BRCA1 Carriers Research Articles

Impact of BRCA mutation on the survival and risk of contralateral breast cancer in Asian breast cancer patients.

Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. A total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical-pathologic characteristics, survival, and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2years old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, p < 0.001). The risk of CBC was significantly higher in BRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. Our study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

Missed Breast Cancers on MRI in High-Risk Patients: A Retrospective Case-Control Study.

Purpose: To determine if MRI features and molecular subtype influence the detectability of breast cancers on MRI in high-risk patients. Methods and Materials: Breast cancers in a high-risk population of 104 patients were diagnosed following MRI describing a BI-RADS 4–5 lesion. MRI characteristics at the time of diagnosis were compared with previous MRI, where a BI-RADS 1–2–3 lesion was described. Results: There were 77 false-negative MRIs. A total of 51 cancers were overlooked and 26 were misinterpreted. There was no association found between MRI characteristics, the receptor type and the frequency of missed cancers. The main factors for misinterpreted lesions were multiple breast lesions, prior biopsy/surgery and long-term stability. Lesions were mostly overlooked because of their small size and high background parenchymal enhancement. Among missed lesions, 50% of those with plateau kinetics on initial MRI changed for washout kinetics, and 65% of initially progressively enhancing lesions then showed plateau or washout kinetics. There were more basal-like tumours in BRCA1 carriers (50%) than in non-carriers (13%), p = 0.0001, OR = 6.714, 95% CI = [2.058–21.910]. The proportion of missed cancers was lower in BRCA carriers (59%) versus non-carriers (79%), p < 0.05, OR = 2.621, 95% CI = [1.02–6.74]. Conclusions: MRI characteristics or molecular subtype do not influence breast cancer detectability. Lesions in a post-surgical breast should be assessed with caution. Long-term stability does not rule out malignancy and multimodality evaluation is of added value. Lowering the biopsy threshold for lesions with an interval change in kinetics for a type 2 or 3 curve should be considered. There was a higher rate of interval cancers in BRCA 1 patients attributed to lesions more aggressive in nature.

Outcomes of support groups for carriers of BRCA 1/2 pathogenic variants and their relatives: a systematic review.

People tested positive for BRCA1/2 face an increased risk of cancer; to help them cope with the genetic information received, support to BRCA1/2 families should be continued after testing. Nonetheless how such support should be provided has not been established yet. As a potentially valuable option is represented by support groups, the aim of this systematic review was to assess studies exploring the outcomes of support groups for BRCA1/2 carriers. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021238416). Peer-reviewed papers published between January 1995 and February 2021 were searched for, using four databases. Among 1586 records identified, 34 papers were reviewed in full-text and eleven were included in the qualitative synthesis of the results. Three themes emerged as major focuses of support groups: risk management decisions, family dynamics and risk communication, and psychosocial functioning. Our findings show that support groups proved helpful in supporting women's decision-making on risk-reducing options. Moreover, during those interventions, BRCA1/2 carriers had the opportunity to share thoughts and feelings, and felt that mutual support through interacting with other mutation carriers help them release the emotional pressure. However, no significant impact was reported in improving family communication. Overall, a high level of satisfaction and perceived helpfulness was reported for support group. The findings suggest that support groups represent a valuable tool for improving BRCA1/2 families care.

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants.

PURPOSETo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.METHODSWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.RESULTSBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.CONCLUSIONIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Evaluation of the indication of BRCA1/2 genetic tests in Iranian women and acceptance rate of risk-reducing surgeries in BRCA mutation carriers.

