Characterization of Patients with Breast Cancer and National Comprehensive Cancer Network Criteria for Performing BRCA1 and BRCA2 Genetic Test / Caracterização de Pacientes com Câncer de Mama e Critérios da National Comprehensive Cancer Network para Realização do Teste Genético BRCA1 e BRCA22 / Caracterización de Pacientes con Cáncer de Mama y Criterios de la National Comprehensive Cancer Network para Realizar Prueba Genética de BRCA1 y BRCA

Introduction: Approximately 10% of breast cancer cases are attibutable to germinative mutations in susceptibility genes, including BRCA1, BRCA2 and others. The National Comprehensive Cancer Network (NCCN) recommends screening women with breast cancer for mutations in BRCA1/2 in defined scenarios. However, these genetic tests are unavailable at the Brazilian Public Health System (SUS). Objective: This study aimed to characterize women with breast cancer and define the criteria for performing BRCA1/2 test. Method: Quantitative, descriptive, analytic, and retrospective study. Medical records of women diagnosed by SUS with breast cancer between January 2016 and December 2018 were analyzed through the software JAMOVI (version 2.3 - 2022). Results: A total of 245 women were diagnosed. According to NCCN guidelines, 97 women met the criteria for performing BRCA1/2 test, with mean age of 47 years old, predominantly white (90,7%), with comorbidities (55.6%), premenopausal (59.8%), diagnosed in early stages 0 - IIb (68.2%) and 48.4% had familial history of breast cancer. Most frequent histology and molecular subtype was invasive ductal carcinoma (87.2%) and luminal type (59.8%). Conclusion: A significant number of women diagnosed by SUS had indication for BRCA1/2 test. These women are younger, had fewer comorbidities, not menopausal, and differ in terms of the molecular subtype when compared with those without indication for performing the test

Introdução: Aproximadamente 10% dos casos de câncer de mama são atribuíveis a mutações germinativas em genes de suscetibilidade, incluindo BRCA1 e BRCA2. A National Comprehensive Cancer Network (NCCN) recomenda a triagem de mulheres com câncer de mama para mutações em BRCA1/2 em cenários definidos. No entanto, esses testes genéticos não estão disponíveis no Sistema Único de Saúde (SUS). Objetivo: Caracterizar as mulheres com câncer de mama e definir os critérios para realização do teste BRCA1/2. Método: Estudo quantitativo, descritivo, analítico e retrospectivo. Foram analisadosprontuários de mulheres com diagnóstico de câncer de mama pelo SUS entre janeiro de 2016 e dezembro de 2018, por meio do software JAMOVI (versão 2.3 - 2022). Resultados: Foram diagnosticadas 245 mulheres. De acordo com as diretrizes da NCCN, 97 mulheres atenderam aos critérios para realizar o teste BRCA1/2, com idade média de 47 anos, predominantemente brancas (90,7%), com comorbidades (55,6%), na pré-menopausa (59,8%), diagnosticadas nos estágios iniciais 0 - IIb (68, 2%), e 48,4% tinham histórico familiar de câncer de mama. A histologia e o subtipo molecular mais frequentes foram carcinoma ductal invasivo (87,2%) e tipo luminal (59,8%). Conclusão: Considerando os critérios da NCCN, um número significativo de mulheres diagnosticadas pelo SUS teve indicação para realização do teste BRCA1/2. Essas mulheres são mais jovens, têm menos comorbidades, estão em período pré-menopausa mais frequentemente e diferem quanto ao subtipo molecular quando comparadas àquelas sem indicação de realização do exame. Palavras-chave: neoplasias da mama; neoplasias ovarianas; síndrome hereditária de câncer de mama e ovário; genes, BRCA1

Introducción: Aproximadamente el 10% de los casos de cáncer de mama son atribuibles a mutaciones germinales en genes de susceptibilidad, incluidos BRCA1 y BRCA2. La National Comprehensive Cancer Network (NCCN) recomienda la detección de mutaciones BRCA1/2 en mujeres con cáncer de mama en entornos definidos. Sin embargo, estas pruebas genéticas no están disponibles en el Sistema Único de Salud (SUS). Objetivo: Caracterizar mujeres con cáncer de mama y definir los criterios para la realización de la prueba BRCA1/2. Método: Estudio cuantitativo, descriptivo, analítico y retrospectivo. Las historias clínicas de las mujeres diagnosticadas con cáncer de mama entre enero de 2016 y diciembre de 2018, usuarias del SUS, fueron analizadas mediante el software JAMOVI (versión 2.3 - 2022). Resultados: 245 mujeres fueron diagnosticadas. Según las pautas de NCCN, 97 mujeres cumplieron con los criterios para someterse a la prueba BRCA1/2. Las mujeres con indicación para la prueba tenían un promedio de edad de 47 años, eran predominantemente blancas (90,7%), con comorbilidades (55,6%), premenopáusicas (59,8%), diagnosticadas en estadios tempranos 0 - IIb (68,2%) y 48,4% tenía antecedentes familiares de cáncer de mama. Los subtipos histológicos y moleculares más frecuentes fueron el carcinoma ductal invasivo (87,2%) y el tipo luminal (59,8%). Conclusión: Considerando los criterios de la NCCN, un número significativo de mujeres, usuarias del SUS, fueron designadas para hacer la prueba BRCA1/2. Estas mujeres son más jóvenes, tienen menos comorbilidades, están en el periodo de la premenopausia con mayor frecuencia y difieren en el subtipo molecular en comparación con aquellas sin orden de realizarse la prueba

Histological and Immunohistochemical Characteristics for Hereditary Breast Cancer Risk in a Cohort of Brazilian Women / Características histológicas e imunohistoquímicas para risco hereditário de câncer de mama em uma coorte de mulheres brasileiras

