Menopausia quirúrgica en pacientes con mutación BRCA, el papel de la terapia hormonal / Surgical Menopause in Patients with BRCA Mutation, the Role of Hormone Therapy

Introducción: las mujeres con mutación BRCA1/2 (mBRCA) tienen un riesgo aumentado de desarrollar cáncer de mama (CM) y ovario (CO). La salpingo-oforectomía bilateral (SOB) se asocia con la reducción del riesgo del 80% para CO y un 50% para CM. Se recomienda realizarla entre los 35 y 40 años. Como consecuencia se produce una menopausia prematura, con un impacto negativo sobre la calidad de vida por la presencia de síntomas climatéricos, aumento del riesgo de enfermedad cardiovascular, osteoporosis y riesgo de alteración cognitiva. La terapia hormonal (THM) es el tratamiento más eficaz para la prevención de estos síntomas. Estado del arte: distintos estudios han demostrado un mayor riesgo de CM en mujeres posmenopáusicas que reciben THM en particular con terapia combinada, estrógeno + progesterona (E+P). Según el metanálisis de Marchetti y cols., en las mujeres portadoras de mBRCA que recibieron THM, no hubo diferencias en el riesgo de CM comparando E solo con E+P. En el estudio de Kotsopoulos, incluso se encontró un posible efecto protector en aquellas que usaron E solo. Otro estudio en portadoras sanas demostró que, en las mujeres menores de 45 años al momento de la SOB, la THM no afectó las tasas de CM. Sin embargo, en las mujeres mayores de 45 años, las tasas de CM fueron más altas. Como el esquema de E+P se asocia con un mayor riesgo relativo (RR) de CM, las dosis de progestágenos utilizados se deberían limitar, eligiendo derivados naturales de progesterona, de uso intermitente para disminuir la exposición sistémica. Según diferentes guías internacionales, a las portadoras de mBRCA sanas que se someten a una SOB se les debe ofrecer THM hasta la edad promedio de la menopausia. Conclusión: la menopausia prematura disminuye la expectativa de vida; es por ello que una de las herramientas para mejorar y prevenir el deterioro de la calidad de vida es la THM. El uso de THM a corto plazo parece seguro para las mujeres portadoras de mBRCA que se someten a una SOB antes de los 45 años, al no contrarrestar la reducción del riesgo de CM obtenida gracias a la cirugía. (AU)

Introduction: women with BRCA1/2 (mBRCA) mutation have an increased risk of developing breast (BC) and ovarian (OC) cancer. Bilateral salpingo-oophorectomy (BSO) is associated with an 80% risk reduction for OC and 50% for BC. The recommended age for this procedure is 35 to 40 years. The consequence is premature menopause, which hurts the quality of life due to the presence of climacteric symptoms, increased risk of cardiovascular disease, osteoporosis, and a higher risk of cognitive impairment. Hormone therapy (MHT) is the most effective treatment for preventing these symptoms. State of the art: different studies have shown an increased risk of BC in postmenopausal women receiving MHT, particularly with combined therapy, estrogen + progesterone (E+P). According to the meta-analysis by Marchetti et al., in women carrying mBRCA who received MHT, there was no difference in the risk of BC compared to E alone with E+P. In the Kostopoulos study, there was also a possible protective effect in those who used E alone. Another study in healthy carriers showed that in women younger than 45 years at the time of BSO, MHT did not affect BC rates. However, in women older than 45 years, BC rates were higher. As the E+P scheme is associated with a higher RR of BC, the doses of progestogens should be limited, choosing natural progesterone byproducts of intermittent use to decrease systemic exposure. According to various international guidelines, healthy mBRCA carriers undergoing BSO should be offered MHT until the average age of menopause. Conclusion: premature menopause decreases life expectancy, which is why one of the tools to improve and prevent deterioration of quality of life is MHT. Short-term use of MHT appears safe for women with mBRCA who undergo BSO before age 45 as it does not counteract the reduction in the risk of MC obtained by surgery. (AU)

BRCA1 promoter methylation & its immunohistochemical correlation in sporadic breast cancer

Background & objectives: Studies have shown that apart from hereditary breast carcinomas, breast cancer susceptibility gene 1 (BRCA1) mutations conferring to its loss are seen in sporadic breast carcinomas (SBC) as well. The aim of the present study was to assess BRCA1 methylation in females presenting at King George’s Medical University, Lucknow, with SBC by both immunohistochemistry (IHC) and methylation PCR with respect to hormonal profile and various morphological prognostic parameters. The primary objective was to look for the association between BRCA1 protein expression and DNA promoter methylation. Methods: 81 mastectomy specimens from SBC of invasive breast carcinoma (no special type) were included in this study. After a detailed morphological assessment, formalin fixed paraffin embedded tissue from a representative tumour area was selected for BRCA1 IHC by heat-mediated antigen retrieval under high pH and DNA extraction and further bisulphate treatment. BRCA1 was studied for methylation by methylated and unmethylated PCR-specific primers. Results: BRCA1 promoter methylation was present in 42/81 (51.9%) participants, with significant BRCA1 protein loss (72.7%; P=0.002). A significant association between BRCA1 loss and hormonal profile was found (P=0.001); maximum in triple negative breast carcinoma (TNBC) (72%; 18/25). Most of the TNBC also harboured methylation (68%). Although not significant grade II and III tumours, lymph vascular invasion, ductal carcinoma in situ, and nodal metastasis (?3) were seen in a higher percentage in methylated tumours. Mortality in SBC was significantly associated with BRCA1 loss (30.3%; P=0.024). Interpretation & conclusions: Study results highlight the concept of “BRCAness” in SBC as well. Hence, we can confer that identification of BRCA1 loss in SBC can make it a perfect candidate for poly ADP- ribose polymerase inhibitors or cisplatin-based therapy like hereditary ones.