BackgroundA higher risk for breast and ovarian cancer has been reported in BRCA carriers and prophylactic surgeries are proposed to reduce this risk. This retrospective cohort study has evaluated the indication of BRCA1/2 genetic tests in Iranian women and the rate of women's acceptance of prophylactic surgeries recommended by the surgeon.MethodsMedical records of 147 high‐risk women according to NCCN clinical practice guidelines who referred for BRCA mutations testing were assessed. Individual information, indications for BRCA1/2 genetic testing and their results, physician recommendations, and type of accepted surgery were registered. To evaluate the current status of women an active visit follow‐up every six months was conducted.ResultsThe mean age of women was 43.40 ± 10.94 and the median follow‐up time was 1.92 years. Genetic test results showed 49(33.3%) women were positive for either BRCA1/2 mutations. Although the occurrence of breast cancer younger than 40 was the most common indication for genetic tests (26.5%), positive breast cancer history in first‐degree relatives and two relatives younger than 50 was the most common indications with positive results. The rate of acceptance of prophylactic mastectomy and bilateral salpingo‐oophorectomy was (14.3% and 34.7%) in BRCA mutation carriers.ConclusionIf the onset of breast cancer at a young age (less than 40) will be the only indication for a BRCA analysis, the rate of a positive result (12.8%) is very low. Further studies are warranted to evaluate the age limit for genetic testing in our country. Prophylactic mastectomy acceptance is very low in BRCA1/2 carriers in our centers.

BRCA1 Variant Assessment Using a Simple Analytic Assay.

We previously developed a biological assay to accurately predict BRCA1 (BRCA1 DNA repair associated) mutation status, based on gene expression profiles of Epstein-Barr virus-transformed lymphoblastoid cell lines. The original work was done using whole genome expression microarrays, and nearest shrunken centroids analysis. While these approaches are appropriate for model building, they are difficult to implement clinically, where more targeted testing and analysis are required for time and cost savings. Here, we describe adaptation of the original predictor to use the NanoString nCounter platform for testing, with analysis based on the k-top scoring pairs (k-TSP) method. Assessing gene expression using the nCounter platform on a set of lymphoblastoid cell lines yielded 93.8% agreement with the microarray-derived data, and 87.5% overall correct classification of BRCA1 carriers and controls. Using the original gene expression microarray data used to develop our predictor with nearest shrunken centroids, we rebuilt a classifier based on the k-TSP method. This classifier relies on the relative expression of 10 pairs of genes, compared to the original 43 identified by nearest shrunken centroids (NSC), and was 96.2% concordant with the original training set prediction, with a 94.3% overall correct classification of BRCA1 carriers and controls. The k-TSP classifier was shown to accurately predict BRCA1 status using data generated on the nCounter platform and is feasible for initiating a clinical validation.

Cancer worry among BRCA1/2 pathogenic variant carriers choosing surgery to prevent tubal/ovarian cancer: course over time and associated factors

ObjectiveHigh cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry.MethodsCancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis.ResultsOf all 577 BRCA1/2-PV carriers, 320 (57%) had high (≥ 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis.ConclusionsSome degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support.Clinical trial registrationThe TUBA-study is registered at ClinicalTrials.gov since December 11th, 2014. Registration number: NCT02321228.

Differences in age at diagnosis of ovarian cancer for each BRCA mutation type in Japan: optimal timing to carry out risk-reducing salpingo-oophorectomy.

ObjectiveBRCA1 and BRCA2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) by age 40 and 45, respectively. However, the carriers have a different way of thinking about their life plan. We aimed to investigate the distribution of age at diagnosis of ovarian cancer (OC) patients to examine the optimal timing of RRSO in the carriers.MethodsWe examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received BRCA genetic testing. Among them, germline BRCA1 mutation (gBRCA1m), germline BRCA2 mutation (gBRCA2m) and germline BRCA wild-type (gBRCAwt) were found in 185, 42 and 241 OC patients, respectively.ResultsThe average age at diagnosis of OC in gBRCA1m and gBRCA2m was 51.3 and 58.3 years, respectively, and the difference from gBRCAwt (53.8 years) was significant. The gBRCA2m carriers did not develop OC under the age of 40. The average age was 50.1 years for L63X and 52.8 years for Q934X in BRCA1, and 55.1 years for R2318X and 61.1 years for STOP1861 in BRCA2. The age at diagnosis in L63X or R2318X carriers was relatively younger than other BRCA1 or BRCA2 carriers, however their differences were not significant. With L63X and R2318X carriers, 89.4% (42/47) and 100% (7/7) of women were able to prevent the development of OC, respectively, when RRSO was performed at age 40.ConclusionThere appears to be no difference in the age at diagnosis of OC depending on the type of BRCA common mutation. Further analysis would be needed.

BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis

BackgroundBRCA1 and BRCA2 pathogenic variants (PVs) are associated with prostate cancer (PCa) risk, but a wide range of relative risks (RRs) has been reported.MethodsWe systematically searched PubMed, Embase, MEDLINE and Cochrane Library in June 2021 for studies that estimated PCa RRs for male BRCA1/2 carriers, with no time or language restrictions. The literature search identified 27 studies (BRCA1: n = 20, BRCA2: n = 21).ResultsThe heterogeneity between the published estimates was high (BRCA1: I2 = 30%, BRCA2: I2 = 83%); this could partly be explained by selection for age, family history or aggressive disease, and study-level differences in ethnicity composition, use of historical controls, and location of PVs within BRCA2. The pooled RRs were 2.08 (95% CI 1.38–3.12) for Ashkenazi Jewish BRCA2 carriers, 4.35 (95% CI 3.50–5.41) for non-Ashkenazi European ancestry BRCA2 carriers, and 1.18 (95% CI 0.95–1.47) for BRCA1 carriers. At ages <65 years, the RRs were 7.14 (95% CI 5.33–9.56) for non-Ashkenazi European ancestry BRCA2 and 1.78 (95% CI 1.09–2.91) for BRCA1 carriers.ConclusionsThese PCa risk estimates will assist in guiding clinical management. The study-level subgroup analyses indicate that risks may be modified by age and ethnicity, and for BRCA2 carriers by PV location within the gene, which may guide future risk-estimation studies.

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: A nationwide cohort study

AimBRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. Patients and methodsBRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. ResultsWe included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). ConclusionRisk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.

Breast cancer surveillance following ovarian cancer in BRCA mutation carriers

ObjectivesBRCA 1 or 2 mutation carriers have increased risk of developing breast cancer (BC) and serous epithelial ovarian cancer (EOC). The incidence of BC over time after EOC is unknown. Optimal BC surveillance for BRCA mutation carriers following EOC has not been defined. MethodsA multi-institutional retrospective chart review was performed. Patients with BRCA -associated EOC diagnosed between 1996 and 2016 were followed for an average of 80 months. Women with previous bilateral mastectomy were excluded; women with prior BC and an intact breast were included. Descriptive statistics, Chi Square, and univariate survival analysis were performed. Results184 patients with BRCA -associated EOC were identified. Eighteen (10%) were diagnosed with BC a median of 48 months following EOC. Two (1%) with prior BC developed contralateral BC and 16 (9%) developed primary BC. The majority of BC (55%) was diagnosed 3 years following EOC. The 3-, 5- and 10-year incidence of BC was 5.6%, 9.5% and 33.3%. Annual mammography was performed in 43% and MRI in 34%. Twenty-eight (15%) women underwent risk-reducing mastectomy (RRM). There was no statistically significant difference in BC screening between women with, and without, a prior BC. BC was most commonly detected on mammogram. Three (17%) women had occult BC at the time of RRM. Nine (50%) had DCIS, and 8 (44%) had stage I/II BC. Median 5- and 10-year survival was 68% and 43% and was comparable between groups. ConclusionsTen percent of women developed BC after EOC. The incidence of BC following EOC in BRCA carriers increases over time, and surveillance is recommended given their enhanced survival of EOC. Timely genetic testing for women with EOC is imperative to better triage BC screening resources and treatment.

Comparing breast cancer imaging characteristics of CHEK2 with BRCA1 and BRCA2 gene mutation carriers

