Genetic Testing For BRCA1 Mutations Research Articles

Abstract PO4-08-08: Is it time for a European BRCA Mutation Registry? An Italian experience

Abstract Background: Knowledge of BRCA 1/2 mutation plays an important role in cancer care. The National Plan to improve BRCA detection in order to increase access to target agents and ameliorate the prevention strategy has several implementations in the Italian regions. Recent guidelines are considering extending genetic testing to a larger population, regardless of family history. We present our experience in Apulia Region on the detection of BRCA 1/2 and its clinical implication at the regional level, to underline the importance of spreading the extension of BRCA detection at the regional level and to propose the creation of a European register for BRCA patients, based on population-based BRCA 1/2 testing. Methods: This is an observational study conducted at a Familiar Cancer Service of the Lecce Hospital. Participants completed a questionnaire (socio-demographic epidemiology of cancer and lifestyle factors), genetic counseling and BRCA testing. Notably, genetic testing for BRCA mutations was carried out based on family cancer history since 2018, according to the Italian cancer guidelines (AIOM) and related updates in 2019 and 2023. A mutational analysis of exons and adjacent intronic regions of BRCA1/BRCA2 genes was performed by Sanger sequencing and MiSeq Illumina NGS platform. Results: Between 2014 and May 2023 a total of 4365 patients were enrolled in the study, of whom 2426 (56%) was evaluable for BRCA detection, 18% men (n=440) and 82% female (n=1986). Median age at diagnosis was 57 yrs. 65% of patients had a cancer diagnosis (n=1575) and 35% were healthy carriers (n=851). In particular, breast cancer (BC) was present in 63% of patients (n=1048), ovarian cancer (OC) in 21% (n=352), pancreatic cancer in 5% (n=85), prostate cancer in 4% (n=65), melanoma in 1% (n=13), and other cancers in 6% (n=92). The table 1 (uploaded) shows the results of patients with BC (n=1048) The presence of BRCA mutation is observed in 20.52% of BC patients (1:4.87). Conclusion These data confirm that BRCA mutation detection is an emerging need to improve prevention and early diagnosis according to the European Beating Cancer Plan. Therefore, it is crucial to improve this topic at regional level until the creation of a shared BRCA registry among European countries. Table. Citation Format: Elisabetta De Matteis, Mariangela Ciccarese, Paolo Tarantino, Tiziana Grassi, Francesco Bagordo, Emanuele Rizzo, Maria Rosaria Tumolo, Graziana Ronzino, Maria Rita De Giorgio, Salvatore Mauro, Nicola Di Renzo. Is it time for a European BRCA Mutation Registry? An Italian experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-08.

Abstract P2-09-17: Family communication and attitude of patients with breast cancer toward positive pathogenic BRCA1 or BRCA2 mutations. A regional perspective

Abstract Background: Since the discovery of breast cancer susceptibility genes BRCA1 & BRCA2 and the availability of genetic testing, a considerable amount of research has been conducted to evaluate rates of genetic test acceptance and to understand the psychological and behavioural impact of genetic test results on both patients and their family members. This study aims to explore the experience of women who tested positive for a cancer-predisposing gene, and to identify risk reduction interventions patients had or planning to have and study if patients communicated genetic test results with at-risk family members and intervention made by the family members. Methods: A questionnaire was designed to assess socio-demographic factors, personal and family history of cancer, genetic test results and family notification of testing, and subsequent testing in relatives. Participants were invited to participate in the study during their visit to their oncologist clinic, in addition to patients that were invited via Teleclinic using different meeting platforms. Results: Ninety-nine patients with the pathogenic BRCA 1 or BRCA 2 mutations, who were diagnosed with breast cancer between the years 2005 and 2020, were enrolled in the study. The Mean age of participants was 45 years (range from 27 to 77 years). The patients reported different emotional reactions to the positive results of cancer genetic testing; 39 (39%) experienced feelings of anxiety, 69 (69%) were afraid about the risk of their children carrying the disease. While 24 (24%) of participants reported they felt comforted because they can take preventive measures for them and their family members and only 5 (5%) were worried about health insurance coverage. Thirteen (13%) of the patients reported that their social status had been affected by the genetic testing results. The majority (n=74, 74%) believed in the importance of communicating the results with their families. Ninety-eight (98%) patients have informed their family members of the results and only 1 (1%) did not inform anyone of the results. In total, 922 relatives were informed of the results of genetic testing and only 31 (3.3%) underwent genetic testing in response. A total of 379 first degree female relatives (mother, sister, and daughter) were informed about the genetic testing results and only 24 (6.6%) underwent genetic testing for BRCA mutations and only 8 (2%) patients underwent a prophylactic mastectomy. The reasons that prevented the informed family members from undergoing the genetic testing were diverse. As reported by the patients participating in the study, the cost of testing was the most reported reason in 54% of the time. And 52 patients (52%) considered fear from having a positive test as the main reason. The social stigma of carrying a cancer gene was also a factor in 16% of cases. Conclusion: Despite the high rate of communicating BRCA results with family members, there is lack of awareness of the proper preventive measures to be followed to decrease the risk of breast cancer. Citation Format: Rawan Mustafa, Khawla Ammar, Rana Damsees, Maryam El-Atrash, Rayan Bater, Sama Almasri, Faris Tamimi, Lama Abujamous, Hikmat Abdel-Razeq. Family communication and attitude of patients with breast cancer toward positive pathogenic BRCA1 or BRCA2 mutations. A regional perspective [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-17.