Abstract Objective The study aimed to characterize the clinical, histological, and immunohistochemical profile of women with invasive breast cancer, according to the risk for Hereditary Predisposition Breast and Ovarian Cancer Syndrome in a Brazilian population. Methods This is a retrospective study performed from a hospital-based cohort of 522 women, diagnosed with breast cancer treated at an oncology referral center in the Southeast region of Brazil, between 2014 and 2016. Results Among the 430 women diagnosed with invasive breast cancer who composed the study population, 127 (29.5%) were classified as at increased risk for hereditary predisposition to breast and ovarian cancer syndrome. There was a lower level of education in patients at increased risk (34.6%) when compared with those at usual risk (46.0%). Regarding tumor characteristics, women at increased risk had higher percentages of the disease diagnosed at an advanced stage (32.3%), and with tumors > 2cm (63.0%), with increased prevalence for both characteristics, when compared with those at usual risk. Furthermore, we found higher percentages of HG3 (43.3%) and Ki-67 ≥ 25% (64.6%) in women at increased risk, with prevalence being about twice as high in this group. The presence of triple-negative tumors was observed as 25.2% in women at increased risk and 6.0% in women at usual risk, with the prevalence of absence of biomarkers being 2.5 times higher among women in the increased risk group. Conclusion From the clinical criteria routinely used in the diagnosis of breast cancer, the care practice of genetic counseling for patients at increased risk of hereditary breast cancer in contexts such as Brazil is still scarce.

Resumo Objetivo O presente estudo buscou caracterizar o perfil clínico, histológico e imunohistoquímico de mulheres com câncer de mama invasivo segundo o risco para a Síndrome de Predisposição Hereditária ao Câncer de Mama e Ovário em uma população brasileira. Métodos Trata-se de um estudo retrospectivo realizado a partir de uma coorte hospitalar composta por 522 mulheres diagnosticadas com câncer de mama entre 2014 e 2016 assistidas em um centro de referência oncológica localizado na região sudeste brasileira. Resultados Entre as 430 mulheres diagnosticadas com câncer de mama invasivo que compuseram a população de estudo, 127 (29,5%) foram classificadas como de risco aumentado para a síndrome de predisposição hereditária ao câncer de mama e ovário. Verificou-se menor nível de escolaridade nas pacientes com risco aumentado (34,6%) quando comparadas àquelas consideradas como de risco habitual (46,0%). Quanto às características do tumor, as mulheres de risco aumentado apresentaram maiores percentuais de doença diagnosticada em estádio avançado (32,3%) e com tumores > 2cm (63,0%), com prevalência aumentada para ambas as características, quando comparadas àquelas de risco habitual. Ainda nas mulheres de risco aumentado, foram encontrados maiores percentuais de GH3 (43,3%) e Ki-67 ≥ 25% (64,6%), com prevalência cerca de duas vezes maior neste grupo. A presença de tumores triplo-negativos foi observada em 25,2% nas mulheres de risco aumentado e 6,0% nas mulheres de risco habitual, com prevalência de ausência de biomarcadores 2,5 vezes maior entre as mulheres do grupo de risco aumentado. Conclusão A partir dos critérios clínicos rotineiramente utilizados no diagnóstico do câncer de mama, a prática assistencial do aconselhamento genético para as pacientes com risco aumentado de câncer de mama hereditário em contextos como o do Brasil ainda é escarça.

Hereditary Breast and Ovarian Cancer Screening Syndrome Profile in Women Diagnosed with Breast Cancer from Paraná State Southwest / Perfil do rastreamento da síndrome hereditária de câncer de mama e ovário em mulheres diagnosticadas com câncer de mama na região sudoeste do Paraná

Abstract Objective This study evaluated the risk of the hereditary breast and ovarian cancer (HBOC) syndrome in patients with breast cancer by using the Family History Screening 7 (FHS-7) tool, a validated low-cost questionnaire with high sensitivity able to screen the HBOC risk in the population. Methods Women diagnosed with breast cancer (n=101) assisted by the Unified Health System at the 8th Regional Health Municipal Office of the state of Paraná answered the FHS-7, and the results were analyzed using IBM SPSS Statistics for Windows, Version 25.0. software (IBM Corp., Armonk, NY, USA). Results The risk of HBOC was 19.80% (n=20). Patients at risk exhibited aggressive tumor characteristics, such as high-grade tumors (30%), presence of angiolymphatic emboli (35%), and premenopausal at diagnosis (50%). Significant associations between the prevalence of high-grade tumors were observed inwomen younger than 50 years at diagnosis with HBOC (p=0.003). Conclusion Our findings suggest a possible family inheritance associated with worse clinical features in women with breast cancer in this population, indicating that HBOC investigation can be initially performed with low-cost instruments such as FHS-7.

Resumo Objetivo Este estudo avaliou o risco da síndrome hereditária de câncer de mama e ovário (HBOC, na sigla em inglês) em pacientes com câncer de mama utilizando a ferramenta Familial History Screening 7 (FHS-7), um questionário validado de baixo custo e com alta sensibilidade capaz de rastrear o risco de HBOC na população. Métodos Mulheres diagnosticadas com câncer de mama (n=101) assistidas pelo Sistema Único de Saúde da 8ª Regional de Saúde do estado do Paraná responderam ao questionário FHS-7, e os resultados foram analisados pelo software IBM SPSS for Windows, Version 25.0. (IBM Corp., Armonk, NY, EUA). Resultados A ocorrência do risco de HBOC foi de 19,80% (n=20). Pacientes em risco exibiram características agressivas do tumor como tumores de alto grau (30%), presença de êmbolos angiolinfáticos (35%) e pré-menopausa ao diagnóstico (50%). Associações significantes foram observadas entre a prevalência de tumores de alto grau e diagnóstico abaixo de 50 anos no grupo HBOC (p=0.003). Conclusão Nossos achados sugerem uma possível herança familiar associada a piores características clínicas em mulheres com câncer de mama nessa população, indicando que a investigação de HBOC pode ser realizada, inicialmente, com instrumentos de baixo custo, como o FHS-7.