Phenocopy in a patient with triple negative breast cancer: a case report

ABSTRACT A total of 1.67 million breast cancer cases per year are reported worldwide. Of these, 5%-10% are caused by inherited mutations. Phenocopy is a rare phenomenon, with only a few cases reported in the literature. In phenocopies, phenotypes identical to those with genetic origin occur because of environmental factors rather than familial mutations. We describe a case of phenocopy in a 44-year-old female patient with triple-negative breast cancer. The mother and sister wee heterozygous for c.1813delA, p.Ile605TyrfsTer9 in BRCA2 . The patient underwent genetic testing for BRCA1 and BRCA2 and exome sequencing. Familial or other cancer variants were not detected. The most accepted phenocopy theory is that patients without genetic variants but who are carriers of these mutations undergo cellular changes due to environmental factors, increasing the risk of breast cancer. Therefore, the detection of phenocopy in patients with breast cancer is important in clinical practice.

Prevalence of Somatic BRCA1 and BRCA2 mutations in ovarian cancer among Filipinos using next generation sequencing

INTRODUCTION@#Ovarian cancer is one of the leading causes of mortality in women. In 2020, 5,395 (6.2%) of diagnosed malignancies in females were ovarian in origin. It also ranked second among gynecologic malignancies after cervical cancer. The prevalence in Asian /Pacific women is 9.2 per 100,000 population. Increased mortality and poor prognosis in ovarian cancer are caused by asymptomatic growth and delayed or absent symptoms for which about 70% of women have an advanced stage (III/IV) by the time of diagnosis. The most associated gene mutations are Breast Cancer gene 1 (BRCA1) which is identified in chromosome 17q21 and Breast Cancer gene 2 (BRCA2) identified in chromosome 13. Both proteins function in the double-strand DNA break repair pathway especially in the large framework repair molecules. Olaparib is a first-line drug used in the management of ovarian cancer. It targets affected cells by inhibition of poly (ADP-ribose) polymerase (PARP) activity which induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double-strand breaks (DSBs).@*OBJECTIVE@#The study aims to determine the prevalence of pathogenic somatic mutations in BRCA1 and BRCA2 among patients diagnosed of having ovarian cancer, to characterize the identified variants into benign/ no pathogenic variant identified, variant of uncertain significance (VUS), and pathogenic, and to determine the relationship of specific mutations detected with histomorphologic findings and clinical attributes.@*METHODOLOGY@#Ovarian cancer tissues available at the St. Luke’s Medical Center Human Cancer Biobank and formalin-fixed paraffin-embedded (FFPE) tissue blocks diagnosed as ovarian cancer from the year 2016 to 2020 were included. Determination of the prevalence of somatic BRCA1 and BRCA2 mutations using Next Generation Sequencing (NGS).@*RESULTS@#A total of 60 samples were processed, and three samples were excluded from the analysis due to an inadequate number of cells. In the remaining 57 samples diagnosed ovarian tumors, pathogenic BRCA1/2 variants were identified in 10 (17.5%) samples. Among the BRCA1/2 positive samples, 3 (5.3%) BRCA1 and 7 (12.3%) BRCA2 somatic mutations were identified.@*CONCLUSION@#Identification of specific BRCA1/2 mutations in FFPE samples with NGS plays a big role in the management of ovarian cancer, particularly with the use of targeted therapies such as Olaparib. The use of this drug could provide a longer disease-free survival for these patients. Furthermore, we recommend that women diagnosed with ovarian cancer should be subjected to genetic testing regardless of the histologic subtypes or clinical features. Lastly, genetic testing should be done along with proper genetic counseling, especially for patients who are susceptible to these mutations.