270P - Evaluation of germ line mutational status among women with triple-negative breast cancer in Russia

BackgroundPathogenic germline BRCA1/2 mutations are found in higher rates in patients with triple negative breast cancer (TNBC). As a result, genetic BRCA mutation testing would be beneficial for this particular group of patients. At the same time, it is less clear if mutational burden in other cancer predisposition genes is more frequent in TNBC and has to be recommended for genetic testing. In the current study we aimed to characterize pathogenic germline mutations in TNBC patients fulfilling NCCN criteria of hereditary cancers from Russian Federation. MethodsIndividuals with diagnosis of TNBC were selected to be included in this study according based on the following criteria: (1) young age of disease onset, (2) the presence of relatives with breast or ovarian cancer diagnosis. The NimbleGen SeqCap EZ Choice kit (“Roche”) was used for target enrichment, and sequencing was performed using Illumina MiSeq (“Illumina”). Custom bioinformatic pipeline, including Annovar, HGMD Professional 2017.4 and BIC databases were used to identify pathogenic mutations. Results128 patients with triple negative breast cancer aged from 24 to 79 years old were included in this study. 42 woman has their first cancer diagnosis before 40 years old, 77 – between 41 and 60 years old, 9 - were older than 60. 42 patients (33%) carried pathogenic or likely pathogenic variant in BRCA1 gene,10 (8%) in BRCA2 gene and 40 (31%) in one of other genes, including BUB1, CDH1, CDKN2A, CHEK2, EPCAM, FANCI, MLH3, MSH6, PALB2, PMS2, POLE, POLE, RAD50, RBBP8, RET, STK11, APC, ATM, BARD1, BLM. 13 woman had double mutation in two genes, and one patient had double mutation in BRCA1 gene. For the BRCA1 carriers subgroup, the median age at diagnosis was 41(24-64), BRCA2 carriers – 44 (27-62) and other genes carriers – 48 (28-79) year old. Patients with double mutation had median age of cancer manifestation at 42 (32-65). ConclusionsApproximately 38% of patients with TNBC fulfilling NCCN criteria of hereditary cancer are carriers of pathogenic and likely pathogenic mutations in BRCA1 and BRCA2 genes. And up to 40% - in other cancer susceptibility genes. Thus, the patients with TNBC might be recommended for extended genetic testing depending on age of onset and the presence of a cancer family history. Legal entity responsible for the studyTatarstan Cancer Center. FundingThe work is supported by Russian Foundation for Basic Research № 18-415-160009 and according to the Russian Government Program of Competitive Growth of Kazan Federal University. DisclosureAll authors have declared no conflicts of interest.