PurposeBreast cancer gene (BRCA) 1 and 2 mutations are frequently studied gene mutations (GM); the incidence of checkpoint kinase 2 (CHEK2) is increasing.We describe the imaging features of breast cancer (BC) in CHEK2 mutations, compared to BRCA 1 and 2 using mammography, ultrasound (US) and magnetic resonance imaging (MRI). MethodInclusion criteria were primary BC in GM carriers, treated in the same hospital. Age at diagnosis, histology, hormone receptor and human epidermal growth factor receptor 2 (HER2) status were retrieved. Mammography descriptors were mass, asymmetry and suspicious microcalcifications. The enhancement pattern (MRI), shape and border, architectural distortion, the presence of a hyperechoic rim and cystic complex structure (US) were documented. Analyses were performed using SAS software (version 9.4). Fishers' exact test was used to test associations between two categorical variables. ResultsIn 191 women, 233 malignant lesions were diagnosed (78 in BRCA1, 109 in BRCA2, 46 in CHEK2). In CHEK2 carriers, mammographically, suspicious microcalcifications (54%) were more prevalent (BRCA2 (48%) and BRCA1 carriers (33%)) (p-value = 0.057) compared to mass lesions (35%). On US, lesions were most frequently ill-defined (86%) (p = 0.579) and irregular (94.5%) (p = 0.098) compared to BRCA2 (77% and 80% resp.) and BRCA1 carriers (71% and 72% resp.). On MRI, mass lesions showed a type 3 curve in CHEK2 (67%) compared to BRCA1 (36%) and BRCA2 (50%) (p = 0.056). ConclusionsMalignant radiological characteristics of breast cancer, more specifically suspicious microcalcifications, were more frequently seen in CHEK2 and BRCA2 compared to BRCA1 mutation carriers (without a significant difference) indicating the importance of mammography in follow-up of CHEK2 carriers.

Impact of BRCA mutations and hormone receptor status on reproductive potential in breast cancer patients undergoing fertility preservation

Objective To identify whether the BRCA mutations and hormone receptor status affect the ovarian reserve and ovarian stimulation outcomes in breast cancer patients undergoing fertility preservation. Methods A total of 117 women diagnosed with breast cancer who were referred to the fertility preservation clinics at Seoul National University Bundang Hospital and Seoul National University Hospital between September 2012 and July 2019 undergone ovarian stimulation for oocyte retrieval. Basal characteristics including age, BMI, basal AMH, basal FSH, and fertility preservation outcomes such as the number of retrieved oocytes and mature oocytes were compared retrospectively. Results BRCA1 mutation was noted in 25 women, and BRCA2 mutation was observed in 35 women. Positive estrogen receptor status was noted in 87 women, and positive progesterone receptor status was noted in 69 women. HER2 was positive in 55 women, and 19 women were diagnosed with triple-negative breast cancers. The number of total oocytes retrieved was lower in patients with BRCA mutation (8.3 ± 5.4 vs. 15.3 ± 8.7, p = .002). The number of mature oocytes retrieved was also lower in BRCA carriers (4.7 ± 4.2 vs. 8.7 ± 7.9, p = .025). Triple-negative breast cancer (TNBC) patients were younger than non-TNBC patients (30.3 ± 4.8 vs. 33.9 ± 5.0, p = .007). The rate of mature oocyte rate was higher in TNBC patients (68.6%±20.6 vs. 52.5%±29.7, p = .037). Conclusions Our study demonstrated that BRCA carriers with breast cancer had comparable ovarian reserve to non-carriers but the response to ovarian stimulation was lower. We also observed that oocyte maturity was higher in TNBC patients, however age might be a confounding factor of this result.

Germinal &lt;i&gt;BRCA&lt;/i&gt;-mutation significance in the tumor microenvironment formation Efficacy of PARP inhibition in late-line therapy of metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer is a difficult problem for a clinical oncologist. In addition, mutations in genes of homologous DNA recombination, including BRCA1/2, suggest an aggressive behavior and therapy resistance. Treatment options for such patients were significantly limited until new drugs - PARP inhibitors have been registered. Nevertheless, there is evidence that BRCA1/2 gene mutations are associated with increased mutational load, neoepitopes formation, increased number of tumor-infiltrating lymphocytes and a response to the immune response checkpoints blockade. Studies have shown that BRCA2-mutated prostate cancer demonstrates high level of immune cells infiltration compared to tumors without mutation, in particular with respect to CD4+, CD8+ and FOXP3+ T-lymphocytes. It should be noted that studies have shown a tendency of CD8+ T-lymphocytes/FOXP3+ T-cells ratio decreasing in BRCA2-mutated tumors. Thus, the mutational status of BRCA2 presumably forms the immune phenotype of prostate cancer with an increase of intratumoral immune cells, but with immunosuppressive properties. At the same time, the use of immune checkpoint blockers in advanced prostate cancer has been unsuccessful in terms of overall survival. Despite the fact that immune checkpoint blocker's efficacy is often associated with a high intracellular CD4+ and CD8+ T lymphocytes, their presence is clearly insufficient for response. Studies showed that PARP inhibitors effect tumor microenvironment significantly. Anti-PD-1/PD-L1 combination with PARP inhibitors is being actively studied due to their properties of modulating the tumor microenvironment. Thus, future immunooncological strategies for primary prostate cancer therapy may include not only an increase in mutational load, but also an impact on the immunosuppressive microenvironment. The article presents clinical cases of 3 brothers, carriers of the germinal BRCA2 c.9371A&gt;T mutation, suffering from prostate cancer with a burdened family history. The disease development under standard therapies was studied and markers of the tumor microenvironment were immunohistochemically evaluated. PARP inhibitor Olaparib efficacy in prostate cancer of older brother in late-line therapy for metastatic castration-resistant disease was analyzed.