The status of homologous recombination deficiency and BRCA1/2 gene mutation in ovarian cancer patients in the Yunnan region and their clinical significance / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：采用基于中国人群单核苷酸多态性位点开发的同源重组缺陷（HRD）检测工具评估云南地区卵巢癌患者的HRD状态和BRCA1/2基因突变频率并探讨其临床意义。方法：共纳入2021年1月至2023年5月间在云南省肿瘤医院收治的卵巢癌患者248例，HRD状态采用基因组瘢痕评分法（GSS）（主要依据拷贝数的长度、类型、位置及基因组断片）或HRD评分法（杂合性缺失、端粒等位基因失衡及大片段移位等基因组不稳定事件的总和）进行评估，当组织样本的GSS≥50分或HRD评分≥42分者或检测到有害的BRCA1/2基因突变时HRD被定义为阳性。分析患者HRD状态与临床病理特征的关系。结果：248名卵巢癌患者中70.97%的患者HRD呈阳性，其中BRCA1/2基因突变率为30.65%。Ⅲ~Ⅵ期、高级别浆液腺癌的卵巢癌患者具有更高的HRD阳性率（均P<0.01），HRD评分更高的患者其合并其他基因突变的频率也越高（P<0.05）。HRD状态与卵巢癌的病理类型、临床分期和其他基因突变均有关联（均P<0.01）。结论：云南地区卵巢癌患者HRD阳性率较高，HRD阳性的卵巢癌患者可以从聚ADP核糖聚合酶（PARP）抑制剂治疗中获得更大的收益。

Expression characteristics and risk analysis of BRCA1 and BRCA2 gene variants in colorectal cancer / 国际外科学杂志

Objective:To explore the relationship between the occurrence and development of colorectal cancer and the risk of BRCA1 and BRCA2 gene mutations. Methods:Sixty-one patients with colorectal adenocarcinoma admitted to Beijing Friendship Hospital Affiliated to Capital Medical University from January 2022 to March 2022 were tested by second-generation sequencing. Information such as age of onset, gender, histological grade and TNM stage were collected. According to whether the BRCA1 and BRCA2 gene had systemic mutation, the patients were divided into BRCA1 and BRCA2 gene system mutation group and unmutated group. There were 8 cases in the BRCA1 and BRCA2 gene system mutant group and 53 cases in the non-mutant group. The main outcome measures were the relationship between pathogenic or likely pathogenic germline mutations in colorectal cancer and clinicopathological data of patients, including age of onset, gender, tumor location, TNM stage, histological differentiation, and family history. The secondary outcome was the relationship between BRCA1 and BRCA2 gene system mutations and clinicopathological data. Measurement data with normal distribution were expressed as mean±standard deviation ( ± s), and comparison between groups was analyzed using the t-test. Measurement data with non-normal distribution were represented as M ( Q1, Q3), and comparison between groups was analyzed using the Mann-Whitney U test. Measurement data were expressed as the number of cases or percentage (%), and Chi-square test was used for comparison between groups. Results:Among 61 colorectal adenocarcinoma patients, the frequency of pathogenic or potentially pathogenic germ line mutations in colorectal cancer was 13.1% (8/61), and the frequency of BRCA1 and BRCA2 mutations was 3.3% (2/61). The frequency of BRCA1 and BRCA2 mutations was 13.1% (8/61). Women with BRCA1 and BRCA2 mutations (75.0% vs 37.7%, χ2=3.947, P=0.047) and right colon cancer (75.0% vs 26.4%, χ2=7.889, P=0.019) were significantly higher than those without mutation. Conclusions:The frequency of BRCA1 and BRCA2 gene mutation is higher in colorectal cancer patients. BRCA1 and BRCA2 gene mutations are recommended for colorectal cancer patients with a family history of breast or ovarian cancer.

Comparison of Clinicopathological Characteristics Between Primary and Contralateral Cancers in BRCA1/2 Carriers with Metachronous Bilateral Breast Cancers / 肿瘤防治研究

Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.

The mechanism of BRCC3/NLRP3 in promoting the transformation of endometriosis to endometriosis-associated ovarian carcinoma / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨NOD样受体蛋白3（NLRP3）炎症小体的活化在子宫内膜异位症（EMT）进展为EMT相关性卵巢癌（EAOC）过程中的作用及其机制。方法：选取2018年4月至2019年6月上海市长宁区幼保健院收治的EAOC、EMT、正常子宫内膜（CON组）组织标本各15例及患者的临床资料，利用免疫组织化学染色法、WB法检测EAOC、EMT和CON组织中NLRP3、caspase-1和IL-1β及含BRCA1/BRCA2的复杂亚基3（BRCC3）的表达水平。构建过表达BRCC3质粒和si-NLRP3质粒并转染EMT细胞CRL-7566，通过WB法检测转染后细胞中BRCC3蛋白的表达水平，利用MTT法、流式细胞术及Transwell实验分别检测转染后细胞增殖、凋亡、迁移与侵袭能力的变化。对过表达BRCC3组细胞进行干扰NLRP3实验，通过WB法检测干扰后BRCC3和NLRP3蛋白的表达水平，检测干扰后细胞增殖、凋亡、迁移与侵袭能力的变化。结果：EAOC和EMT组织中NLRP3、caspase-1、IL-1β和BRCC3的表达水平较CON组均呈明显升高（均P<0.01），且EAOC组织中NLRP3与BRCC3的表达呈正相关（r=0.65，P<0.01）。在CRL-7566细胞中过表达BRCC3显著促进细胞的增殖、迁移和侵袭并抑制细胞凋亡（均P<0.01），敲减NLRP3则抑制CRL-7566细胞的上述表型（均P<0.01），过表达BRCC3增强NLRP3的表达水平（P<0.01），而干扰BRCC3则抑制NLRP3表达（P<0.01）；干扰NLRP3可以部分逆转BRCC3对细胞凋亡的抑制作用（P<0.01）、对细胞迁移（P<0.05）和侵袭（P<0.01）的促进作用。结论：EAOC和EMT组织中NLRP3和BRCC3均呈高表达，过表达BRCC3可促进CRL-7566细胞的增殖、迁移和侵袭并抑制细胞凋亡，与EMT向EAOC转化有关，BRCC3/NLRP3是潜在的EAOC炎癌转化预测标志物及治疗靶点。

