Prevalence Of BRCA1 Research Articles

Patterns and Prevalence of BRCA1 and BRCA2 Germline Mutations Among Patients with Triple-Negative Breast Cancer: Regional Perspectives.

BackgroundAmong all subtypes, patients with triple-negative (TN) breast cancer is known for their poor outcome and their higher risk of harboring BRCA1 or BRCA2 pathogenic mutations. Identification of such mutations has clinical impact on breast and ovarian cancer prevention and treatment decisions. We here report on patterns and prevalence of BRCA1 and BRCA2 mutations among Arab patients diagnosed with TN subtype.Patients and MethodsPatients with TN-breast cancer (n=197) were enrolled regardless of their age or family history. Following a detailed genetic counseling, BRCA1/2 testing was performed at reference labs. BRCA1 and BRCA2 variants were classified as negative, pathogenic/likely pathogenic (positive) and variants of uncertain significance (VUS).ResultsMedian age of enrolled patients was 42 (range, 19–74) years and 27 (13.7%) were non-Jordanian Arabs. Among the study group, 50 (25.4%) were tested positive for BRCA1 (n=36, 18.3%) or BRCA2 (n=14, 7.1%), while 14 (7.1%) others had VUS. Compared to older ones, mutation rates were higher among patients <40 years (32.9%, P= 0.034), those with close relatives with breast, ovarian, pancreatic or prostate cancer (37.8%, P=0.002) and those with two or more breast cancers (41.4%, P=0.032). Among eligible patients, 23 (63.9%) patients underwent prophylactic mastectomy, while 19 (52.8%) patients had risk-reducing salpingo-oophorectomy. None of the patients with VUS underwent any prophylactic surgery.ConclusionArab patients with TN-breast cancer have relatively high BRCA1 or BRCA2 mutation rates. Young age at diagnosis and personal and family history of breast cancer further increase this risk.

Isparta Bölgesinde Meme ve/veya Over Kanseri Riski Taşıyan Hastalarda BRCA1 ve BRCA2 Gen Mutasyonlarının Yeni Nesil Dizileme Yöntemi ile Belirlenmesi

and/or ovarian cancers. BRCA1 / BRCA2 genes are associated with 20-25% of these diseases. The&#x0D; spectrum and prevalence of BRCA1 and BRCA2 gene mutations are different in each population.&#x0D; Determining the prevalence of pathogenic mutations in susceptibility genes and identifying new&#x0D; mutations are important for developing national health policies. In this retrospective study, mutations&#x0D; in the BRCA1 / 2 genes of patients who applied to Süleyman Demirel University Faculty of Medicine&#x0D; Medical Genetics Clinic between 2018-2020 with the suspicion of breast / or ovarian cancer in the&#x0D; Isparta region were investigated.&#x0D; Material and Methods: In our study, BRCA1 and BRCA2 gene mutation analyzes were performed by&#x0D; Next Generation Sequencing (NGS) method in 76 patients who applied to the Medical Genetics Clinic&#x0D; with the indication of breast cancer, breast mass, family history, and ovarian cancer.&#x0D; Results: As a result of our data analysis, 4 pathogenic, 1 likely pathogenic, 5 variants of unknown&#x0D; significance (VUS), and 11 benign variants were detected in the BRCA1 gene. Also, 3 pathogenic, 3&#x0D; VUS, 11 benign, and 1 new variant were detected in the BRCA2 gene.&#x0D; Conclusion: We believe that the results of our study will contribute to the determination of the prevalence&#x0D; of BRCA1 and BRCA2 gene mutations and the detection of breast and/or ovarian cancer.

Prevalence of BRCA1 and BRCA2 genes promoter hypermethylation in breast cancer tissue.

Recent advances in the treatment of breast cancer (BC) have been related to the personalization of therapy. The methylation status of the promoter regions of tumor suppressor genes such as BRCA1and BRCA2is supposed to be useful as a prognostic factor in BC patients. To investigate the frequency of hypermethylation in the promoter regions of BRCA1and BRCA2genes in tumor tissue of BC patients, and the relation of hypermethylation to the clinical course of the disease. Molecular genetic studies were performed on 50BC tissue samples in order to determine the methylation status of the promoter regions of the BRCA1and BRCA2genes. Hypermethylation of the BRCA1promoter region was detected in 34% of BC cases, hypermethylation of the BRCA2promoter region- in 50% of cases, and hypermethylation of the promoter region of both genes- in 20% of cases. A significant increase in the incidence of hypermethylation of the BRCA2promoter region was found in the group of patients older than 56years, mainly in patients with triple-negative breast cancer and without family history of BC. The high frequency of hypermethylation in the promoter regions of BRCA1and BRCA2genes, as well as their co-methylation in tumor tissue of BC patients has been detected.