Patrón de agregados de cáncer entre familias en Irak / Cancer Aggregates Pattern among Families in Iraq

Breast cancer is first ranking malignancies in Iraq. Family history of cancer is an important factor for cancer occurrence and development in next generation. The study aimed to determine the validity of family history of cancer by population-based and clinic-based family registries, evaluate the concurrence of cancer affected by family history in their first-, and second-degree relatives. An observational studies of total 62 relatives membered of 44 Iraqi breast cancer families were included. We conducted study at period between December 2018 and June 2019. Data collected according NCCN Genetic Testing Criteria for Hereditary Breast and Ovarian Cancer Syndrome. Risk ratio (RR) used to evaluating predilection of family cancer risk. We addressed forty-four Iraqi breast cancer families who have sixty-two members with cancer. The age mean±SD was 51.8±12.6, and median=48.5 years. Meanwhile the age mean±SD= 51.6±11.9 years for relatives. M:F ratio equal to 3:1. Sister, mother and aunt/uncle were most common relative affected. Breast cancer represented the most frequent types found in 46.7% of patients. Mothers (RR=1.313), and/or sisters (RR=1.6), lead to increased risk of cancer development in other family members or next generation. The first degree relatives recorded more than the second degree relatives. This is the first study conducting in Iraq dealing with cancer risk at the level of families. The age of patients didn't differ from age at diagnosis, concluding there is no active screening programs run through Iraqi families. Sister, mother and aunt/uncle are the most relatives affect. The 1st-degree relatives more frequent than the 2nd-degree. Breast cancer represented the most common types found members studied. Mothers and sisters have highly risk ratio for developing family cancer among other individuals.

Avaliação de painel multigenes em mulheres brasileiras com câncer de mama / Evaluation of a multigene panel in Brazilian women with breast cancer

Introdução: Apenas 5-10% dos casos de câncer de mama estão relacionados a variantes genéticas herdadas e mutações nos genes BRCA1 e BRCA2, relacionadas à Síndrome do câncer de mama e ovário hereditário (SMOH), são identificadas na maioria desses casos. Além dos genes BRCA1 e BRCA2, outros genes também estão associadas a um risco elevado e moderado para o câncer de mama, como TP53, STK11, CDH1, PTEN, ATM, CHEK2 e PALB2 e fazem parte do grupo de genes acionáveis com estratégias de manejo clínico e prevenção bem estabelecidos. A implementação do Sequenciamento de Nova Geração (NGS) vem permitindo a análise simultânea de múltiplos genes através dos painéis multigenes com maior rapidez na análise e menor custo quando comparada ao sequenciamento de um gene único e, atualmente, vem sendo amplamente utilizado em Oncologia para identificação das síndromes de predisposição hereditária ao câncer. Objetivo: O objetivo desse estudo é avaliar a contribuição do painel multigenes na detecção de mutações germinativas em outros genes, além de BRCA1 e BRCA2, em pacientes com critérios clínicos para câncer de mama hereditário. Pacientes e Métodos: Um painel NGS de 94 genes foi realizado em 321 pacientes com diagnóstico atual ou prévio de câncer de mama que apresentavam critérios clínicos para SMOH, e que realizaram o teste genético para os genes BRCA1 e BRCA2 no Laboratório de Diagnóstico Genômico do A.C.Camargo Cancer Center, entre agosto de 2016 e maio de 2018. Resultados: A análise dos dados do painel das 321 pacientes resultou em um total de 84 variantes patogênicas/provavelmente patogênicas (VP/PP) que foram identificadas em 81 pacientes e a positividade do teste genético foi de 25,2% (n=81/321). Três pacientes (n=3/81 ­ 3,7%) apresentaram duas VP/PP em genes distintos e foram diagnosticadas com Síndrome da Neoplasia Hereditária Multialélica (MINAS). Do total de VP/PP, 42,9% (n=36/84) foram identificadas em genes de alta penetrância para câncer de mama (BRCA1, BRCA2 e TP53) e 21,4% (n=18/84) em genes de penetrância moderada (ATM, PALB2 e CHEK2). O restante, correspondente a 35,7% (n=30/84) das VP/PP, foram identificadas em genes de baixa penetrância para câncer de mama e foram considerados como achados incidentais, uma vez que não apresentaram correlação genótipo-fenótipo. Em relação ao subtipo molecular do câncer de mama, o subtipo triplo negativo apresentou frequência de VP/PP de 31,6% (n=25/79), com predomínio de mutações no gene BRCA1 (12,6% - n=10/79). Entre o subtipo luminal, 18,7% (n=29/155) apresentavam VP/PP e destes, mutações em genes não-BRCA1/2 predominaram com frequência de 12,2% (n=19/155). Para o subtipo Luminal B HER2, 40% (n=16/40) apresentaram uma VP/PP, com predomínio do gene ATM (12,5% - n=5/40). Finalmente, o subtipo hiperexpressor de HER2 apresentou frequência de VP/PP de 30,8% (n=4/13), sem predominância de genes específicos. Variantes de significado incerto foram identificadas em 77,6% (n=249/321) das pacientes e dessas, 24,5% (n=61/249) apresentaram também ao menos uma VP/PP. Conclusão: O painel 94 genes contribuiu para identificar VP/PP em outros genes além de BRCA1/2, aumentando a positividade do teste genético de 9,9% (BRCA1/2) para 25,2%. Considerando-se apenas os genes acionáveis, o aumento na positividade do teste em nossa coorte foi de 6,9%. Esses resultados indicam que mulheres com critérios clínicos para SMOH podem se beneficiar da realização de um painel multigenes, pois o mesmo permite identificar variantes patogênicas em outros genes de predisposição ao câncer de mama, incluindo os genes acionáveis, que impactam diretamente no acompanhamento desses pacientes e familiares, uma vez que são genes com estimativas de risco para câncer estabelecidas e estratégias de rastreamento e prevenção bem definidas