Tamizaje para cáncer de mama con resonancia magnética en mujeres portadoras de mutaciones BRCA y no-BRCA / Magnetic resonance imaging breast cancer screening in women who are carriers of BRCA and non-BRCA gene mutations / Rastreamento de câncer de mama com ressonância magnética em mulheres com mutações BRCA e não BRCA

Introducción: la predisposición hereditaria causada por mutaciones patogénicas de la línea germinal (MPG) explica hasta el 10% de los cánceres de mama. Para reducir su impacto en mujeres mutadas se han propuesto diferentes estrategias, tales como las cirugías reductoras de riesgo o el screening con resonancia magnética (RM) de mamas. Métodos: en este estudio observacional retrospectivo se analizaron los registros de mujeres portadoras de MPG para evaluar las diferentes acciones tomadas luego del test genético. A las pacientes no mastectomizadas se les recomendó ingresar a un programa anual de cribado con RM y se evaluó el porcentaje de adherencia al plan, el número de biopsias efectuadas y el número de cánceres de mama detectados. Resultados: se incluyeron 134 mujeres con MPG, con una distribución en tercios iguales de los genes BRCA1, BRCA2 y genes no-BRCA. Entre las mutadas con indicación de seguimiento, 64% ingresaron al programa de cribado con RM. Las razones que llevaron a las mujeres a no ingresar al programa de seguimiento fueron: la oposición del médico tratante (53%), oposición de la paciente (38%), y falta de recursos (9%). Se realizaron seis biopsias por hallazgos en la RM entre las cuales se detectó un cáncer de mama. La incidencia de cáncer fue de 11 cada 1.000 mujeres-años de riesgo. Conclusiones: nuestro programa de seguimiento con RM de pacientes mutadas logró captar un porcentaje alto de candidatas. Una proporción significativa de las mujeres no ingresó debido la desaprobación del médico tratante o de la propia paciente. La evidencia obtenida revela una necesidad imperiosa de reforzar los programas educativos que destaquen la importancia del seguimiento con RM de las pacientes de alto riesgo en nuestro país.

Summary: Introduction: genetic propensity caused by germline pathogenic mutations explain up to 10% of breast cancer cases. Different strategies have been proposed to reduce its impact on women who are carriers of mutations, such as risk-reducing surgeries or breast magnetic resonance screening. Method: observational, retrospective study analyzing the medical records of women who are carriers of germline pathogenic mutations to assess the different measures taken after the genetic test. Non-mastectomized patients were advised to join an annual MRI screening program and the percentage of adherence to plan was evaluated, along with biopsies performed and the number of breast cancer cases detected. Results: 134 women carriers of germline pathogenic mutations were included in the study, with equal distributions in thirds for BRCA1, BRCA2 and non-BRCA genes. 64% of carriers of mutations who were subject to follow-up checkups joined the RMI screening program. The reasons why women failed to join the follow-up program were: the treating physician objected to the program (53%), the patients opposed to program (38%) and lack of resources (9%). Six biopsies were performed as a consequence of findings in the RMI, and one case of breast cancer was detected. Cancer incidence was 11 out of 1000 women - risk years. Conclusions: our RMI follow-up program for women who are carriers of mutations managed to attract a high percentage of candidates. A significant amount of women failed to join the program because of their treating physician's or their own disapproval. Evidence obtained reveals the dramatic need to reinforce educational programs that emphasize on the importance of RMI follow-up of high risk patients in our country.

