldwide access to therapeutic advances remains the global challenge in breast cancer care for the future.

Genomics and breast cancer screening.

Many women fear the risk of developing breast cancer, and some women have increased fear because of their family history. Thankfully, the study of genetics has brought forth tools to better identify women at risk. An understanding of genetics and cancer has led to genetic testing protocols which enable at-risk women to take preventative action through medication, surgery, and intensive screenings. These protocols not only have the potential to prevent cancer but also lead to early detection. Appropriate screening for women at risk for genetic breast cancer is essential for patient care. These screenings include specific risk assessment tests, genetic counseling, and genetic testing. To provide the best possible care for patients, providers must have a basic understanding of cancer, genetics, screening tests, genetic testing, and available prevention measures.

Risk-Reducing Bilateral Salpingo-Oophorectomy for BRCA Mutation Carriers and Hormonal Replacement Therapy: If It Should Rain, Better a Drizzle than a Storm.

Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer. The most effective strategy to reduce this risk is the bilateral salpingo-oophorectomy, with or without additional risk-reducing mastectomy. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is recommended between age 35 and 40 and between age 40 and 45 years for women carriers of BRCA1 and BRCA2 mutations, respectively. Consequently, most BRCA mutation carriers undergo this procedure prior to a natural menopause and develop an anticipated lack of hormones. This condition has a detrimental impact on various systems, affecting both the quality of life and longevity; in particular, women carrying BRCA1 mutation, who are likely to have surgery earlier as compared to BRCA2. Hormonal replacement therapy (HRT) is the only effective strategy able to significantly compensate the hormonal deprivation and counteract menopausal symptoms, both in spontaneous and surgical menopause. Although recent evidence suggests that HRT does not diminish the protective effect of RRBSO in BRCA mutation carriers, concerns regarding the safety of estrogen and progesterone intake reduce the use in this setting. Furthermore, there is strong data demonstrating that the use of estrogen alone after RRBSO does not increase the risk of breast cancer among women with a BRCA1 mutation. The additional progesterone intake, mandatory for the protection of the endometrium during HRT, warrants further studies. However, when hysterectomy is performed at the time of RRBSO, the indication of progesterone addition decays and consequently its potential effect on breast cancer risk. Similarly, in patients conserving the uterus but undergoing risk-reducing mastectomy, the addition of progesterone should not raise significant concerns for breast cancer risk anymore. Therefore, BRCA mutation carriers require careful counselling about the scenarios following their RRBSO, menopausal symptoms or the fear associated with HRT use.