Real-world prevalence of homologous recombination repair gene (BRCA1/2 and ATM) mutations (HRRm) in patients (pts) with advanced prostate cancer (aPC) as detected by comprehensive genomic profiling (CGP) of circulating cell-free DNA (cfDNA).

256 Background: PARP inhibitors, olaparib and rucaparib recently improved survival outcomes (in the Profound and Triton-2 trials) in pts with aPC harboring HRRm. Notably, ~35% of pts screened for the PROfound trial did not meet eligibility solely due to the lack of adequate quality/quantity of tumor tissue required for CGP (De Bono, NEJM, 2020). cfDNA analysis non-invasively assesses tumor-derived genomic alterations. We evaluated the prevalence of HRRm in a real-world aPC population, who had commercially available cfDNA assay results available. Methods: cfDNA based CGP (using a clinically-validated 73- to 74-gene panel i.e. Guardant360 or G360) from consecutive aPC pts between 11/2016–8/2020 were used for detection of HRRm. Frameshift and nonsense mutations were included as pathogenic. Variants of unknown significance were excluded. In this unmatched study, the prevalence of each HRRm was compared with those reported in literature using the chi square test. Results: cfDNA CGP from 7701 aPC pts were available for interrogation of BRCA1/BRCA2 mutations, &amp; from 4671 aPC pts for ATM mutations. Prevalence of BRCA1 and 2 as detected by cfDNA was similar to historical CGP of primary tissue. Prevalence of BRCA1 was higher than historical CGP of metastatic tissue. Prevalence of ATM in cfDNA was higher than historic tumor tissue CGP but similar to prior reports from cfDNA testing (Table). Conclusions: In this large real-world population of pts with aPC undergoing routine cfDNA CGP by a CLIA certified lab, prevalence of HRRm was similar (or higher for BRCA1 and ATM) to what has been previously reported from the tumor tissue. These data provide the rationale for utilizing cfDNA CGP as a routine test for detection of HRRm in men with aPC to identify men who are candidates for PARPi. [Table: see text]

Abstract PS8-34: High rates of BRCA1 and BRCA2 germline mutations among Arab patients with triple-negative breast cancer

Abstract Background: Patients with triple-negative (TN) disease, which represent 10-15% of all breast cancer cases, is associated with the worst prognosis among all breast cancer subtypes. Because of higher risk for BRCA mutation, patients diagnosed at age ≤60 years with triple-negative disease should undergo genetic testing. Identification of BRCA1 or BRCA2 mutation has clinical impact on breast and ovarian cancer prevention and treatment. Many drugs were recently approved for patients with BRCA mutation carriers. We here investigate the patterns and prevalence of BRCA1 and BRCA2 mutations among Arab patients diagnosed with this breast cancer subtypes and treated at our institution. Patients and Methods: We utilized our database of all breast cancer patients, from Jordan and neighboring Arab countries, tested for BRCA mutations (n=1302) as per the NCCN guidelines. Patients with no expression of estrogen (ER) or progesterone (PR) receptors and negative for HER2 (triple-negative) were enrolled regardless of their age or family history. Following a detailed genetic counselling in a clinic established for this purpose, BRCA testing was then performed at 3 reference labs in UK and USA. BRCA1 and BRCA2 mutations were classified as pathogenic/likely pathogenic and variant of uncertain significance (VUS). Results: During the three-year study period, a total of 171 (13.1%) of all patients in database fulfilled our inclusion criteria. Twenty-two (12.9%) patients were from Palestine, Syria and Iraq. Median age was 41 (range, 19-77) years and all were females. Among this group, a total of 45 (26.3%) were tested positive for BRCA1 (n=32, 18.7%) or BRCA2 (n=13, 7.6%) while 12 (7.0%) others had VUS. Mutations were detected in 26 (31.7%) of 82 patients who were triple-negative and diagnosed at age 40 years or younger. Additionally, 26 (36.6%) of 71 patients with triple-negative disease who had one or more close relatives with breast, pancreatic, or prostate cancer (Gleason score ≥7) had positive BRCA1 or BRCA2 mutation, too. In multivariate analysis, the impact of younger age on mutation rates was considered insignificant (OR: 1.86; 95%CI: 0.89-3.91; p=0.10). However, breast cancer diagnosis at any age with 2 or more close relatives with breast cancer have is associated with a significantly higher BRCA mutation rate (OR: 2.76; 95%CI: 1.13, 6.71; p = 0.03). Conclusions: Arab patients with triple-negative breast cancer subtype have very high BRCA1 or BRCA2 mutation rates. Family history of breast cancer in close relatives further increase this risk. Citation Format: Hikmat Abdel-Razeq, Lama Abujamous, Rayan Bater. High rates of BRCA1 and BRCA2 germline mutations among Arab patients with triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-34.