BRCA1/2 Mutation Types Do Not Affect Prognosis in Ovarian Cancer Patients.

Background: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. Methods: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1–27.5) and the median OS was 92.9 months (95% CI 69.8–116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. Conclusions: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.

The challenging screen detection of ovarian cancer in BRCA mutation carriers adhering to a 6-month follow-up program: results from a 6-years surveillance.

Approximately 25% of ovarian cancer (OC) cases are related to an inherited predisposition. Genetic mutations for the oncosuppressor genes BRCA1 and 2 have the best-known linkage to a higher incidence of OC and breast cancer, in approximately 70% to 80% of hereditary OC cases. To provide the first comprehensive clinical description of screen-detected (SD) OCs during a 6-years surveillance of a cohort of young BRCA carriers and carriers who refuse risk-reducing salpingo-oophorectomy. A prospective cohort study in a university hospital describing 191 women with BRCA1 and 2 mutations adhering continuously to our surveillance between 2015 and 2020, including a 6-monthly evaluation of cancer antigen 125 (CA 125) with concomitant transvaginal ultrasound (TVUS) performed by a dedicated specialist. Main outcomes were tumor's laterality, CA 125 at diagnosis, TVUS and computed tomography (CT) findings. Risk-reducing salpingo-oophorectomy was performed in 58/191 (30.4%) of mutation carriers during the study period (one OC case identified). Nine SD-OCs and no interval OCs were found in the remaining 133 women. OCs (FIGO stage I or II: 88.9%) occur mainly in BRCA 1 (77.8%), being bilateral in 85.7% BRCA 1 and unilateral in 100% BRCA 2. No lesions involved only the tubes: left ovaries/tubes were more frequently involved. We have described three new possible scenarios regarding imaging: 1) Evident cases (33.3%, TVUS and CT obvious for OC, CA 125 sensitivity: 100%), 2) Possible cases (55.6%, TVUS and CT are in general accordance, documenting new TVUS signs: increased solid pattern of the ovary with peripheral cortical small cysts, hypoechoic circular mass near the ovary, intraparenchymal small hyperechoic foci), and 3) Hidden cases (11.1%, the smallest lesion but the highest stage (IIIA2), with CA 125 44.2 U/mL and concomitant endometrial hyperplasia). Different diagnostic tools must integrate to ensure early diagnosis of OC in BRCA mutation carriers adhering to a follow-up program.

A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO.

Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations. BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI: 0.73-0.84 and 0.70, 95% CI: 0.60-0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94]). The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.

Risk-Reducing Salpingo-Oophorectomy and the Use of Hormone Replacement Therapy Below the Age of Natural Menopause: Scientific Impact Paper No. 66 October 2021: Scientific Impact Paper No. 66.