Views of Icelandic women towards genetic counseling - and testing of BRCA2 mutations

Introduction The aim of this study was to explore the attitudes of Icelandic women towards existing genetic information, genetic counseling and genetic testing for BRCA mutations which dramatically increase risk for aggressive cancers. Materials and methods Women attending the cancer prevention clinic in Reykjavik, capital of Iceland, from October 12th until November 20th 2015 received an invitation to participate. Participation involved answering a short online questionnaire about background, family history of cancer as well as attitudes towards genetic counseling, BRCA testing and preventive use of such information. Descriptive statistics and chi-square tests were used to describe differences in attitudes towards those questions between subgroups of women. Results 1129 women (69% response rate) answered the questionnaire. Mean age was 47 years (span 21-76 years). Around half (47%) had heard fairly much about the mutations. Independent of family history of cancer, the majority of women were positive towards receiving genetic counseling (79%) and to undergo genetic testing (83%) for BRCA mutation with younger women being more interested than older women. On the other hand, only 4% of the women had already received genetic counseling and 7% undergone genetic testing. Women with family history of cancer were more knowledgeable about BRCA mutations (p<0.0001) and were less afraid of the consequence of being a mutation carrier (p<0.0001) compared to those with little or no family history. Regardless of family history, half (49%) worried that results from genetic testing could influence their health insurance. Almost all, or 97% of the women, were positive or very positive toward using existing genetic information obtained through scientific work, to inform affected indi-viduals of their mutation status. Conclusion Icelandic women are positive towards genetic counseling and testing for BRCA mutations although half of them worry that a positive result might affect their health insurance. Nevertheless, almost all women believe that existing genetic information should be used to inform carriers for preventive purposes.

498 (PB-131) - Genetic testing for BRCA mutations in breast cancer in Europe: Barriers and opportunities

498 (PB-131) - Genetic testing for BRCA mutations in breast cancer in Europe: Barriers and opportunities

Could recurrent aphthous stomatitis be linked to cancer development?

Background: Recurrent aphthous stomatitis is a common multifactorial oral mucosal disorder. Genetic and local factors causing RAS may contribute to the development of cancer. This study aims to explore this connection by examining a family with a history of RAS and ovarian cancer. Case Description: The family described in the case exhibits a history of minor recurrent aphthous stomatitis. The severity of this condition increases with each generation. One member of the family has no history of RAS but was diagnosed with ovarian cancer. Genetic testing for BRCA mutations was negative indicating a different genetic cause of the cancer. All affected members of the family indicate high levels of stress or difficulty responding to stressful situations. No treatment for RAS was performed due to its self-limiting nature. Practical Implications: Further research is needed before dentists begin to tell their patients with RAS they may be at higher risk of developing cancer. Diligent oral cancer screening and stress management counseling can decrease the risk to the patient.

BRCA1 and BRCA2 mutation predictions using the BRCAPRO and Myriad models in Korean ovarian cancer patients

ObjectiveTo evaluate the predictive efficacies including sensitivity and positive predictive value of the genetic risk prediction model BRCAPRO and the Myriad BRCA risk calculator in Korean ovarian cancer patients. MethodsIndividuals undergoing genetic testing for BRCA mutations from November 2010–August 2016 were recruited from the Department of Obstetrics and Gynecology at a single institute in Korea. The observed BRCA1 and BRCA2 mutation statuses were compared with the predicted carrier probabilities using BRCAPRO and the Myriad BRCA risk calculator. ResultsTwo hundred thirty-two patients were recruited, of whom 99.1% (230/232) were of Korean ethnicity. Of the 232 individuals, 206 and 26 had ovarian and double primary breast/ovarian cancer, respectively. Thirty-six individuals had a family history of breast/ovarian cancer in first-degree relatives. Fifty-seven patients (24.6%) tested positive for BRCA mutation (41 BRCA1, 16 BRCA2). The mean BRCAPRO and Myriad scores for all patients were 6.4% and 7.7%, respectively. The scores were significantly higher for patients with positive BRCA mutation status (29.0% vs. 6.1%, P<0.001, 12.1% vs. 7.7%, P<0.001, respectively). For all patients, the respective areas under the receiver operating characteristics curves were 0.720 and 0.747 for the BRCAPRO and Myriad models to predict the risk of carrying a BRCA mutation. Both models overestimated the mutation probability in patients with a family history of breast/ovarian cancer (1.55-fold and 1.50-fold, respectively) and underestimated the probability in patients without a family history (both, 0.54-fold). ConclusionBRCAPRO and Myriad seem to be acceptable risk assessment tools for determining the risk of carrying BRCA mutations in Korean ovarian cancer patients.