Abstract PS4-31: Characteristics of HER2/neu positive breast cancer among patients with and without germline BRCAmutations

Abstract Introduction: Breast cancer in BRCA 1/2 carriers is a well-characterized disease process, and its association with triple negative breast cancer has been extensively studied. In contrast, there is limited data on BRCA carriers and HER2/neu positive breast cancer, which identifies this topic as an area for further investigation. The BRCA protein plays an important role in DNA replication, whereas HER2/neu is a proto-oncogene that, when overexpressed, correlates with aggressive cancers. The relationship between these two mutations is poorly understood. There have been major strides with anti-HER2/neu therapies for HER2/neu positive disease and PARP inhibitors for BRCA germline positive patients, however there is a clinical knowledge gap in BRCA carriers who also have HER2/neu positive breast cancer. Further research into the characteristics of this population, treatment strategies, and outcomes is needed. More specifically, determining the utility of anti-HER2/neu therapies, PARP inhibitors, or the combination in this population could prove to have clinical utility. We aim to characterize the clinical characteristics, treatment strategies, and outcomes within this population. Methods: Using a prospective research patient database at the UT MD Anderson Cancer Center 1038 patients were identified to have HER2/neu associated breast cancer who had undergone genetic counseling and testing for hereditary breast cancer syndromes between 1996 and 2019. This population was descriptively characterized to evaluate the prevalence of BRCA 1/2 positivity. Clinical and pathological characteristics as well as treatment, and recurrence were collected. Chi-square was used for statistical analysis. The Kaplan-Meier method was used to compare overall survival based on BRCA status. Results: Amongst 1038 patients, germline BRCA mutation was detected in 49 (4.7%) of the patients. The median age at diagnosis for patients with BRCA mutations was significantly younger, 41.7 years (27-76), compared to 44.9 years (21-83) in the BRCA negative group (p= 0.0147). More patients were premenopausal in the BRCA positive group (p=0.027). Further characteristics are shown in Table 1. Overall survival was 71.6 months for the BRCA1 population, 81.3 months for the BRCA2 population, and 70.7 months for the BRCA negative population (p = 0.63). Recurrence free survival was 71 months for the BRCA1, 51.2 months for the BRCA2, and 59.6 months for the BRCA negative cohort (p = 0.4). Conclusion: HER2/neu positive breast cancer patients with and without germline BRCA mutations have different clinical presentations. While we did not detect a survival difference due to small number of patients, this presents an opportunity to evaluate whether new treatment strategies, such as combining anti-HER2/neu therapies with PARP inhibitors can further improve outcomes for these patients. Table 1:BRCA negativeBRCA positivep valuen%n%RaceASIAN666.724.10.0122BLACK979.8510.2HISPANIC16716.936.1NATIVE AMERICAN50.500.0OTHER111.148.2WHITE64365.03571.4Menopause Status at DxN/A40.400.00.0268POST17818.036.1PRE53454.03265.3Unknown27327.61428.6Age at Dxavg (range)44.9 (21-83)41.7 (27-76)0.0147Histology Typeductal93694.64591.80.3741lobular181.812.0mixed262.636.1other90.900.0StageI23523.81632.70.3293II46747.22040.8III28228.51224.5Unknown50.512.0Hormone Receptor StatusER and/or PR positive62663.33061.20.7271ER/PR negative35736.11938.8Unknown60.600.0Nuclear GradeI90.912.00.3474II22222.4714.3III69370.13673.5Unknown656.6510.2Ki67avg (range)40.5 (0-99)46 (10-90)0.1858Chemotypeadj32733.11632.70.2932neoadj56757.32551.0no chemo959.6816.3Herceptin Trxadj27027.31428.60.4093neoadj50651.22142.9none21121.31428.6unknown20.200.0Adj HormoneN44244.72449.00.5558Y54755.32551.0XRTN38038.42244.90.3637Y60961.62755.1989100.049100.0 Citation Format: Mihir A Shukla, Angelica Gutierrez Barrera, Stephen Karl Gruschkus, Rachel M Layman, Rashmi K Murthy, Banu K Arun. Characteristics of HER2/neu positive breast cancer among patients with and without germline BRCAmutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-31.

