BRCA1 Mutation Carriers Research Articles

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.

Reimagining prostate cancer screening: the IMPACT of germline mutations.

Structured prostate-specific antigen (PSA) screening allows for the early detection of prostate cancer in men aged 55–69 years with a reduction in the incidence of metastatic disease at presentation and cancer-specific mortality at 16 year's follow-up. 1 Hugosson J Roobol MJ Månsson M et al. A 16-yr follow-up of the European randomized study of screening for prostate cancer. Eur Urol. 2019; 76: 43-51 Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar Population-based screening has been associated with a non-negligible risk of overdiagnosis (ie, the detection of cancers that would not have caused symptoms), which can be as high as 40%, and has limited its adoption at a large scale 2 Martin RM Donovan JL Turner EL et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial. JAMA. 2018; 319: 883-895 Crossref PubMed Scopus (210) Google Scholar such that no national prostate cancer screening programmes exist in the USA and Europe. 3 Van Poppel H Hogenhout R Albers P van den Bergh RCN Barentsz JO Roobol MJ A European model for an organised risk-stratified early detection programme for prostate cancer. Eur Urol Oncol. 2021; (published online Aug 4)https://doi.org/10.1016/j.euo.2021.06.006 Summary Full Text Full Text PDF Scopus (11) Google Scholar Restricting the use of repeated PSA testing to men at risk of early-onset disease because of a family history of prostate cancer or germline mutations has been proposed as a means of improving the effectiveness of screening. 2 Martin RM Donovan JL Turner EL et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial. JAMA. 2018; 319: 883-895 Crossref PubMed Scopus (210) Google Scholar , 4 Gandaglia G Albers P Abrahamsson PA et al. Structured population-based prostate-specific antigen screening for prostate cancer: the European Association of Urology Position in 2019. Eur Urol. 2019; 76: 142-150 Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar , 5 Page EC Bancroft EK Brook MN et al. Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers. Eur Urol. 2019; 76: 831-842 Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective studyAfter the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. Full-Text PDF Open Access

Selective progesterone receptor blockade prevents BRCA1-associated mouse mammary tumors through modulation of epithelial and stromal genes

Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p=0.04), and increased tumor latency (p=0.03). In benign mammary glands, UPA decreased Ki67 (p<0.001) and increased PR expression (p<0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.

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.

Clinicopathological features and BRCA1 and BRCA2 mutation status in a prospective cohort of young women with breast cancer.

Breast cancer in young women is more likely to have higher risk features and be associated with germline BRCA1/BRCA2 mutations. We present the clinicopathologic features of breast cancers in a prospective cohort of young women, and associations between surrogate molecular subtype and BRCA1/BRCA2 mutation status. Histopathological features, biomarker status, tumour stage and BRCA status were collected. Invasive tumours were categorised as luminal A-like (ER + and/or PR + , HER2-, grade 1/2), luminal B-like (ER + and/or PR + , HER2 + , or ER + and/or PR + , HER2-, and grade 3), HER2-enriched (ER/PR-, HER2 + ) or triple-negative. In all, 57.3% (654/1143) of invasive tumours were high grade. In total, 32.9% were luminal A-like, 42.4% luminal B-like, 8.3% HER2-enriched, and 16.4% triple-negative. Among different age groups, there were no differences in molecular phenotype, stage, grade or histopathology. 11% (131) of tumours were from BRCA mutation carriers; 64.1% BRCA1 (63.1% triple-negative), and 35.9% BRCA2 (55.3% luminal B-like). The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.

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.

Preimplantation genetic testing for BRCA gene mutation carriers: a cost effectiveness analysis

BackgroundGynecologic oncologists should be aware of the option of conception through IVF/PGT-M for families with high BRCA related morbidity or mortality. Our objective was to investigate the cost-effectiveness of preimplantation genetic testing for selection and transfer of BRCA negative embryo in BRCA mutation carriers compared to natural conception.MethodsCost-effectiveness of two strategies, conception through IVF/PGT-M and BRCA negative embryo transfer versus natural conception with a 50% chance of BRCA positive newborn for BRCA mutation carriers was compared using a Markovian process decision analysis model. Costs of the two strategies were compared using quality adjusted life years (QALYs’). All costs were discounted at 3%. Incremental cost effectiveness ratio (ICER) compared to willingness to pay threshold was used for cost-effectiveness analysis.ResultsIVF/ PGT-M is cost-effective with an ICER of 150,219 new Israeli Shekels, per QALY gained (equivalent to 44,480 USD), at a 3% discount rate.ConclusionsIVF/ PGT-M and BRCA negative embryo transfer compared to natural conception among BRCA positive parents is cost effective and may be offered for selected couples with high BRCA mutation related morbidity or mortality. Our results could impact decisions regarding conception among BRCA positive couples and health care providers.