Abstract P6-12-09: Uptake of genetic testing for BRCA mutations in a medically underserved population

Abstract Introduction: Genetic testing for hereditary cancer syndromes is recommended in specific populations to identify individuals at increased risk for developing malignancies. The uptake of genetic testing for BRCA mutations in studies has ranged from 44%-81% but has not been well studied in medically underserved populations. In this study we identified factors that predicted uptake of genetic testing among a medically underserved population undergoing genetic counseling in the Cancer Risk Program at a safety net hospital in Chicago. Methods: A retrospective cohort design was used. Data were abstracted from the medical records of 150 consecutive individuals who underwent genetic counseling for BRCA mutation testing in the Cancer Risk clinic at John H Stroger Jr., Hospital of Cook County between October 2013 and July 2014. The primary outcome measure was the uptake of genetic testing among individuals in whom the test was recommended after genetic counseling. Final testing status was assessed as of April 30, 2015. Individuals referred for testing of genetic syndromes other than hereditary breast and ovarian cancers were excluded from this analysis. Data regarding personal and family history of cancer and socio-demographic determinants- age, sex, ethnicity and insurance status were collected. Results: Among the 150 individuals who underwent genetic counseling, the mean age was 49 years (range 19-74 years) and only 5 were men. Forty-three percent were African American, 34% were Hispanic and 11% were Caucasian. Sixty seven percent were uninsured and 30% had public insurance. Forty-one percent had a personal history of cancer (36% with breast cancer, 3% with pelvic cancer). Eighty five percent of the individuals had 2 or more relatives with cancer in the family. Genetic testing was recommended in 112 individuals (75%) after assessment and counseling by the genetic counselor. Of those recommended, 89 individuals (80%) underwent genetic testing. Among the men, 4 (80%) were recommended for testing and 3 (75%) underwent testing. Genetic testing was not recommended for 20 individuals (13%) and of the remaining 18 individuals (12%), testing of a living affected relative was recommended first. Only one of the 18 individuals returned with genetic test results from an affected family member during the study period. The only positive predictor of testing was age less than 50 years (OR 3.63; 95% CI 1.31-10.08). Having one or more siblings with cancer was a negative predictor of uptake of testing (OR 0.35; 95% CI 0.13-0.90). Conclusions: Uptake of genetic testing was high among our cohort of medically underserved individuals. While prior studies have shown a variable association between age and uptake of testing, younger individuals in our cohort were more likely to undergo testing. Interestingly, while most studies have shown an increased uptake of testing among individuals who have a family history of cancer, having cancer in a sibling was a barrier to testing in our cohort and warrants further study. The very low number of men counseled and tested during the study period also suggests that strategies are needed to extend genetic counseling and testing to at-risk men in medically underserved communities. Citation Format: Gaber RS, Thekkekara RJ, Gil DN, Holden CM, Aluen Metzner I, Marcus E, Ganschow PS. Uptake of genetic testing for BRCA mutations in a medically underserved population. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-12-09.