BRCA and Breast Cancer-Related High-Penetrance Genes.

Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on theKorean Hereditary Breast Cancer Research at this time.

Prevalence of BRCA1 and BRCA2 Mutations in Patients with Primary Ovarian Cancer - Does the German Checklist for Detecting the Risk of Hereditary Breast and Ovarian Cancer Adequately Depict the Need for Consultation?

Background BRCA1/2 mutations are the leading cause of hereditary epithelial ovarian cancer (EOC). The German Consortium for Hereditary Breast and Ovarian Cancer has defined inclusion criteria, which are retrievable as a checklist and facilitate genetic counselling/testing for affected persons with a mutation probability of ≥ 10%. Our objective was to evaluate the prevalence of the BRCA1/2 mutation(s) based on the checklist score (CLS). Methods A retrospective data analysis was performed on EOC patients with a primary diagnosis treated between 1/2011 – 5/2019 at the Central Essen Clinics, where a BRCA1/2 genetic analysis result and a CLS was available. Out of 545 cases with a BRCA1/2 result (cohort A), 453 cases additionally had an extended gene panel result (cohort B). Results A BRCA1/2 mutation was identified in 23.3% (127/545) in cohort A, pathogenic mutations in non- BRCA1/2 genes were revealed in a further 6.2% in cohort B. In cohort A, 23.3% (127/545) of patients had a BRCA1 (n = 92) or BRCA2 (n = 35) mutation. Singular EOC (CLS 2) was present in 40.9%. The prevalence for a BRCA1/2 mutation in cohort A was 10.8%, 17.2%, 25.0%, 35.1%, 51.4% and 66.7% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. The mutation prevalence in cohort B was 15.9%, 16.4%, 28.2%, 40.4%, 44.8% and 62.5% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. Conclusions The BRCA1/2 mutation prevalence in EOC patients positively correlates with a rising checklist score. Already with singular EOC, the prevalence of a BRCA1/2 mutation exceeds the required 10% threshold. Our data support the recommendation of the S3 guidelines Ovarian Cancer of offering genetic testing to all patients with EOC. Optimisation of the checklist with clear identification of the testing indication in this population should therefore be aimed for.

Prevalence of Tissue BRCA Gene Mutation in Ovarian, Fallopian Tube, and Primary Peritoneal Cancers: A Multi-Institutional Study.

Background and objective:Ovarian, fallopian tube, or primary peritoneal cancer patients with BRCA gene mutation have enhanced sensitivity to platinum-based regimens and PARP inhibitors. However, the knowledge regarding BRCA mutation in Thai patients is limited. This study aimed at identifying the prevalence and characteristics of somatic and germline BRCA 1 and 2 mutations in Thai patients with these cancers. Materials and Methods:The paraffin blocks of tumors with histology of high grade serous, high grade endometrioid, or clear cell carcinoma obtained between June 2016 and December 2017 were analyzedto evaluate BRCA mutation using next-generation sequencing system. Blood or normal tissue paraffin blocks of positive patients were further tested for germline BRCA mutation. Results:Tissue paraffin blocks of 178 patients were collected but only 139 were analyzed. Positive BRCA mutation was identified in 24 patients (17.3%): BRCA1 in 13 cases, BRCA2 in 10 cases, and BRCA1 and 2 in the rest one. Germline mutation study in blood or normal tissue in 23 positive patients revealed BRCA mutation in 14 cases, BRCA1 in 8 cases and BRCA 2 in 6 cases. Overall, the prevalence of somatic and germline mutation was 6.5% (9 out of 138 patients) and 8.7% (14 out of 138 patients), respectively. The most common histology associated with BRCA mutation was high grade serous cancer (27.3%). No significant difference was found between patients with or without BRCA mutation in terms of stage, outcome, platinum status, and survival outcome. Conclusion: BRCA mutation was demonstrated in less than 10% of Thai ovarian cancer patients. Higher rate of mutation was found in high grade serous cancer.