BRCA1/Trp53 heterozygosity and replication stress drive esophageal cancer development in a mouse model

BRCA1 germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that BRCA1 mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a Brca1/Trp53 mouse model to show that unresolved replication stress (RS) in BRCA1 heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, Brca1 heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (∼90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These Brca1 mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of Brca1 heterozygosity (LOH). This uniquely accelerated Brca1 tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor.

S95 BRCA Mutations and Pancreatic Cancer: A Systematic Review and Meta-Analysis

Introduction: Pancreatic cancer (PC) carries a high mortality and is a leading cause of cancer death in the United States. The lifetime risk of PC in the population is 1.3%, approaching >5% in high-risk individuals such as those with mutations in BRCA genes. We conducted a systematic review and meta-analysis to assess the incidence of PC in BRCA-1 and BRCA-2 mutation carriers and estimate their incidence in patients with PC. Methods: Major databases were searched until January 2021. A random-effects model was used to calculate the pooled rates and 95% confidence intervals (CI). Outcomes assessed were pooled proportion of BRCA-1 and BRCA -2 mutations in PC and incidence of PC in these mutation carriers. Results: Nine studies reported on the incidence of BRCA-1 and BRCA-2 mutations in PC patients, whereas, thirteen studies reported the incidence of PC among BRCA mutation carriers. In 4462 patients with PC, 47 were found to have germline mutation in BRCA-1. Pooled proportion of mutation carriers was 1.1% (CI 0.3-1.8; I2=58.88%). Among 4426 patients with PC, 158 were found to have germline mutations in BRCA-2. Pooled proportion of mutation carriers was 7.9% (CI 4.8-11; I2=91.15%). Among 27,501 BRCA-1 mutation carriers, 121 developed PC. Pooled incidence ratio was 1.78 (CI 1.4-2.26; I2=13%). A total of 144 out of 16,256 BRCA-2 mutation carriers developed PC. Pooled incidence ratio was 3.98 (CI 1.26-12.52; I2=96%). Conclusion: Our results support the current recommendations of PC screening in high-risk individuals such as those with mutations in BRCA-1 and BRCA-2 genes.Figure 1.: BRCA 2.

Association between pathogenic germline mutations in BRCA2 and ATM and tumor-infiltrating lymphocytes in primary prostate cancer.

Pathogenic mutations in homologous recombination (HR) DNA repair genes may be associated with increased tumor mutational burden and numbers of tumor-infiltrating lymphocytes (TIL). Though HR-deficient prostate tumors have been anecdotally associated with improved responses to immunotherapy, it is unclear whether HR mutations or HR deficiency (HRD) scores predict for increased T-cell densities in this cancer. We evaluated 17 primary prostate tumors from patients with pathogenic germline BRCA2 mutations (gBRCA2) and 21 primary prostate tumors from patients with pathogenic germline ATM (gATM) mutations, which were compared to 19 control tumors lacking HR gene mutations, as well as the TCGA prostate cancer cohort. HRD score was estimated by targeted sequencing (gBRCA2 and gATM) or by SNP microarray (TCGA). Tumor-associated T-cell densities were assessed using validated automated digital image analysis of CD8 and FOXP3 immunostaining (gBRCA2 or gATM) or by methylCIBERSORT (TCGA). CD8 + and FOXP3 + T-cell densities were significantly correlated with each other in gBRCA2 and gATM cases. There was no significant difference between CD8 + or FOXP3 + TIL densities in gBRCA2 or gATM cases compared to controls. In the TCGA cohort, HRD score was associated with predicted CD8 + and FOXP3 + TILs. Associations were also seen for HRD score and TIL density among the germline-mutated cases. In contrast to mismatch repair-deficient primary prostate tumors, cancers from germline BRCA2 or ATM mutation carriers do not appear to be associated with elevated TIL density. However, measures of genomic scarring, such as HRD score, may be associated with increased tumor-infiltrating T-cells.

Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers.

Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual’s genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.

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.

21P Analysis of germline variants in the immune response-related genes in BRCA1 mutation carriers: Possible modifying effect on age-dependent BRCA1 penetrance

Most female carriers of germline BRCA1 mutation develop breast/ovarian cancer during the lifetime. However, the penetrance of BRCA1 pathogenic variants does not reach 100%, and the age of BRCA1-associated breast cancer (BC) onset varies widely. BRCA1-driven tumors are chromosomally unstable and may have excessive antigenicity. We hypothesized that hereditary variations in immune response pathways may contribute to the variability of BRCA1 penetrance. We evaluated whether genetic variations in the immune response-related genes contribute to this heterogeneity.