This paper deals with the use of hormone replacement therapy (HRT) after the removal of fallopian tubes and ovaries to prevent ovarian cancer in premenopausal high risk women. Some women have an alteration in their genetic code, which makes them more likely to develop ovarian cancer. Two well-known genes which can carry an alteration are the BRCA1 and BRCA2 genes. Examples of other genes associated with an increased risk of ovarian cancer include RAD51C, RAD51D, BRIP1, PALB2 and Lynch syndrome genes. Women with a strong family history of ovarian cancer and/or breast cancer, may also be at increased risk of developing ovarian cancer. Women at increased risk can choose to have an operation to remove the fallopian tubes and ovaries, which is the most effective way to prevent ovarian cancer. This is done after a woman has completed her family. However, removal of ovaries causes early menopause and leads to hot flushes, sweats, mood changes and bone thinning. It can also cause memory problems and increases the risk of heart disease. It may reduce libido or impair sexual function. Guidance on how to care for women following preventative surgery who are experiencing early menopause is needed. HRT is usually advisable for women up to 51 years of age (average age of menopause for women in the UK) who are undergoing early menopause and have not had breast cancer, to minimise the health risks linked to early menopause. For women with a womb, HRT should include estrogen coupled with progestogen to protect against thickening of the lining of the womb (called endometrial hyperplasia). For women without a womb, only estrogen is given. Research suggests that, unlike in older women, HRT for women in early menopause does not increase breast cancer risk, including in those who are BRCA1 and BRCA2 carriers and have preventative surgery. For women with a history of receptor-negative breast cancer, the gynaecologist will liaise with an oncology doctor on a case-by-case basis to help to decide if HRT is safe to use. Women with a history of estrogen receptor-positive breast cancer are not normally offered HRT. A range of other therapies can be used if a woman is unable to take HRT. These include behavioural therapy and non-hormonal medicines. However, these are less effective than HRT. Regular exercise, healthy lifestyle and avoiding symptom triggers are also advised. Whether to undergo surgery to reduce risk or not and its timing can be a complex decision-making process. Women need to be carefully counselled on the pros and cons of both preventative surgery and HRT use so they can make informed decisions and choices.

Prognostic difficulties of men with breast cancer.

Most adequately powered studies confirm a worse prognosis for males versus matched females with breast cancer. There is in-stage migration for stage I cancers with a different ratio of tumor/normal breast tissue in males. Younger men have a better prognosis, largely the result of increased morbidity in the elderly, exacerbated by smoking, low socioeconomic differences, and ethnic disparity. BRCA2 carriers with MBC have a worse outcome than noncarriers as do men with amplification of EMSY. Men with tumors having a high cytosol level of plasminogen activator inhibitor 1 (PAI-1) may have more invasive cancers leading to earlier spread and hence a worse outcome. PREDICT+ is a useful prognostic model for MBC and multigene testing enables more specific systemic therapies to be used.

Bilateral Salpingo-Oopherectomy for BRCA Mutation Carriers Via Transvaginal Natural Orifice Transluminal Endoscopic Surgery Approach

<h3>Study Objective</h3> As the experience of Transvaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) has been accumulating, it has been questioned whether it can serve as an alternative approach for laparoscopic salphingo-oopherectomy for BRCA mutation carrier women, due to challenging accessibility and perhaps limited visualization of the abdominal cavity. The aim of this study is to report preliminary results using the vNOTES approach for risk reducing bilateral salphingo-oopherectomy for BRCA carrier women. <h3>Design</h3> A retrospective cohort study, February 2019 to January 2021. <h3>Setting</h3> Single medical center. <h3>Patients or Participants</h3> BRCA mutation carrier women that underwent risk reducing bilateral salphingo-oopherectomy via vNOTES approach. <h3>Interventions</h3> Data were collected from women's' medical files including demographics, medical and obstetrical history, operative characteristics and pathology results. All operations were performed by a single high skilled surgeon. Primary outcome was defined as successful bilateral salpingo-oopherectomy removal by vNOTES approach. <h3>Measurements and Main Results</h3> Thirty-seven women met inclusion criteria. Of them, 43% (n=16) and 57% (n=21) BRCA1 and BRCA2 mutations carriers, respectively, and 8% (n=3) both mutations carriers. Median age conducting risk reducing operation was 41(IQR39-54) years. Median parity was 2(2-3) with none of the women having past cesarean deliveries. All operations were completed using the vNOTES approach only. Diaphragmatic screening was reported normal in all of the women. No complications were documented in any of the operations including: Bleeding, damage to adjacent organ and need to transfer to laparoscopy. Operation median time was 60(57-68) minutes. All women were released from hospitalization the following day of the surgery. On follow up visit a month post operation, only one woman reported withdrawal bleeding, and all others reported being satisfied from the operation. Histo-pathological examination were clear in all of the women. <h3>Conclusion</h3> Risk reducing bilateral salphingo-oopherectomy by vNOTES provides a feasible new approach for the treatment of BRCA mutation carriers, with improved women comfort and better cosmetic results.