Abstract IS01: Brca testing in high-risk populations

Abstract The traditional family-history (FH) based approach to genetic testing for BRCA mutations misses &amp;gt;50% of at risk carriers. BRCA mutations (founder mutations) are more prevalent in some populations (e.g. Ashkenazi Jews). Risk models used for this purpose are moderately affective at predicting a mutation but have poor ability/NLR at ruling out a BRCA mutation. Technological advances have raised the possibility of systematic population-based genetic testing for BRCA mutations in these populations but some uncertainty has remained on whether risks outweigh the benefits. A randomised controlled trial (GCaPPS, ISRCTN73338115) of BRCA1/2 gene-mutation testing in the Ashkenazi-Jewish (AJ) population compares psychological/quality-of-life consequences of Population-Screening (PS) with testing those fulfilling standard FH-based clinical criteria alone. A decision analytic model has compared cost-effectiveness of population-based BRCA testing with the standard FH-based approach in AJ women over 30 years. Model probabilities utilise GCaPPS trial/published literature to estimate total costs, effects in terms of Quality-Adjusted-Life-Years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER) and population impact. AJ population and BRCA-test result data (from 2000-2010) obtained through ONS and all London NHS clinical genetics laboratories provide NHS BRCA detection rates. This along with BRCA prevalence estimates were used to calculate and simulate (n=10000000) time-to-detect all FH-positive BRCA-carriers in the London AJ-population (BRCA incidence=binomial distribution; rate of detection=Poisson distribution). Impact of changes in NHS funding and BRCA prevalence were assessed assuming correlations: ρ=0.25, 0.5, 0.75. 30 BRCA-carriers were identified in 1034 Ashkenazi-Jews, giving a BRCA1/2 prevalence= 2.9%(CI:1.97,4.12): BRCA1= 1.55%(CI:0.89,2.5), BRCA2= 1.35%(CI:0.74,2.26). 18/30 (60%) were FH-negative and not identified using clinical criteria. The prevalence of FH-positive/FH-negative carriers= 1.16%/1.74%. FH-based testing has a sensitivity= 40%(CI:22.7,59.4%), specificity= 88.45%(CI:86.3,90.4%), PLR= 3.46 (CI:1.95,5.34) and NLR= 0.68 (CI:0.46,0.87). There was no significant difference between FH and PS-arms at 7-days or 3-months for a range of psychological measures of anxiety, depression, health-anxiety, distress, uncertainty and quality-of-life. Overall anxiety (p=0.0001), and uncertainty (p=0.0008) associated with genetic testing decreased, but quality-of-life and health anxiety did not change with time. The BRCA detection rate in London AJ from 2006-2010 =34.2/year, with the pattern being randomly spread (Poisson-model goodness-of-fit test (p=0.439). Modelling BRCA detection rates and BRCA prevalence estimated it would take 44.8 years (CI: 21.02, 66.76) to detect all FH-positive BRCA carriers in London. Compared to FH-based testing population-screening can save 0.090 more life-years and 0.101 more QALYs resulting in 33 days gain in life-expectancy. Population-screening is cost saving with a baseline discounted ICER of -2079£/QALY. This approach may lead to 276 fewer ovarian and 508 fewer breast cancer cases in the UK. Compared to FH-based testing, population-based genetic testing in Ashkenazi-Jews doesn't adversely affect short term psychological/quality-of-life outcomes, detects additional BRCA carriers and is highly cost effective. Efficient, acceptable and more cost-effective ways of delivering information on genetic risk on a population basis are also necessary for this. Telephone and DVD based approaches have been found to be cost efficient. This suggests the feasibility of a population based approach in some populations with a high BRCA prevalence. It could have significant policy implications for the AJ population (and potentially other similar populations) which can save lives, but will require a change in the current paradigm of a FH-based approach to genetic testing in such populations. Citation Format: Ranjit Manchanda, MD, MRCOG, PhD. Brca testing in high-risk populations [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr IS01.

Exome sequencing in a breast cancer family without BRCA mutation.

PurposeWe performed exome sequencing in a breast cancer family without BRCA mutations.Materials and MethodsA family that three sisters have a history of breast cancer was selected for analysis. There were no family members with breast cancer in the previous generation. Genetic testing for BRCA mutation was negative, even by the multiplex ligation-dependent probe amplification method. Two sisters with breast cancer were selected as affected members, while the mother of the sisters was a non-affected member. Whole exome sequencing was performed on the HiSeq 2000 platform with paired-end reads of 101 bp in the three members.ResultsWe identified 19,436, 19,468, and 19,345 single-nucleotide polymorphisms (SNPs) in the coding regions. Among them, 8,759, 8,789, and 8,772 were non-synonymous SNPs, respectively. After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother. Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined.ConclusionUsing exome sequencing, we found 7 variants for a breast cancer family without BRCA mutations. Genetic evidence of disease association should be confirmed by future studies.

Pros and Cons of Screening for BRCA Mutations

Estimates suggest that about 80% of breast cancers and 90% of ovarian cancers are sporadic [1]; only 5% to 10% of breast cancers are hereditary. Hereditary mutations of the BRCA1 and BRCA2 genes account for 60% of inherited breast and ovarian cancers [1]. According to data from the National Cancer Institute [2], the risk of a BRCA2 mutation carrier developing breast cancer by age 70 years is 45%, and her risk of developing ovarian cancer is 11%–17%; BRCA1 mutation carriers have a slightly higher risk of breast cancer (55%–65%) and a higher risk of ovarian cancer (39%). Until recently, the management of breast cancers resulting from a BRCA mutation did not differ from management of sporadic tumors. However, genetic information is now important in planning surgeries and adjuvant therapies, and genetic testing for BRCA mutations is increasingly being used for risk assessment. This article will examine the pros and cons of such testing and discuss how it can affect patient care.