Introdução: a predisposição hereditária causada por mutações germinativas patogênicas (GMP) explica até 10% dos cânceres de mama. Para reduzir seu impacto em mulheres com mutações, diferentes estratégias têm sido propostas, como cirurgias de redução de risco ou ressonância magnética (RM) das mamas. Métodos: neste estudo observacional retrospectivo, os registros de mulheres portadoras de MPG foram analisados para avaliar as diferentes ações tomadas após o teste genético. Pacientes não mastectomizadas foram recomendadas a entrar em um programa anual de triagem por ressonância magnética e foram avaliados o percentual de adesão ao plano, o número de biópsias realizadas e o número de cânceres de mama detectados. Resultados: foram incluídas 134 mulheres com MPG, com uma distribuição de terços iguais dos genes BRCA1, BRCA2 e não-BRCA. Entre as mulheres com mutações com indicação de acompanhamento, 64% entraram no programa de triagem por ressonância magnética. Os motivos que levaram as mulheres a não ingressarem ao programa de acompanhamento foram: oposição do médico assistente (53%), oposição da paciente (38%) e falta de recursos (9%). Seis biópsias foram realizadas devido a achados de ressonância magnética, entre os quais foi detectado um câncer de mama. A incidência de câncer foi de 11 por 1.000 mulheres-ano de risco. Conclusões: nosso programa de acompanhamento de ressonância magnética para pacientes com mutação conseguiu capturar uma alta porcentagem de candidatas. Uma proporção significativa de mulheres não entrou devido à falta de aprovação do médico assistente ou da própria paciente. As evidências obtidas revelam a necessidade urgente de reforçar programas educacionais que destaquem a importância do acompanhamento por RM de pacientes de alto risco no Uruguai.

Implicações éticas dos testes genéticos de suscetibilidade ao câncer de mama / Ethical implications of genetic testing of susceptibility to breast cancer / Implicaciones éticas de las pruebas genéticas de susceptibilidad al cáncer de mama

Resumo O câncer de mama representa um problema de saúde pública por ser a neoplasia maligna de maior incidência em mulheres no mundo. A forma hereditária corresponde a cerca de 5% a 10% de todos os casos e está diretamente relacionada à herança de mutações genéticas, sendo as principais nos genes supressores de tumor BRCA1 e BRCA2. A identificação dessas mutações é de extrema importância pelo elevado risco de desenvolvimento de câncer de mama nessa população, permitindo estratégias de rastreamento diferenciado e adoção de medidas de redução de risco. Entretanto, é importante e necessário refletir sobre os aspectos éticos relacionados ao uso indiscriminado de testes genéticos. O objetivo deste trabalho foi avaliar o conhecimento e a opinião de médicos de um centro de referência oncológico sobre a indicação dos testes genéticos de suscetibilidade ao câncer de mama mediante dilemas éticos aos quais são submetidos na prática médica.

Abstract Breast cancer is a public health problem because it is the malignant neoplasm with the highest incidence in women worldwide. The hereditary form corresponds to about 5% to 10% of all cases and is directly related to the inheritance of genetic mutations. The main ones occur in the BRCA1 and BRCA2 tumor suppressor genes. The identification of these mutations is extremely important because of the high risk of breast cancer development in this population, allowing differentiated screening strategies and the adoption of risk reduction measures. However, reflections on the ethical aspects related to the indiscriminate use of genetic testing are important and necessary. The objective of this study was to evaluate the knowledge and opinion of physicians of an oncology reference center on the indication of genetic tests for susceptibility to breast cancer given the ethical dilemmas to which they are submitted in medical practice.

Resumen El cáncer de mama representa un problema de salud pública, ya que es la neoplasia maligna con mayor incidencia en las mujeres de todo el mundo. La forma hereditaria corresponde a entre el 5% y el 10% de todos los casos y está directamente relacionada con la herencia de mutaciones genéticas, y las principales se dan en los genes supresores de tumores BRCA1 y BRCA2. La identificación de estas mutaciones es extremadamente importante debido al elevado riesgo de esta población de desarrollar cáncer de mama, además de permitir estrategias de rastreo diferenciadas y la adopción de medidas de reducción del riesgo. Sin embargo, es importante y necesario reflexionar sobre los aspectos éticos relacionados con el uso indiscriminado de las pruebas genéticas. El objetivo de este estudio fue evaluar el conocimiento y la opinión de los médicos de un centro oncológico de referencia sobre la indicación de las pruebas genéticas de susceptibilidad al cáncer de mama mediante los dilemas éticos a los que se ven sometidos en la práctica médica.

Identificación de variantes del gen BRCA 1 Y BRCA 2 en pacientes con cáncer de próstata resistente a la castración del Hospital Central Militar / Identification of BRCA 1 AND BRCA 2 gene variants in patients with castration-resistant prostate cancer at the Hospital Central Militar

Resumen El cáncer de próstata metastásico resistente a la castración (CPRC) es una neoplasia heterogénea letal entre los hombres. 30% de los tumores acumulan errores deletéreos en genes implicados en la respuesta al daño del ADN (DNA damage response en inglés, DDR). Algunos de estos genes asociados a cáncer son BRCA 1 y BRCA 2. Mutaciones en estos genes favorecen la pérdida o la modificación de la función provocando un cambio permanente y transmisible, lo que conduce al desarrollo de cáncer de próstata agresivo. El objetivo del estudio fue identificar mediante secuenciación dirigida (Next-generation sequencing; NGS) variantes génicas de BRCA 1 y BRCA 2 en el genoma de pacientes con CPRC del Hospital Central Militar. Es importante destacar que los resultados demostraron una serie de alteraciones clínicas, así como una pérdida de la función de las proteínas relacionadas con mecanismos de reparación del ADN. Curiosamente, algunas de las variantes en el gen BRCA, de las que se informa aquí, son de significado incierto, lo que nos ha sido comunicado por primera vez.