Prevalence of BRCA1 and BRCA 2 and other mutations in Chilean population.

e13553 Background: Arturo López Pérez Foundation (FALP) is a Chilean Institution aimed to treatment of cancer patients. Since 2016 it has an Unit for Oncological Genetic Counseling (AGO) for patients with warning flags of potential cases of cancer of genetic origin AGO Unit is aimed to capture patients with warning flags and deliver information through pre-test counseling, offer possibility of a genetic test and post-test counseling. The purpose of this review is to provide relevant results of four years of this Unit. Methods: A descriptive study was carried out from patient care in the Oncological Genetic Counseling Unit of FALP between 2016 and 2019. It was considered those cases in which the process of pretest/post-test counseling was performed. Six "warningflags" were established: cancer in patients under 50 years of age, triple negative breast cancer, breast cancer in men, ovarian cancer, history of 2 or more primary cancers and a family history of cancer The number of test performed was analyzed. The results were expressed in positive pathogenic variants, uncertain variants and negative results. Results: 365 genetic counseling processes were carried out during the period. The average consultation age was 43.2 years (20.8 and 75.5) and 90.1% (329 attentions ) were female. Of the patients, 79.7% (294) perform the genetic test. 18.5% tested positive for a pathogenic variant, 6.5% for a pathogenic variant plus an uncertain variable, and 2.8% for two pathogenic variants. The mutations found were BRCA2 32.6% BRCA1 29.1%, ATM 10.1% RAD51C 6.7% CDKN2 A 5.6%, MUTYH 3.4% TP53 3.4%, MSH2 3.4% RAD51D 2.4%), NF1 1.1%, NTHL1 1.1%, RET 1.1% A 64.9% (237 patients) had cancer diagnosed at the time of the consultation, versus 33.1% of healthy care. 2% had no information. The type of cancer present was 79.7% breast cancer (189), 8.0% ovarian cancer, 2.1% thyroid cancer, 1.7% breast and ovarian cancer, 0.9% colon and/or endometrial cancer and 7.6% other cancers. The warning flags present were 41.2% age below 50 years, 26.2% family history, 15.4% relatives of people with positive results, 8.5% patients with triple-negative breast cancer, 5.3% patients with ovarian cancer, 2.8% patients with 2 or more primary cancers, and 0.6% male breast cancer patients. Conclusions: The highest percentage of patient care was for women with breast cancer, under 50 years of age. The overall test positivity rate is a cumulative 29%. Mutations in BRCA 1 and BRCA 2 were the most detected mutations, as reported in the literature. The slight predominance of BRCA 2 may be due to a familiar component. This is the largest report made in the Chilean population.

Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome.

Pathogenic variants (PVs) carriers in BRCA1 or BRCA2 are associated with an elevated lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). The prevalence of BRCA1 and BRCA2 germline alterations is extremely variable among different ethnic groups. Particularly, the rate of variants in Italian BC and/or OC families is rather controversial and ranges from 8% to 37%, according to different reports. By In Vitro Diagnostic (IVD) next generation sequencing (NGS)-based pipelines, we routinely screened thousands of patients with either sporadic or cancer family history. By NGS, we identified new PVs and some variants of uncertain significance (VUS) which were also evaluated in silico using dedicated tools. We report in detail data regarding BRCA1/2 variants identified in 517 out of 2351 BC and OC patients. The aim of this study was to report the incidence and spectrum of BRCA1/2 variants observed in BC and/or OC patients, tested in at Policlinico Gemelli Foundation Hospital, the origin of which is mainly from Central and Southern Italy. This study provides an overview of the variant frequency in these geographic areas of Italy and provides data that could be used in the clinical management of patients.

Breast cancer risk (un)awareness among women suffering from neurofibromatosis type 1 in Poland.

The main goal of this study was to draw the attention of physicians to commonly undisclosed risk of breast cancer (BrCa) in women suffering from neurofibromatosis type 1 (NF-1), which is 5-fold higher than in the general population. NF-1 related BrCa arises earlier (< 50 years) and is more advanced, with an increased mortality. NF-1 is one of the most frequent monogenic diseases worldwide and a tumor predisposition syndrome. The Nf1 gene is an important negative regulator of the Ras oncogene and belongs to the family of the 12 the most important BrCa predisposition genes. Planning introduction of BrCa screening guidelines for NF-1 women in Poland we started with assessment of BrCa risk awareness and current preventive practices in this population by a survey published in an open access internet profile dedicated exclusively to patients with NF-1 in Poland, with 1928 participants. As a result, we revealed that the awareness of this specific risk was declared by only 30% out of 138 responders, and only 21% of them received this information from medical professionals. In all 4 (2.89%) women suffering from BrCa the cancer was diagnosed before the 50th year of age. It exceeds significantly the expected prevalence of BrCa in the general population of Polish women. We conclude that the limited awareness of NF-1 related BrCa risk in Polish patients warrants the educational effort directed both to the NF-1 patients by professional counseling and to the medical community, in order to increase the efficacy of preventive measures and decrease BrCa mortality.