Implementation of a breast cancer genetic service in South Africa – lessons learned

Genetic testing for BRCA mutations has been available in the Western Cape of South Africa since 2005, but practical implementation of genetic counselling and testing has been challenging. To describe an approach to breast cancer genetic counselling and testing developed in a resource-constrained environment at Tygerberg Hospital in Cape Town, Western Cape. Genetic counselling is offered in a stepwise manner to our diverse patient population, with a focus on affected probands, and subsequent cascade testing. A record review of BRCA testing between 2005 and 2011 was performed. RESULTS; During this period 302 probands received genetic testing, with increasing numbers tested over time. Of 1 520 women treated for breast cancer since 2008, 226 (14.9%) accepted BRCA testing, and 39 tested positive (17.3% of those tested, and 2.6% of all women). Common founder mutations were detected in 11.9% of women (36/302), and comprised 73% (36/49) of mutations detected. Cascade testing increased after 2010: 16 female and 4 male family members of 19 probands accepted testing, with 6 positives being detected. A protocol-driven approach focusing on probands, with initial pre-test counselling by primary care staff has proven effective in establishing the service. Involvement of a clinical geneticist/genetic counsellor has permitted more detailed post-test counselling and increased use of cascade testing.

A guide for functional analysis ofBRCA1variants of uncertain significance

Germline mutations in the tumor suppressor gene BRCA1 confer an estimated lifetime risk of 56-80% for breast cancer and 15-60% for ovarian cancer. Since the mid 1990s when BRCA1 was identified, genetic testing has revealed over 1,500 unique germline variants. However, for a significant number of these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical significance. Importantly, these methods may provide a framework for genome-wide pathogenicity assignment.

Identification of the prevalent BRCA1 and BRCA2 mutations in the female population of Puerto Rico

Mutations in the breast cancer 1, early onset (BRCA1) and breast cancer 2 (BRCA2) genes are responsible for the majority of hereditary breast cancers. Knowledge of the incidence and prevalence of BRCA mutations in a specific population or ethnic group is necessary to provide accurate genetic counseling for breast cancer patients and their families; however, these data have not been gathered in the population of Puerto Rico. We conducted a retrospective study of female breast cancer patients undergoing genetic testing for BRCA mutations in the highest-volume breast surgery practices in San Juan, Puerto Rico. Data collection includes three-generation family cancer history and results from complete BRCA sequencing. A total of six different deleterious mutations were observed, including one mutation in BRCA1 and five mutations in BRCA2. Three recurrent mutations (BRCA1 del exon1-2, BRCA2 4150G>T, and BRCA2 6027del4) account for over 70% of all the BRCA mutations observed in this study population. This study examines for the first time the characteristics of hereditary breast cancer in Puerto Rico and assesses the accuracy of existing genetic risk assessment tools in that population. This data is expected to contribute to providing accurate and efficient tools for the clinical management of hereditary breast cancer in Puerto Rico.

Associations betweenBRCAMutations in High-Risk Breast Cancer Patients and Familial Cancers Other than Breast or Ovary

PurposeWe investigated the relationship between BRCA mutations and the distribution of familial cancers other than breast or ovary in high-risk breast cancer patients.MethodsPatients with breast cancer who had at least one of the following risk factors were enrolled: reported family history of breast or ovarian cancer; 40 years of age or younger age at diagnosis; bilateral breast cancer; or male gender. Genetic testing for BRCA mutation and questionnaires about personal and family histories of malignancies were performed.ResultsAmong the 238 eligible patients, 49 (20.6%) patients had BRCA1/2 mutations, which were more frequent in patients with multiple risk factors (p<0.0001). There were 271 members of 156 (65.5%) families who had histories of other primary cancer. The distribution of the families was 119 (63.0%) and 37 (75.5%) in the BRCA-negative and positive group, respectively (p=0.0996). Multiple familial cancers occurred in 70 families, which were significantly more frequent in BRCA-positive families (p=0.0034). By ordinal logistic regression, the occurrence of multiple familial cancers was associated with BRCA mutations (p=0.0045), not with other risk factors. The most common site of disease was the stomach, which is the most common in nationwide. And the proportional incidence of pancreatic cancer (6.8%) was significantly higher than that of nationwide cancer statistics (2.4%, p=0.0137).ConclusionBRCA mutations in high-risk breast cancer patients were associated with multiple risk factors and multiple family members with other primary cancers. Genetic counseling based on accurate information should be provided to families with BRCA mutation carriers.