Abstract Metastatic castration-resistant prostate cancer (CRPC) is a heterogeneous lethal neoplasm among men. 30% of tumors harbor deleterious errors in genes involved in the DNA damage response (DDR). Some of these cancer-associated genes are BRCA 1 and BRCA 2. Mutations to these genes favor loss or modification of function causing a permanent and transmissible change, leading to the development of aggressive prostate cancer. The aim of the study was to identify by Next-generation sequencing (NGS) BRCA 1 and BRCA 2 gene variants in peripheral blood of patients with CRPC at the Hospital Central Militar. Importantly, the results demonstrated a number of clinical alterations, as well as a loss of function of proteins related to DNA repair mechanisms. Interestingly, some of the variants in the BRCA gene, reported here, are of uncertain significance, which has been reported to us for the first time.

BRCA mutations: Implications of genetic testing in ovarian Cancer

Ovarian cancer (OC) is one of the most lethal gynecological cancers with a 5?year survival rate that ranges from 30% to 40%. Breast cancer genes (BRCA1 and BRCA2) play a key role in maintaining genomic stability. Mutations in BRCA1/2 genes lead to the accumulation of double?strand breaks, resulting in tumorigenesis. The risk of developing OC in women with BRCA1 and BRCA2 mutations is 39% and 11%, respectively, by 70 years of age. BRCA1/2 mutation testing is thus important to identify women at greatest risk of developing OC in addition to its impact on diagnosis, prognosis, and targeted therapy. Genetic testing is required to identify the BRCA mutations and thus select patients who can benefit from polyadenosine diphosphate (ADP)杛ibose polymerase (PARP) inhibitor therapy. Tumor BRCA mutation testing can detect both germline and somatic mutations allowing implementation of preventive strategies on a broader population. Various international guidelines recommend BRCA1/2 mutation genetic testing in all OC patients irrespective of age and family history. This review focuses on the role of BRCA mutation testing in OC

A review on mechanisms of resistance to PARP inhibitors

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP?ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA?associated cancers, especially high?grade OC and breast cancers. They lead to synthetic lethality in BRCA?mutated cells by stalling the replication forks in homologous recombination?deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA?associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance

Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer / Variantes patóge nas de línea germinal en mexicanas con cáncer de mama triple negativo hereditario

Abstract: Objective: Describe the prevalence of breast cancer (BC)-associated germline pathogenic variants (PVs) among Mexican patients with triple-negative BC (TNBC). Materials and methods: The spectrum of PVs identified among patients with TNBC who were enrolled in a prospective registry and underwent genetic testing was analyzed. Results: Of 387 patients with invasive TNBC and a median age at diagnosis of 39 years (range 21-72), 113 (29%) were carriers of PVs in BC-susceptibility genes: BRCA1 (79%), BRCA2 (15%), and other (6%: ATM, BRIP1, PALB2, PTEN, RAD51C, and TP53). PV carriers were younger at BC diagnosis (37 vs. 40 years, p=0.004) than non-carriers. Conclusion: A large proportion of TNBC in Mexican patients is associated with germline PVs, the vast majority in BRCA. The incremental yield of PVs in other BC-susceptibility genes was modest, and a stepwise approach starting with BRCA testing may be justified if it is more cost-effective than multigene panel testing.

Resumen: Objetivo: Describir la prevalencia de variantes patógenas (VPs) germinales en genes asociados con cáncer de mama (CM) en pacientes mexicanos con CM triple negativo (CMTN). Material y métodos: Se analizó el espectro de VPs identificadas en pacientes con CMTN que fueron incluidos prospectivamente en un registro y se realizó un estudio genético. Resultados: Se analizó un total de 387 pacientes con una mediana de edad al diagnóstico de 39 años; 113 (29%) eran portadores de VPs en genes de susceptibilidad a CM: BRCA1 (79%), BRCA2(15%), y otros (6%: ATM, BRIP1, PALB2, PTEN, RAD51C y TP53). Los portadores de VPs eran más jóvenes al diagnóstico de CM (37 vs. 40 años, p=0.004). Conclusiones: Existe una alta prevalencia de VPs en pacientes mexicanos con CMTN y la mayoría se encuentra en genes BRCA. La realización de pruebas genéticas se puede optimizar mediante la adopción de un proceso escalonado para la detección de VPs.

Advances in Treatment of Triple Negative Breast Cancer / 肿瘤防治研究

TNBC is a special type of breast cancer with strong aggressiveness and poor prognosis. Chemotherapy is still the main treatment for TNBC, due to poor efficacy of endocrine therapy and targeted therapy. However, TNBC is a kind of heterogeneous disease, so it is urgent to study the precise molecular types and explore new precision treatment. This paper will summarize the results of clinical trials and analyze treatment strategies for TNBC, including surgical treatment, radiotherapy, chemotherapy, targeted therapy and immunotherapy, in order to provide evidence for clinical management.