Prevalence of BRCA 1 and BRCA 2 in Breast Cancer Patients in India

Abstract Background Breast cancer is the most common cancer affecting women all over the world In India it is the second most common solid organ malignancy after carcinoma cervix Worldwide approximately ten percent of the cases have been associated with various germline mutations However in India studies correlating germline BRCA mutation with various clinico pathological variables are rare In this study we have tried to find out the difference in BRCA mutated and BRCA nonmutated patients Materials and Methods Fifty patients with carcinoma breast were subjected to BRCA mutational studies by next generation sequencing and further subdivided into BRCA mutated and BRCA nonmutated subgroups Their clinical pathological and response to primary treatment were recorded and compared between two subgroups They were followed up for a minimum of nine months and response to treatment was also recorded Results Out of fifty patients with carcinoma of the breast only six patients were detected to be mutated and pathological mutations were detected in two patients only All the BRCA positive patients were female only The most common age of presentation was less than fifty years while BRCA positive patients presented earlierT riple negative breast cancer was the most common presentation and most patients presented in Stage three Conclusion BRCA mutated carcinoma breast presents at younger age and more frequently with bilateral presentation as compared to BRCA negative disease BRCA mutated carcinoma breast presents with more advanced disease and usually has a significant family history of either first or second degree relatives being affected Overall TNBC status was more commonly found in both subsets of the patients Overall BRCA positive disease had more aggressive course of the illness as compared to BRCA negative patients

Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term outcomes.

Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. North London Ashkenazi-Jewish (AJ) population. AJ women/men. Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. AJ women/men >18years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3years. Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. In all, 1034 individuals (691 women, 343 men) were randomised to PS (n=530) or FH (n=504) arms. There was a statistically significant decrease in anxiety (P=0.046) and total anxiety-&-depression scores (P=0.0.012) in the PS arm compared with the FH arm over 3years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P=0.018), health-anxiety (P<0.0005) and quality-of-life (P=0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.

Germline mutation profile among Hispanic women with epithelial ovarian cancer (EOC).

1584 Background: Hospital-based studies have reported a 15% prevalence of BRCA1/ BRCA2( BRCA) mutations, with a slightly higher yield of other predisposition genes on multigene panel testing (MGPT) among women with EOC, and National Comprehensive Cancer Network guidelines recommend genetic cancer risk assessment for women with EOC. However, there is limited data about the genetic epidemiology of EOC among underrepresented populations, such as Hispanics. Consequently, we determined the germline mutation profile of Hispanics with EOC, and compared them with non-Hispanics. Methods: We included all women with a personal history of EOC from the U.S. and Latin America (LatAm; Mexico, Colombia, and Peru), enrolled in the Clinical Cancer Genomics Community Research Network registry. We assessed the prevalence of pathogenic variants (PV) in BRCA1/ BRCA2( BRCA) and other genes, contrasting the germline mutation profile between Hispanics living in LatAm, U.S. Hispanics, women of Ashkenazi Jewish (AJ) ancestry in the US, and other U.S. non-Hispanics. Results: Among 1186 women with EOC (209 from LatAm, 254 U.S. Hispanics l, 78 AJ, and 645 other non-Hispanic), 262 (22%) had a PV in BRCAgenes. Hispanics from LatAm and the U.S. had a similar frequency of BRCAmutations to AJ (30.6%, 29.9%, and 38.4%, respectively; p = 0.14); while non-Hispanics showed a significantly lower frequency of BRCAmutations (14.2%, p = 0.03). The most frequently mutated gene was BRCA1(n = 197, 74.6%), followed by BRCA2(n = 67, 25.3%). Among BRCA-negative cases (n = 924), 59% (n = 545) were evaluated by MGPT and PVs were identified in 2.9% [6 Hispanics (1.2%), 3 AJ (3.8%) and 26 Non-Hispanics (4%)]), of which 66% (n = 23) were in mismatch repair genes ( MSH2, MLH1, MSH6, PMS2), and 34% (n = 12) in other EOC-associated genes ( BRIP1, NBN, PALB2, RAD51C, and RAD51D). Clinically actionable PVs in ATM (n = 4; 0.3% ) and CHEK2 (n = 6; 0.5% ) were also observed. Conclusions: Hispanics with EOC have an elevated frequency of PV, similar to that of classic founder populations such as AJ, and significantly higher than other non-Hispanics. This is partially explained by a high prevalence of recurrent LatAm-specific PV, highlighting the importance of conducting genetic studies in underrepresented populations. There was modest incremental benefit of MGPT.