The impact of risk information exposure on women's beliefs about direct-to-consumer genetic testing for BRCA mutations.

Despite an increase in direct-to-consumer (DTC) genetic testing, little is known about how variations in website content might alter consumer behavior. We evaluated the impact of risk information provision on women's attitudes about DTC BRCA testing. We conducted a randomized experiment; women viewed a 'mock' BRCA testing website without [control group (CG)] or with information on the potential risks of DTC testing [RG; framed two ways: unattributed risk (UR) information and risk information presented by experts (ER)]. Seven hundred and sixty-seven women participated; mean age was 37 years, mean education was 15 years, and 79% of subjects were white. Women in the RG had less positive beliefs about DTC testing (mean RG = 23.8, CG = 25.2; p = 0.001), lower intentions to get tested (RG = 2.8, CG = 3.1; p = 0.03), were more likely to prefer clinic-based testing (RG = 5.1, CG = 4.8; p = 0.03) and to report that they had seen enough risk information (RG = 5.3, CG = 4.7; p < 0.001). UR and ER exposure produced similar effects. Effects did not differ for women with or without a personal/family history of breast/ovarian cancer. Exposing women to the potential risks of DTC BRCA testing altered their beliefs, preferences, and intentions. Risk messages appear to be salient to women irrespective of their chance of having a BRCA mutation.

Risk of having BRCA mutations in women with triple-negative breast cancer: A systematic review and meta-analysis.

160 Background: Increased prevalence of BRCA1 mutations (BRCA1) has been associated with the occurrence of triple-negative breast cancer (TNBC) (estrogen receptor [ER]- and progesterone receptor [PR]-negative, HER2-negative) in independent clinical studies. However, BRCA2 mutation (BRCA2) has not been found to overrepresent in women with TNBC. We have performed a meta-analysis of these studies to provide further statistical evidence of the association between BRCA positivity and TNBC. Methods: A Medline search of the MeSH terms “BRCA”, “triple”, and “negative” yielded 37 articles. A search of ASCO abstracts yielded 18 relevant articles. Random effects model was used for analysis due to heterogeneity among the proportions of included studies (Cochran’s Q = 18.52 and 15.18, tau2 = 0.61 and 1.29, I2 = 73% and 80% for BRCA1 and BRCA2 respectively). Mantel-Haenszel method was applied to calculate the pooled event-based odds ratio (OR) with 95% confidence interval (CI). Results: 6 studies including 1,602 BC patients were eligible for analysis of BRCA1 and 4 studies including 1297 BC patients for BRCA2. 172 patients with BRCA1 mutations and 79 patients with BRCA2 mutations were analyzed. Among these 6 studies, 1 included Ashkenazi Jewish women exclusively and 1 included only women of Chinese descent. The overall prevalence of BRCA1 was 10.05% (172 out of 1,602), and for TNBC patients 21.94% (95 out of 433) with an odds ratio of 5.90 (CI: 2.75, 12.66, p &lt; 0.00001). TNBC was not a risk for BRCA2 (OR = 0.67, CI: 0.19, 2.39, p = 0.53). Chinese women with TNBC did not have an elevated risk of BRCA1 (OR = 0.94, CI: 0.24, 3.66) in contrast to Jewish women with TNBC who had the highest risk of BRCA1 among the populations studied (OR = 21.79, CI: 9.03, 52.55). Conclusions: Women with TNBC carry a significantly high risk of having BRCA1 but not BRCA2 mutations. We recommend genetic testing for BRCA1 mutations in women with TNBC especially in Ashkenazi Jewish population. Further studies on Chinese population are needed to further establish the relationship between TNBC and BRCA1 mutations in this cohort.

Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ

It is unclear whether women with ductal carcinoma in situ (DCIS), like their counterparts with invasive breast cancer, warrant genetic risk assessment and testing on the basis of high-risk variables. The authors of this report identified predictive factors for mutations in the breast cancer-susceptibility genes BRCA1 and BRCA2 in women who were diagnosed with DCIS. One hundred eighteen women with DCIS who were referred for genetic counseling and underwent genetic testing for BRCA1/BRCA2 mutations between 2003 and 2010 were included in the study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. Of 118 high-risk women with DCIS, 27% (n = 32) tested positive for BRCA1/BRCA2 mutations. Of those, 10% (n = 12) and 17% (n = 20) had BRCA1 and BRCA2 mutations, respectively. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. In a multivariate logistic model, ≥2 relatives with ovarian cancer (OC) (odds ratio [OR], 8.81; 95% confidence interval [CI], 1.38-56.29; P = .034), and a score ≥10% according to the BRCAPRO mathematical model for calculating the probability that a particular family member carries a germline BRCA mutation (OR, 6.37; 95% CI, 2.23-18.22; P = .0005) remained as independent significant predictors for a BRCA mutation. Fifty-seven percent of mutation carriers but only 25% of noncarriers underwent prophylactic mastectomy(P = .0037). This difference remained significant for patients aged ≤40 years (P = .025). Women who had DCIS and a family history of OC or who had BRCAPRO scores ≥10% had a high rate of BRCA positivity regardless of age at diagnosis. These findings suggest that high-risk patients with DCIS are appropriate candidates for genetic testing for BRCA mutations in the presence of predictive factors even if they do not have invasive breast cancer.

Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ.

1512 Background: The frequency of a BRCA mutation among women with ductal carcinoma in situ (DCIS) has not been well described. Consequently, patients with DCIS were not historically considered ideal candidates for genetic testing even in the presence of a family history of breast and ovarian cancer. Therefore, we examined the prevalence of BRCA1/2 mutations in women diagnosed with DCIS. Methods: Patients with DCIS, who were referred for genetic counseling and underwent genetic testing, were included in the study. Patient characteristics were obtained from a prospectively maintained research database. This study was approved by institutional review board. The likelihood of carrying a BRCA mutation was calculated using the BRCAPRO model (Version 5.1). Chi-square analysis was used to determine the difference among mutations carriers vs. non-carriers with DCIS. Results: One hundred and twenty nine patients diagnosed with DCIS underwent genetic testing for BRCA mutations. Twenty-eight percent (37/129) of DCIS patients tested positive for a deleterious BRCA mutation (15 BRCA1, and 22 BRCA2). In addition, 6 were found to have a variant of uncertain significance (VUS). The average age of diagnosis was 46.2 yrs (30-69) in BRCA positive patients and 43.5 yrs (26-65) in BRCA negative patients (p =0.177). Patients who tested positive for the BRCA mutations had significantly more family history of breast and ovarian cancer (p=0.021, p=0.006 (respectively) than those who tested negative; as reflected by the BRCAPro calculation (p ≤0.0001). Fifty seven percent of BRCA positive patients had one breast removed for prophylactic reasons while only 28% BRCA negative patients did (p=0.004). This effect was significantly stronger for patients ≤40 (p=0.007). Conclusions: Patients with DCIS and a family history of breast and/or ovarian cancer have a high rate of BRCA positivity regardless of age. These findings suggest that patients with DCIS are appropriate candidates for genetic testing in the presence of family history and regardless of age even if they do not have invasive cancer.

Genetic Testing for BRCA Mutations Can Save Lives

JAMA Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality Susan M. Domchek, MD; Tara M. Friebel, MPH; Christian F. Singer, MD, MPH; D. Gareth Evans, MD; Henry T. Lynch, MD; Claudine Isaacs, MD; Judy E. Garber, MD, MPH; Susan L. Neuhausen, PhD; Ellen Matloff, MS; Rosalind Eeles, PhD; Gabriella Pichert, MD; Laura Van t’veer, PhD; Nadine Tung, MD; Jeffrey N. Weitzel, MD; Fergus J. Couch, PhD; Wendy S. Rubinstein, MD, PhD; Patricia A. Ganz, MD; Mary B. Daly, MD, PhD; Olufunmilayo I. Olopade, MD; Gail Tomlinson, MD, PhD; Joellen Schildkraut, PhD; Joanne L. Blum, MD, PhD; Timothy R. Rebbeck, PhD Context: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. Objective: To estimate risk and mortality reduction stratified by mutation and prior cancer status. Design, Setting, and Participants: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. Main Outcomes Measures: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. Results: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). Conclusions: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality. doi:10.1001/jama.2010.1237.