Introduction: Only 5-10% of breast cancer are related to inherited genetic variants and BRCA1 and BRCA2 mutations, associated to the Hereditary Breast and Ovarian Cancer Syndrome (HBOC), are responsible for the majority of cases. In addition to BRCA1 and BRCA2, other genes are also associated with a high and moderate risk for breast cancer, such as TP53, STK11, CDH1, PTEN, ATM, CHEK2 and PALB2, considered actionable genes, once they have well-established guidelines for clinical management and prevention. The implementation of Next Generation Sequencing (NGS) has allowed to sequence multiple genes simultaneously, faster and lower-cost when compared to the sequencing of a single gene and, currently, it has been widely used in Oncology for identification of hereditary cancer predisposition syndromes. Objective: The aim of this study is to evaluate the contribution of the multigene panel in detection of germline mutations in other genes besides BRCA1/2 in patients with clinical criteria for hereditary breast cancer. Patients and Methods: A NGS panel of 94 cancer predisposition genes was performed on 321 patients with current or previous diagnosis of breast cancer and clinical criteria for HBOC, who were referred for BRCA1/2 testing between August 2016 and May 2018. Results: Panel analysis of 321 patients resulted in a total of 84 pathogenic/likely pathogenic (P/LP) variants were identified in 81 patients and the positivity rate of the genetic test was 25.2% (n=81/321). Three patients (n=3/81 - 3.7%) had two P/LP variants in different genes and were diagnosed with the multilocus inherited neoplasia alleles syndrome (MINAS). Of the total deleterious mutations, 42.9% (n=36/84) were identified in high-risk breast cancer genes (BRCA1/2 and TP53) and 21.4% (n= 8/84) in moderate-penetrance genes (ATM, PALB2 and CHEK2). The remainder of the mutations, corresponding to 35.7% (n=30/84), were identified in low-risk genes and were considered unexpected findings, since they did not demonstrate a genotype-phenotype correlation. Regarding the molecular subtype of breast cancer, triple negative breast cancer had a mutation frequency of 31.6% (n=25/79), with a predominance in BRCA1 (12.6% - n=10/79). Among the luminal subtype, 18.7% (n=29/155) had deleterious mutations and of these, mutations in non-BRCA1/2 genes predominated with a frequency of 12.2% (n=19/155). For Luminal B HER2-positive subtype, 40% (n=16/40) had a P/LP variants, with a predominance of ATM gene (12.5% - n=5/40). Finally, HER2-enriched subtype presented a mutation frequency of 30.8% (n=4/13). Variants of uncertain significance were identified in 77.6% (n = 249/321) of the patients and of these, 24.5% (n=61/249) also had at least one P/LP variant. Conclusion: The NGS panel contributed to identify P/LP variants in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.9% (BRCA1/2) to 25.2%. Considering only the actionable genes, the increase in positivity in our cohort was 6.9%. These results indicate that women with clinical criteria for HBOC may benefit from a multigene panel testing, as it allows to identify P/LP variants in other breast cancer susceptibility genes, including actionable genes, that directly impact the clinical management of these patients and family members, since they are genes with established risk assessment and well-defined screening and prevention strategies

Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome

BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) is caused by pathogenic variants in BRCA and other cancer-related genes. We analyzed variants in BRCA gene and other cancer-related genes in HBOC patients to evaluate the clinical validity of next-generation sequencing (NGS) multi-gene panel testing. METHODS: The BRCA1/2 NGS testing was conducted for 262 HBOC patients. Multiplex ligation-dependent probe amplification and direct Sanger sequencing were performed for confirmation. Multi-gene panel testing was conducted for 120 patients who did not possess BRCA1/2 pathogenic variants but met the National Comprehensive Cancer Network criteria. RESULTS: Pathogenic variants in BRCA1/2 were detected in 30 HBOC patients (11.5%). Additionally, four out of the 120 patients possessed pathogenic variants by multi-gene panel testing (3.3%): MSH2 (c.256G>T, p.Glu86*), PMS2 (c.1687C>T, p.Arg563*), CHEK2 (c.546C>A, p.Tyr182*), and PALB2 (c.3351-1G>C). All the four patients had a family history of cancer. CONCLUSIONS: Multi-gene panel testing could be a significant screening tool for HBOC patients, especially for those with a family history of cancer.

Knowledge and Anxiety Related to Hereditary Ovarian Cancer in Serous Ovarian Cancer Patients / 여성건강간호학회지

PURPOSE: The awareness of hereditary breast and ovarian cancer (HBOC) and BRCA testing is increasing in Korea. Compared to the sizable research on HBOC knowledge among breast cancer women, studies in the ovarian cancer population are limited. This paper aimed to investigate the level of knowledge of hereditary ovarian cancer and anxiety in women diagnosed with serous ovarian cancer in Korea and determine differences in the knowledge and anxiety according to whether genetic testing was undertaken and whether BRCA1 or BRCA2 mutations were present.METHODS: Using a descriptive research design, a cross-sectional survey was conducted on 100 women diagnosed with serous ovarian cancer at N hospital in Gyeonggi-do, Korea, from July to November 2018. The collected data were analyzed by descriptive statistics, independent t-tests, one-way analysis of variance, and Pearson's correlation coefficient using the SPSS 21.0 program.RESULTS: The hereditary ovarian cancer-related knowledge score was mid-level (mean score 8.90±3.29 out of a total of 17), as was the state anxiety level was mid-level (mean score 47.96±3.26 out of possible score range of 20–80). Genetic knowledge of hereditary ovarian cancer was associated with age, education, occupation, genetic counseling, and BRCA mutations. There were no statistically significant factors related to anxiety and there were no statistically significant correlations between knowledge level and anxiety.CONCLUSION: More comprehensive education on gene-related cancer is needed for ovarian cancer patients, especially for items with low knowledge scores. A genetic counseling protocol should be developed to allow more patients to alleviate their anxiety through genetic counseling.