BRCA1/2 germline mutations and response to PARP inhibitor treatment in lung cancer.

e13007 Background: Germline mutations in BRCA1/2 (BReast CAncer genes 1 and 2), which are targets for PARP inhibitors in breast and ovarian cancer, have been previously identified in patients with non-small cell lung cancer (NSCLC). However, its prevalence and clinical outcomes to targeted therapy in NSCLC still remains unknown. Methods: We conducted a retrospective review of 9,324 Chinese NSCLC patients who underwent targeted next-generation sequencing (NGS) during 2015/11/01 and 2018/10/31. Patients with BRCA1/2 somatic and germline mutations were identified. We summarized their prevalence and explored their co-existing driver mutations. Then we initially reviewed the response to PARP-inhibitor targeted therapy in patient with BRCA2 germline mutation. Results: 459 (4.9%) patients are BRCA1/2 positive (germline/somatic mutation). Most patients are diagnosed with LUAD (372, 81.1%), with a median age of 63 years (range: 2-101). Slightly more male patients were carrying BRCA1/2 mutations (59.9%, 275 out of 459). The prevalence of BRCA1 and BRCA2 somatic mutations was similar (145, 1.56% vs. 169, 1.81%, p = 0.19). BRCA2 germline mutation was more common in lung cancer than BRCA1 germline mutation (148, 1.59% vs. 20, 0.21%, p &lt; 0.0001). When specified to the common driver gene mutation subgroups, the prevalence of BRCA2 germline mutation is similar to the entire population (EGFR 1.79%; ALK 1.74%; KRAS 2.05%; BRAF 2.86%; ERBB2 0.93%; p &gt; 0.05). K2729N is the most common BRCA2 germline mutation (41, 27.7%), followed by C315S (26, 17.6%), V2109I (12, 8.1%), R2108C (11, 7.4%), I2490T (10, 6.8%), T582P (5, 3.4%). About 20% patients with BRCA2 germline mutation carried at least one concomitant mutations of DNA repair genes, including MLH1, MLH3, MSH6, CHEK2, BARD1, BLM, BRCA1, MUTYH, RAD50, RECQL4 and XRCC1. One 56-year-old male LUAS patient, with germline BRCA2 rs80359490 frameshift deletion mutation (p.S1722Yfs*4), received the targeted therapy with PARP inhibitor Olaparib after multi lines therapies. This patient showed a great PR response to Olaparib, with a PFS of at least 6 months. Conclusions: BRCA1/2 germline mutations were rare in Chinese NSCLC patients. Patients with BRCA2 germline mutations might benefit from PARP-inhibitor treatment.

A non-interventional, multicenter study to assess prevalence of BRCA1 and BRCA2 mutation among ovarian, primary peritoneal, and fallopian tube cancer patients in India.

e13073 Background: BRCA1 and BRCA2 are tumour suppressor genes.1,2 Functional BRCA proteins regulate cell growth and prevent abnormal cell division that might lead to tumour development. Approximately 17% (Range 3 – 27 %) of ovarian cancer patients worldwide have a BRCA mutation.3 This study aimed to estimate the prevalence of germline BRCA mutations among previously and newly diagnosed ovarian, primary peritoneal or fallopian tube cancer patients in India. Methods: This is a non-interventional, cross-sectional, multicenter, prospective, observational study conducted at 15 sites from different geographical regions across India. The study targets to enroll 240 patients over 6 months. The calculated sample size for this study is 228, assuming 5 % precision and a dropout rate of 10 %. The study enrolled females with new or previous diagnosis of ovarian, primary peritoneal, or fallopian tube cancer. No study medication was administered as a part of study procedure. Results: In the interim analysis performed on the first 100 enrolled patients, 22% of Ovarian, primary peritoneal or fallopian tube cancer patients were found to be BRCA1/BRCA2 mutation positive (CI 0.1433-0.3139). 52% of these enrolled patients were found to have serous histopathology, 23.1% of which were found to be BRCA1/2 positive. The percentage of BRCA1/2 mutation status in patients who had a family history of ovarian or breast cancer was found to be 66.7% and 62.5% respectively. Conclusions: In this study, the prevalence of BRCA1 and BRCA2 mutations among patients with ovarian, primary peritoneal and fallopian tube cancer patients in the first 100 patients enrolled was found to be 22%.