CN19 BRCA mutation carriers’ and stakeholders’ perspectives on cancer risk management and decision-making: A qualitative study

Women with BRCA+ gene mutation require relevant information to help them to make informed decisions about managing their cancer risk. However, there is a lack of targeted informational support for women living with BRCA+ in Ireland. The objective of this study is to identify the information needs of women with BRCA+ gene mutation regarding cancer risk management and decision-making.

Weight Gain and the Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers.

Weight gain and other anthropometric measures on the risk of ovarian cancer for women with BRCA mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among BRCA1 and BRCA2 mutation carriers. In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer. This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; P = 0.02). Current BMI of 26.5 kg/m2 or greater was associated with an increased risk of ovarian cancer in BRCA1 mutation carriers, compared with those with a BMI less than 20.8 kg/m2 (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; P = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer. Adult weight gain is a risk factor for ovarian cancer in women with a BRCA1 or BRCA2 mutation. These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.

ASO Author Reflections: Prophylactic Nipple-Sparing Mastectomy as an Effective Risk-Reducing Strategy for BRCA Mutation Carriers.

ASO Author Reflections: Prophylactic Nipple-Sparing Mastectomy as an Effective Risk-Reducing Strategy for BRCA Mutation Carriers.

Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology.

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c.1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.

ASO Visual Abstract: How Protective are Nipple-Sparing Prophylactic Mastectomies in BRCA1 and BRCA2 Mutation Carriers?

ASO Visual Abstract: How Protective are Nipple-Sparing Prophylactic Mastectomies in BRCA1 and BRCA2 Mutation Carriers?

OTHR-03. Brain Metastasis Among Ovarian Cancer Patients

BackgroundBrain metastasis (BM) are uncommon among ovarian cancer (OC) patients. Their frequency, risk factors and clinical repercussions are not well described. We assessed OC patients who developed BM, the role of BRCA status and survival implications.MethodsStudy cohort included OC patients treated at our center, from 2002–2020. We retrospectively evaluated clinical parameters, risk for BM development and association with survival data.ResultsAmong 972 OC patients, 28 (2.9%) were diagnosed with BM. Comparing the BM to non-BM group, median age of 60 across both groups, stage III-IV at diagnosis was more common among BM group (96.4% vs. 84.8%, p=0.0065) while platinum sensitivity was similar (92.3% in BM vs. 80.8% in non-BM, p=0.2193). Out of 658 patients tested for BRCA, 33.6% (n=221) were BRCA mutation carriers (BRCA+). Of the patients with BM, 22 tested for BRCA, 13 were carriers. BRCA+ was significantly higher in the BM group compared to the non-BM group (59.1% vs. 32.9%, p=0.0123). Among BRCA+ the rate of BM was higher than among BRCA- (5.8% vs. 2.1%, p=0.0123, HR=3.029; 95%CI: 1.4–6.5). Median time from OC diagnosis to BM and from disease recurrence to BM, was longer for BRCA+ compared to BRCA- (44.3mo vs. 32.3mo and 11.8mo vs. 0.7mo, respectively). Median survival (mOS) was not significantly different among patients with BM compared to those without BM (59.4mo vs. 71.2mo, p=0.36). Following diagnosis of BM, mOS was 20.6mo among BRCA+ and 12.3mo among BRCA- (p=0.4266). No correlation was demonstrated with PARP inhibitors or bevacizumab treatment and subsequent development of BM.ConclusionBM are an infrequent event among OC patients. However, the risk is three-folds higher among BRCA+. Interestingly, BM do not significantly alter survival among OC patients. Our work suggests that the higher rate of BM in BRCA+ may be related to longer survival. Another hypothesis requiring further evaluation, is possible higher brain tropism among this population.

Bilateral Salpingo-oophorectomy and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Assessing the Evidence.

Without preventive interventions, women with germline pathogenic variants in BRCA1 or BRCA2 have high lifetime risks for breast cancer and tubo-ovarian cancer. The increased risk for breast cancer starts at a considerably younger age than that for tubo-ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is effective in reducing tubo-ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, but whether it reduces breast cancer risk is less clear. All studies of rrBSO and breast cancer risk are observational in nature and subject to various forms of bias and confounding, thus limiting conclusions that can be drawn about causation. Early studies supported a statistically significant protective association for rrBSO on breast cancer risk, which is reflected by several international guidelines that recommend consideration of premenopausal rrBSO for breast cancer risk reduction. However, these historical studies were hampered by the presence of several important biases, including immortal person-time bias, confounding by indication, informative censoring, and confounding by other risk factors, which may have led to overestimation of any protective benefit. Contemporary studies, specifically designed to reduce some of these biases, have yielded contradictory results. Taken together, there is no clear and consistent evidence for a role of premenopausal rrBSO in reducing breast cancer risk in BRCA1 or BRCA2 mutation carriers.