Contralateral Breast Cancer and Ipsilateral Breast Tumor Recurrence in BRCA1/2 Carriers and Non-Carriers at High-Risk of Hereditary Breast Cancer / 한국유방암학회지

The influence of BRCA variants of unknown significance on cancer risk management decision-making / 부인종양

OBJECTIVE: To compare gynecological cancer risk management between women with BRCA variants of unknown significance (VUS) to women with negative genetic testing METHODS: Ninety-nine patients whose BRCA genetic testing yielded VUS were matched with 99 control patients with definitive negative BRCA results at a single institution. Demographics and risk management decisions were obtained through chart review. Primary outcome was the rate of risk-reducing bilateral salpingo-oophorectomy (RRBSO). Chi square tests, t-tests, and logistic regression were performed, with significance of p<0.05. RESULTS: VUS patients were more likely to be non-Caucasian (p=0.000) and of Ashkenazi-Jewish descent (p=0.000). There was no difference in gynecologic oncology referrals or recommendations to screen or undergo risk-reducing surgery for VUS vs. negative patients. Ultimately, 44 patients (22%) underwent RRBSO, with no significant difference in surgical rate based on the presence of VUS. Ashkenazi-Jewish descent was associated with a 4.5 times increased risk of RRBSO (OR=4.489; 95% CI=1.484–13.579) and family history of ovarian cancer was associated with a 2.6 times risk of RRBSO (OR=2.641; 95% CI=1.107–6.299). CONCLUSION: In our institution, patients with VUS were surgically managed similarly to those with negative BRCA testing. The numbers of patients with VUS are likely to increase with the implementation of multi-gene panel testing. Our findings underscore the importance of genetic counseling and individualized screening and prevention strategies in the management of genetic testing results.

A Study on Genetic Knowledge and Anxiety in Patients with Breast Cancer

PURPOSE: The purpose of the study was to understand the levels of knowledge about hereditary breast cancer and anxiety among patients with breast cancer and to identify the relationship between knowledge and anxiety. METHODS: The data were collected from 100 patients with breast cancer in Seoul in 2013. A 15-item hereditary breast cancer knowledge questionnaire and 20-item anxiety state questionnaire were used to measure knowledge and anxiety, respectively. The data were analyzed using descriptive statistics, t-tests, one-way ANOVA, LSD post hoc tests, and Cronbach's α tests in SPSS/WIN 21.0. RESULTS: The mean score of knowledge was 8.34±3.17, indicating 0.56 when converted to 1. Knowledge was different by age, education, marital status, monthly family income, risk for hereditary breast cancer, and needs for genetic counseling. The mean score of anxiety was 46.05±10.53. There was positive correlation between knowledge and anxiety (r=.25, p=.014). CONCLUSION: The results of this study indicate that oncology professionals need to provide genetic knowledge for early detection and prevention of secondary cancer to patients with breast cancer, while considering and relieving their emotional distress, such as anxiety.

Síndrome de cáncer hereditario de mama y ovario: aplicación clínica / Hereditary breast and ovarian cancer syndrome: Clinical application

Aportar al ginecólogo herramientas para la identificación de pacientes con riesgo de síndrome de cáncer hereditario de mama y ovario (SCHMO), y brindar consejería en el manejo preventivo de pacientes con este síndrome.Materiales y métodos: a partir de un caso hipotético se formulan preguntas relacionadas con el riesgo de desarrollar cáncer de mama y ovario en pacientes con SCHMO. Para responder estas preguntas se realizó una revisión de la literatura pertinente en las bases de datos Medline vía PubMed, ScienceDirect y SciELO. Se utilizaron los términos MESH "Síndrome de cáncer de mama y ovario hereditario", "Neoplasias ováricas", "Neoplasias de la mama", "Genes BRCA1", "Genes BRCA2" y su equivalente en inglés. Los resultados se restringieron a artículos publicados entre el 2005 y 2015.Resultados: a través de la búsqueda en PubMed se obtuvieron 56 artículos, de los cuales se seleccionaron 45. En ScienceDirect y SciELO se encontraron 7 artículos. Además, se incluyeron 4 artículos de fuentes no ligadas a estas bases de datos.Conclusiones: el ginecoobstetra debe identificar pacientes con riesgo de presentar el síndrome de cáncer hereditario de mama y ovario, y explicar a los pacientes la importancia de la realización de las pruebas moleculares de los genes BRCA1 y BRCA2 y de participar en equipos multidisciplinarios que además deben incluir al genetista, cirujano, los oncólogos y al paciente para la toma de decisiones médicas de acuerdo con los resultados moleculares...

To provide gynaecologists with tools for the identification of patients at risk of hereditary breast and ovarian cancer syndrome (HBOC) and present advise regarding the preventive management of patients with this syndrome.Materials and methods: Questions were asked in relation to the risk of patients with HBOC developing breast and ovarian cancer. To answer those questions, a review of the relevant literature was conducted in the Medline database via PubMed, and in ScienceDirect and SciELO. The MESH terms used were Breast and Ovarian Cancer Syndrome, Ovarian Neoplasms, Breast Neoplasms, BRCA1 Genes, BRCA2 Genes, and their equivalent in English. Results were limited to articles published between 2005 and 2015.Results: Overall, 56 articles were found in PubMed, of which 45 were selected. The search in ScienceDirect and SciELO resulted in 7 articles. Additionally, 4 articles from other sources not linked to these data bases were also included.Conclusions: Obstetric gynaecologists must identify patients at risk of presenting Hereditary Breast and Ovarian Cancer Syndrome, and explain to the patients the importance of performing molecular testing for BRCA1 and BRCA2 genes; and they must participate in multi-disciplinary teams consisting also of geneticists, surgeons, oncologists and patients for medical decision-making in accordance with the molecular results...