Germline genetic mutations in high-risk patients for breast cancer: profile of a group in the city of Florianopolis, Santa Catarina

To analyze the occurrence of genetic mutations in a sample of patients with high risk of breast cancer in Florianopolis/ SC from December 1st, 2021, to January 31, 2022. Methods: An observational, descriptive and retrospective study carried out through data collection of a preexisting database. A total of 194 tests were analyzed. Of these, 192 met the inclusion criteria and composed the final sample of 205 genes. Data were classified and reported the frequency and percentage of the variables: gene and presence or absence of mutation. Results: Mean age of the analyzed patients was 52.3 years, and most underwent the test due to personal history of breast cancer (80%). Clinical significance classification showed that, of the 192 gene panels, 62% were variants of uncertain significance; 14% were pathogenic; and 24%, negative. Of the 205 mutations, the most prevalent genes were: ATM 8.7%, MUTYH 5.8%, POLE 5.8%, BRCA2 4.8%, MSH6 4.8% and RECQL4 4.8%. Of the pathogenic tests regarding genetic predisposition to cancer (n=38/14.1%), the most common mutations were MUTYH (23%) and BRCA1 (15%), with mean age of 52 years (±14.3). In variants of uncertain significance panels (n=168/62%) the frequency rates were ATM (7.7%), POLE (7.1%) and MSH6 (5.9%) genes. The high penetrance genes were present in 18% of the genetic predisposition to cancer panels. Of those with positive family history (n=40), 19% of the genes were pathogenic, 53% were variants of uncertain significance; and 26% were negative. Furthermore, in patients with pathogenic mutations and positive family history (n=11), the most common mutations were in BRCA1 (27%) and BRCA2 (27%). Of the patients who tested due to personal history (n=152), 64% of the genes presented variants of uncertain significance, 13% were pathogenic and 22% were negative.

Correlation between the number of false positive variants and the quality of results using Ion Torrent PGM™ sequencing to screen BRCA genes / Correlación entre el número de variantes de falsos positivos y la calidad de los resultados en la secuenciación con Ion Torrent PGM™ para seleccionar genes BRCA

Abstract | Introduction: Next Generation Sequencing (NGS) is cost-effective and a faster method to study genes, but its protocol is challenging. Objective: To analyze different adjustments to the protocol for screening the BRCA genes using Ion Torrent PGM sequencing and correlate the results with the number of false positive (FP) variants. Materials and methods: We conducted a library preparation process and analyzed the number of FP InDels, the library concentration, the number of cycles in the target amplification step, the purity of the nucleic acid, the input, and the number of samples/Ion 314 chips in association with the results obtained by NGS. Results: We carried out 51 reactions and nine adjustments of protocols and observed eight FP InDels in homopolymer regions. No FP Single-Nucleotide Polymorphism variant was observed; 67.5% of protocol variables were jointly associated with the quality of the results obtained (p<0.05). The number of FP InDels decreased when the quality of results increased. Conclusion: The Ion AmpliSeq BRCA1/BRCA2 Community Panel had a better performance using four samples per Ion-314 chip instead of eight and the optimum number of cycles in the amplification step, even when using high-quality DNA, was 23. We observed better results with the manual equalization process and not using the Ion Library Equalizer kit. These adjustments provided a higher coverage of the variants and fewer artifacts (6.7-fold). Laboratories must perform internal validation because FP InDel variants can vary according to the quality of results while the NGS assay should be validated with Sanger.

Resumen | Introducción. La secuenciación de nueva generación es un método rentable y rápido para el estudio de los genes, pero su protocolo entraña desafíos. Objetivo. Investigar diferentes ajustes del protocolo de selección de los genes BRCAmediante secuenciación de Ion Torrent PGM™ y correlacionar los resultados con el número de variantes de falso positivo. Materiales y métodos. El proceso de preparación de la biblioteca, el número de falsos positivos InDels, la concentración de la biblioteca, el número de ciclos en el paso de amplificación de objetivos, la pureza del ácido nucleico, la entrada y el número de muestras por chip del Ion-314 se analizaron en asociación con los resultados obtenidos por secuenciación de nueva generación secuenciación de nueva generación. Resultados. Se hicieron 51 reacciones y nueve ajustes de los protocolos, y se observaron ocho falsos positivos InDels en las regiones de homopolímeros. No se observó ninguna variante de polimorfismo de nucleótido simple falso positivo. En 67,5 % de los casos, las variables de protocolo en su conjunto se asociaron con la calidad de los resultados obtenidos (p<0,05). El número de falsos positivos InDels disminuyó al aumentar la calidad de los resultados. Conclusiones. El panel comunitario Ion AmpliSeq BRCA1/BRCA2 tuvo un mejor rendimiento, con cuatro muestras por chip Ion-314 en lugar de ocho, y el número de ciclos en el paso de amplificación, incluso con ADN de alta calidad, fue mejor con 23. Se observaron mejores resultados con el proceso de ecualización manual y sin el uso del kit Ion Library Equalizer. Estos ajustes proporcionaron una mayor cobertura de las variantes y menos artefactos. Los laboratorios deben realizar la validación interna porque las variantes de falsos positivos InDel pueden variar según la calidad de los resultados. La secuenciación de próxima generación debe validarse con Sanger.