Prevalence of BRCA1 and BRCA2 gene mutations in Chinese patients with high-risk breast cancer.

BackgroundBreast cancer is the most common cancer among women worldwide. Here, we report the prevalence of BRCA1/2 mutations in patients with high‐risk breast cancer from Inner Mongolia and Jilin, China, which was a part of a nationwide project on the detection of BRCA1/2 mutations in Chinese patients with hereditary breast cancer.MethodsAccording to the criteria, index patients from a total of 245 independent families were initially recruited. All 49 exons of BRCA1 and BRCA2 and adjacent noncoding regions were screened for mutations based on next‐generation sequencing from collected saliva.ResultsWe detected 17 BRCA1/2 variants in 18 of 216 (8.3%) index patients with high‐risk breast cancer. Among these, seven mutations were novel, including four BRCA1 mutations (c.123_124delCAinsAT, c.5093_5096delCTAA, c.5396‐2A>G, and c.2054delinsGAAGAGTAACAAGTAAGAAGAGTAACAAGAAG), and three BRCA2 mutations (c.304A>T, c.7552_7553insT, and c.9548_9549insA). The BRCA1/2 variants were identified in 14% (8/57) of the patients with triple‐negative breast cancer and in 6.3% (10/159) of the patients with non‐triple‐negative breast cancer. There was no significant difference between the two groups (p = 0.07). A higher frequency for BRCA1 mutations was observed in patients with triple‐negative breast cancer than in those with non‐triple‐negative breast cancer (12.3% vs. 2.5%, p = 0.004). The frequencies of the BRCA2 mutations were not significantly different between patients with triple‐negative breast cancer and those with non‐triple‐negative breast cancer (1.8% vs. 3.8%, p = 0.46).ConclusionWe found that patients with triple‐negative breast cancer had a higher frequency of BRCA1 mutations than those with non‐triple‐negative breast cancer. In this study, no significant associations between the BRCA1/2 mutation status and age, family history of breast cancer, ovarian cancer, pancreatic cancer and prostate cancer, number of primary lesions, tumor size, or lymph node metastasis were observed.

Prevalence of BRCA mutations among hereditary breast and/or ovarian cancer patients in Arab countries: systematic review and meta-analysis

BackgroundTo systematically assess the prevalence of BRCA1 and BRCA2 gene mutations in women with Hereditary Breast and/or Ovarian Cancer (HBOC) in Arab countries and to describe the variability in the BRCA gene mutations in different regions of the Arab world.MethodsObservational studies reporting prevalence of BRCA mutations from 22 Arab countries were systematically searched in databases including PUBMED, EMBASE, Web of Science, and Google Scholar. Two reviewers independently screened the studies and extracted data and assessed the risk of bias. Hoy’s risk of Bias tool was used to assess the biases in individual studies. Due to substantial heterogeneity, pooled weighted estimates were calculated using Quality Effect Models (QEM) that adjust for bias, while the Random Effect Models (REM) estimates served as the sensitivity estimates.ResultsFourteen studies reporting prevalence of BRCA were included. The pooled estimate of BRCA among HBOC was 20% (95% CI: 7–36%). Subgroup analysis including only those with low risk of bias provided an estimate of 11% (95% CI: 1–27%). Levant region had higher prevalence 28% (95% CI: 11–49%) compared to Arabian Gulf region and North Africa but differences are not statistically significant, when tested using Z-test for proportions.ConclusionGiven the pooled estimates vary widely with substantial heterogeneity, larger, well-designed studies are warranted to better understand the frequency and the impact of BRCA gene mutations among Arab women.Trial registrationInternational Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42018095905.

P092 - Prevalence of BRCA 1 and BRCA 2 in breast cancer in India

P092 - Prevalence of BRCA 1 and BRCA 2 in breast cancer in India