Alteração da via da recombinação homóloga de reparo de DNA no câncer epitelial de ovário / Homologous recombination deficiency in ovarian carcinoma

Justificativa:Os carcinomas de ovário apresentam deficiência da via da recombinação homóloga de reparo de DNA em aproximadamente 50% dos casos, em 15 a 20% dos casos atribuída a mutações germinativas em BRCA1 ou BRCA2. Tumores com mutações germinativas em BRCA1 ou BRCA2 são mais sensíveis aos tratamentos com inibidores de PARP e com esquemas quimioterápicos baseados em platina. O papel de outras alterações da via da recombinação homóloga na sensibilidade a essas modalidades de tratamento bem como a forma de identificar os tumores com deficiência dessa via ainda não estão definidos. Escores avaliando o perfil de alterações estruturais genômicas causadas especificamente por deficiência da via da recombinação homóloga têm sido estudados como potenciais marcadores da deficiência desta via. Nosso objetivo foi caracterizar uma coorte de pacientes com carcinoma de ovário quanto à deficiência da via da recombinação homóloga utilizando escores calculados a partir das alterações do número de cópias genômicas e de perdas de heterozigose e avaliar o papel destes escores na identificação de pacientes com sensibilidade prolongada à platina. Métodos: Selecionamos uma coorte de 31 pacientes com carcinoma de ovário com recidiva classificada clinicamente com platina resistente e que foram reexpostas ao tratamento com quimioterapia baseada em platina. Amostras de tumores armazenados em parafina de 14 pacientes foram submetidas ao ensaio ONCOSCAN para avaliação de alterações de números de cópias, perda de heterozigose e identificação de mutações específicas em 9 genes relacionados a neoplasias. A partir destes dados caracterizamos os escores de Telomeric Allelic Imbalance (TAI), escore de perda de heterozigose (cnLOH+L) escore de Large Scale Transition (LST) e escore de deficiência da recombinação homóloga (HRD) em cada tumor e avaliamos a sua associação com a taxa de resposta à quimioterapia, sobrevida global e fatores clínico patológicos. Resultados: Na coorte de 31 pacientes, DNA foi extraído de 28 amostras e 15 amostras de 14 pacientes foram analisadas de forma efetiva. Na maioria dos casos encontramos o padrão esperado de grande instabilidade genômica com diversas regiões de ganhos e perdas do genoma e regiões de perda de heterozigose. Todos os casos analisados mostraram cnLOH ou delLOH no cromossomo 17, 12 de 14 pacientes apresentaram cnLOH ou delLOH no braço longo do cromossomo 13 e o cromossomo 22 apresentou perdas ou ganhos na maioria dos casos. Mutação em TP53 foi encontrada em 2 casos, mutação em NRAS em 2 casos, e um caso com mutação em TP53apresentou mutação em PTEN associada a deleção da região do PTEN. A mediana dos escores foi de 19,5 para TAI, 12,5 para cnLOH+L, 26,0 para LST e 6,3 para HRD. Levando-se em conta os escores com pontos de corte previamente definidos na literatura encontramos 10 de 14 (escore cnLOH+L) e 9 de 14 (escore LST) pacientes com tumores com escores altos sugerindo deficiência da via da recombinação homóloga. Tanto a coorte como um todo quanto as 14 pacientes submetidas à análise molecular apresentaram taxa de resposta acima do esperado sendo 16 de 31 pacientes (51,6%) e 7 de 14 pacientes (50,0) respectivamente. Não houve diferença estatisticamente significativa entre as taxas de resposta das pacientes de com escores altos versus baixos, embora 6 de 10 pacientes com escore cnLOH+L elevado tenham apresentado resposta e 1 de 4 pacientes com escore cnLOH+L baixo tenham apresentado resposta e 6 de 9 pacientes com escore LST elevado tenham apresentado resposta e 1 de 5 pacientes com escore LST baixo tenham apresentado resposta. Numericamente os escores cnLOH+L, LST e HDR foram mais altos nas pacientes que responderam quando comparados com os escores das pacientes que não responderam, com medianas deTAI = 19,0 vs 24,0, TAIm = 16,0 vs 19,0, cnLOH+L 13 vs 12, LST = 28,0 vs 18,0, LSTm = -4,0 vs -20,0, HRD 8,7 vs 0,3 para respondedoras versus não respondedoras. Essa diferença não foi estatisticamente significativa. A sobrevida global mediana foi 13,4 meses desde o inicio do tratamento de reexposição à platina e não houve diferença de acordo com os valores dos escores. Dentre os fatores clinicopatológicos a presença de história familiar de câncer de mama ou ovário ou a história pessoal de câncer de mama foi o único fator associado a uma maior taxa de resposta. Os tumores primários apresentaram escore TAI mais elevado que os tumores coletados no momento da recidiva e comparando duas amostras de uma mesma paciente houve diferença na classificação da deficiência da via da recombinação homóloga de acordo com os escores cnLOH+L e LST. Conclusões: Os escores de deficiência da via da recombinação homóloga se mostraram potenciais marcadores de resposta à reexposição à platina no cenário de doença platina resistente, necessitando melhor definição dos pontos de corte e do impacto da heterogeneidade tumoral e da necessidade de avaliação do material coletado no momento da recidiva. História familiar positiva é um fator clínico capaz de identificar pacientes com mais chance de resposta á reexposição á platina. Nossos dados fortalecem a hipótese da contribuição de mutações em PTEN para o desenvolvimento de deficiência da via da recombinação homóloga e o papel das mutações de NRAS nos carcinomas serosos de ovário.

Background: Homologous recombination deficiency s presente in up to 50% of ovarian carcinomas, in 15 to 20% due to germline BRCA1 or BRCA2 mutations. BRCA mutated tumors are more sensitive to PARP inhibitors and platinum based chemotherapy. The role of other homologous recombination mechanisms on PARP inhibitors and platinum sensitivity as well as the methods to identify homologous recombination deficiency is not clear yet. Scores evaluating structural genomic abnormalities caused specifically by homologous recombination deficiency have been studied as markers of deficiency of this DNA repair pathway. The main objective of the present study was to characterize a cohort of ovarian cancer patients regarding homologous recombination deficiency using scores based on copy number alterations and loss of heterozygosity and to evaluate the impact of these scores in prolonged platinum sensitivity. Methods: We selected a cohort of 31 ovarian cancer patients with platinum resistant recurrence reexposed to platinum based chemotherapy. Paraffin embedded tumor samples from 14 patients were analyzed through ONCOSCAN assay for copy number alterations, loss of heterozygosity and specific point mutations in 9 cancer related genes. Based on these alterations we calculated the scores Telomeric Allelic Imbalance (TAI), loss of heterozygosity score (cnLOH+L) Large Scale Transition score (LST) and homologous recombination deficiency score (HRD) for each tumor sample and tested their association to response rate to platinum rechallenge, overall survival and to the clinical pathologic factors. Results: From the cohort of 31 patients, DNA was extracted from 28 samples and 15 samples from 14 patients were effectively analyzed. Most cases presented the expected high genomic instability pattern with lots of genomic losses, genomic gains and loss of heterozygosity segments. All cases showed cnLOH or delLOH in chromosome 17, 12 of 14 patients showed cnLOH or delLOH in the long arm of chromosome 13, and chromosome 22 presented losses or gains in most of cases.TP53 mutations were present in 2 cases, NRAS mutations in 2 cases, and one patient with TP53 mutation showed also a PTEN mutation together with a genomic loss in PTEN region. Median scores were 19,5 for TAI, 12,5 for cnLOH+L, 26,0 for LST and 6,3 for HRD. Considering previously literature defined cutoffs we found 10 out of 14 (for cnLOH+L score) and 9 out of 14 (for LST score) patients with tumors with high scores suggesting homologous recombination deficiency. In the cohort of 31 patients 16 had response to platinum reexposition and in the cohort of 14 patients analyzed by ONCOSCAN assay 7 patients had response. There was no statistically significant difference between response rates for high versus low scores, even though 6 out of 10 patient with high cnLOH+L score while 1 out of 4 patients with low cnLOH+L score had response and 6 out of 9 patient with high cnLOH+L score while 1 out of 5 patients with low cnLOH+L score had response. Numerically, the scores cnLOH+L, LST and HDR were higher in patients with response to treatment compared to those without a response, with medians of TAI = 19,0 vs 24,0, TAIm = 16,0 vs 19,0, cnLOH+L 13 vs 12, LST = 28,0 vs 18,0, LSTm = -4,0 vs -20,0, HRD 8,7 vs 0,3 for responders versus non responders respectively. These differences were not statistically significant. Median overall survival was 13,4 months from the beginning of platinum rechallenge and there was no difference in survival according to scores. Among clinical pathologic factors, family history of breast or ovarian cancer or personal history of breast cancer was associated to a higher response rate to platinum rechallenge. Primary tumors had a higher TAI score compared to recurrent tumors and comparing two different samples from the same patient there was divergence on the homologous recombination deficiency classification according to cnLOH+L and LST scores. Conclusions: Homologous recombination deficiency scores showed to be potential markers of response to platinum rechallenge in the platinum resistant setting. It is still necessary to clarify the best cutoffs for each score, the impact of tumor heterogeneity and the need of tumor samples to be collected in the moment of treatment. Positive family history is a clinical factor predictvie of platinum rechallenge response. Our data support the hypothesis of a role for PTEN in homologous recombination deficiency as well as a role of NRAS mutations in ovarian serous carcinomas.

Analysis of BRIP1 Variants among Korean Patients with BRCA1/2 Mutation-Negative High-Risk Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The aim of the current study is to assess the spectrum of genetic variation in the BRIP1 gene among Korean high-risk breast cancer patients who tested negative for the BRCA1/2 mutation. MATERIALS AND METHODS: Overall, 235 Korean patientswith BRCA1/2 mutation-negative high-risk breast cancerwere screened for BRIP1 mutations. The entire BRIP1 gene was analyzed using fluorescent-conformation sensitive gel electrophoresis. In silico analysis of BRIP1 variants was performed using PolyPhen-2 and SIFT. RESULTS: A total of 20 sequence alterations including 12 exonic and eight intronic variantswere found. Among the 12 exonic variants, 10 were missense and two were silent mutations. No protein-truncating mutation was found among the tested patients. Among the 10 missense variants, four (p.L263F, p.L340F, p.L474P, and p.R848H) were predicted to be pathogenic by both PolyPhen-2 and SIFT, and these variants were found in five patients. Of the four missense variants, p.L263F, p.L474P, and p.R848H localize to regions between the helicase motifs, while p.L340F resides in an iron-sulfur domain of BRIP1. CONCLUSION: No protein-truncating mutation in BRIP1 was found among the tested patients. The contribution of BRIP1 variants is thought to be minor in Korean non-BRCA1/2 high-risk breast cancer.

Clinical Implications of Genetic Testing for Hereditary Breast and Ovarian Cancer Syndrome in the Era of Genomic Medicine: Clinician's Perspectives

Hereditary breast and ovarian cancer syndrome accounts for approximately 5% to 10% of breast or ovarian cancers, with which the high-penetrant BRCA1/2 genes have been associated. With the recent development of next-generation sequencing (NGS), germline mutation testing and its related medical and surgical management have been rapidly changing. In this review, we summarize the current status and perspectives of NGS testing for not only BRCA1/2 but also the other breast and ovarian cancer susceptibility genes.

Comparison of Targeted Next-Generation and Sanger Sequencing for the BRCA1 and BRCA2 Mutation Screening

No abstract available.

Association of family risk and lifestyle/comorbidities in ovarian cancer patients / Associação de história familiar e estilo de vida a comorbidades em pacientes com câncer de ovário.

Summary Objectives: to analyze factors that might indicate familial predisposition for ovarian cancer in patients diagnosed with this disease. Methods: in a prospective single center cohort study at the Institute of Cancer of the State of São Paulo (ICESP), 51 women diagnosed with ovarian cancer were included. Familial predisposition for ovarian cancer was defined as having a higher than 10% chance of having a BRCA1/2 mutation according to the Manchester scoring system, a validated method to assess the likelihood of mutation detection. Each patient was interviewed with a standardized questionnaire on established risk factors for ovarian cancer and other factors that might influence the risk to develop ovarian cancer. Logistic regression analyses were performed to estimate the impact of the evaluated factors on the likelihood of mutation detection, by calculating odds ratios and 95% confidence intervals. Results: seventeen out of 51 patients had a family history of breast and/or ovarian cancer, four patients had a history of breast or endometrial cancer, 11 were diagnosed before the age of 50, and 12 presented a risk of familial predisposition to ovarian cancer higher than 10%. Patients with comorbidities, such as hypertension, diabetes, hormonal disorders, dyslipidemia and psychiatric conditions, presented a lower chance of having a familial predisposition for ovarian cancer (OR: 0.22; 95% CI: 0.06-0.88; p=0.03). Conclusion: in this study, having comorbidities was associated with a lower risk of having a familial predisposition for ovarian cancer. Other factors associated with the risk of ovarian cancer did not have an impact on this predisposition. .

Resumo Objetivos: analisar fatores que possam indicar uma predisposição familiar ao câncer de ovário em pacientes com este diagnóstico. Métodos: em estudo de coorte prospectiva realizado no Instituto do Câncer do Estado de São Paulo (ICESP), foram incluídas 51 mulheres diagnosticadas com câncer de ovário entre janeiro de 2009 e dezembro de 2011. Predisposição familiar para câncer de ovário foi definida como um risco maior de 10% de apresentar uma mutação em BRCA1/2, de acordo com o sistema de pontes de Manchester, um método validado para avaliar a probabilidade de detecção de mutação nesses genes. Cada paciente foi entrevistada com um questionário padronizado, abordando fatores de risco para câncer de ovário e outros fatores que pudessem influenciar o risco de desenvolver a doença. O impacto dos fatores avaliados na probabilidade de detecção da mutação foi avaliado com regressões logísticas. Resultados: dezessete das 51 pacientes referiram história familiar de câncer de mama e/ou ovário, quatro pacientes apresentavam antecedente pessoal de câncer de mama ou endométrio, 11 haviam sido diagnosticadas antes dos 50 anos e 12 apresentaram um risco maior que 10% de predisposição familiar a câncer de ovário. Pacientes com comorbidades como hipertensão, diabetes, disfunções hormonais, dislipidemia e distúrbios psiquiátricos apresentaram menor risco de predisposição familiar ao câncer de ovário (OR: 0.22; IC 95%: 0.06-0.88; p=0.03). Conclusão: neste estudo, apresentar alguma comorbidade foi associado a um menor risco de ter uma predisposição familiar ao câncer de ovário. Outros fatores associados ao risco de câncer de ovário não tiveram nenhum impacto sobre esta predisposição. .

Cancers héréditaires du sein selon les scores actuels

Les cancers du sein sont suspects d'origine héréditaires dans près de 15 % de cette localisation. Cette origine héréditaire semble liée à la mutation des gènes BRCA 1 et 2. En 2011, Bonaïti et coll ont publié un nouveau système de score qui aide à mettre en évidence les prédispositions aux cancers du sein et de l'ovaire associés à BRCA 1 et 2. A partir de 61 observations rassemblées entre le 31 juillet 2009 et le 30 juin 2013, nous avons appliqué ce nouveau score pour démontrer leur origine héréditaire. Nous avons ainsi constaté que le score de Manchester a conduit à poser l'indication d'une consultation d'oncogénétique chez 40 patientes sur 61 tandis que celui d'Eisinger l'a entrainée chez 58

Blood thicker than water: A case report on familial ovarian cancer / Philippine Journal of Obstetrics and Gynecology

Reported is a case of a 43 year-old Gravida 3 Para 3 (3003) admitted due to progressive abdominal enlargement, weight loss and dyspnea. Admitting Impression was Ovarian New Growth, bilateral, malignant, with secondary Pleural Effusion. She underwent Total Abdominal Hysterectomy, with Bilateral Salpingooophorectomy, bilateral lymph node dissection, peritoneal fluid cytology, and infracolic omentectomy. Histopathology report showed a Malignant Mixed Mullerian Tumor of both ovaries with metastasis to the colorectal serosa. It is noteworthy that the patient has two siblings who succumbed to advanced stage ovarian cancer. This case report will discuss the possible hereditary genetic mutations involved in the development of familialovarian carcinoma.

Diagnostic screening workflow for mutations in the BRCA1 and BRCA2 genes

Screening for mutations in large genes is challenging in a molecular diagnostic environment. Sanger-based DNA sequencing methods are largely used; however, massively parallel sequencing [MPS] can accommodate increasing test demands and financial constraints. This study aimed to establish a simple workflow to amplify and screen all coding regions of the BRCA1 and BRCA2 [BRCA1/2] genes by Sanger-based sequencing as well as to assess a MPS approach encompassing multiplex polymerase chain reaction [PCR] and pyrosequencing. This study was conducted between July 2011 and April 2013. A total of 20 patients were included in the study who had been referred to Genetic Health Services New Zealand [Northern Hub] for BRCA1/2 mutation screening. Patients were randomly divided into a MPS evaluation and validation cohort [n = 10 patients each]. Primers were designed to amplify all coding exons of BRCA1/2 [28 and 42 primer pairs, respectively]. Primers overlying known variants were avoided to circumvent allelic drop-out. The MPS approach necessitated utilisation of a complementary fragment analysis assay to eliminate apparent false-positives at homopolymeric regions. Variants were filtered on the basis of their frequency and sequence depth. Sanger-based sequencing of PCR amplified coding regions was successfully achieved. Sensitivity and specificity of the combined MPS/homopolymer protocol was determined to be 100% and 99.5%, respectively. In comparison to traditional Sangerbased sequencing, the MPS workflow led to a reduction in both cost and analysis time for BRCA1/2 screening. MPS analysis achieved high analytical sensitivity and specificity, but required complementary fragment analysis combined with Sanger-based sequencing confirmation in some instances