Solicitud de Test genético BRCA1/2: Análisis retrospectivo en 103 pacientes / BRCA1 / 2 Genetic Test: Retrospective Analysis in 103 Patients

Introducción: Las guías de la National Comprehensive Cancer Network (NCCN) establecen criterios para solicitud de estudios BRCA1/2. La identificación de pacientes portadores de variantes patogénicas, constituye una oportunidad para dirigirlos hacia programas de cuidado específicos. Objetivo: Analizar si los criterios para la solicitud de estudio genético BRCA1 y 2, cumplen con los criterios indicados en las guías de la NCCN 2019. Describir las características de los pacientes con mutaciones patogénicas para BRCA 1/2; estrategias de prevención y reducción de riesgo llevadas a cabo. Resultados: Se solicitó el estudio a 103 pacientes, de las cuales 101 (98%) cumplían con al menos 1 criterio acorde a NCCN 2019 y realizaron el estudio 77 pacientes (76%). Obtuvimos 15 resultados positivos para una mutación patogénica en BRCA 1y 2 (19.4%), 61 resultados negativos (79.22%) y 1 variante de significado incierto (VUS) en BRCA1 (1.29%). El 46.66 % de las pacientes con mutación patogénica (PMP) eligió al menos una estrategia quirúrgica de disminución de riesgo. Conclusiones: El 98% de los pacientes a quienes se les solicito el estudio cumplían con al menos un Criterio de las Guías NCCN 2019.El hallazgo de 19.4% de mutaciones, probablemente se deba a la correcta selección de pacientes.

Introduction: National Comprehensive Cancer Network Guidelines (NCCN) establish BRCA 1/2 testing criteria. Identification of mutations carriers gives an opportunity to direct them towards specific care programs. Objective: Analyze whether the BRCA 1/2 testing criteria met the NCCN 2019 guidelines criteria. To describe the characteristics of BRCA 1/2 pathogenic mutations carriers, risk reduction and prevention strategies carried out. Results: The study was requested to 103 patients, 101 patients (98%) met at least one NCCN 2019 testing criteria and 77 patients (76%) did the test. We obtained 15 positive results for a BRCA 1/2 pathogenic mutation (19.4%), 61 negative results (79.22%) and 1 BRCA 1 variant of uncer- tain significance (VUS) (1.29%). The 46.66% of patients with a pathogenic mutation chose at least one surgical risk reducing strategy. Conclusions: Al least one NCCN 2019 testing criteria was fulfilled by the 98 % of the patients to whom the test was requested. Probably due to the correct patient selection we found 19.4% mutations in our study.

Caracterización epidemiológica del cáncer de mama / Epidemiological characterization of cancer breast

Con el objetivo de realizar la caracterización epidemiológica del cáncer de mama de las pacientes que asisten a la consulta externa de ginecología oncológica en el Instituto Guatemalteco de Seguridad Social (IGSS) de enero a marzo de 2,018, se realizó un estudio descriptivo transversal en 155 pacientes que acudieron a la clínica de mama del Hospital de Gineco Obstetricia del IGSS, con una media de edad de 62 años, el adenocarcinoma ductal infiltrante es el tipo histológico más frecuente en nuestra población tanto en edad reproductiva como en menopausia. Como factor protector el 69% dio lactancia materna. La etapa clínica más comúnmente diagnosticada es IIA. El Luminal A, el más frecuentemente diagnosticado por inmunohistoquímica, seguido del Luminal B y HER2neu. Se diagnostican pacientes mayormente en etapas clínicas tempranas (I y II).

In order to carry out the epidemiological characterization of breast cancer in patients attending the outpatient gynecology oncology consultation at the Guatemalan Social Security Institute (IGSS) from January to March 2018, a descriptive cross-sectional study was carried out in 155 patients who attended the breast clinic of the IGSS Obstetrics Gynecology Hospital, with a mean age of 62 years, infiltrating ductal adenocarcinoma is the most frequent histological type in our population both in reproductive age and in menopause. As a protective factor, 69% breastfed. The most diagnosed clinical stage is IIA. Luminal A, the most frequently diagnosed by immunohistochemistry, followed by Luminal B and HER2neu. Patients are diagnosed mostly in early clinical stages (I and II).

Cáncer de mama triple negativo: terapias sistémicas actuales y experiencia local / Triple negative breast cancer: current systemic therapy and local experience

Resumen El cáncer de mama (CM) es la principal causa de muerte por cáncer en mujeres chilenas. Es una enfermedad heterogénea, en la cual se han identificado cuatro subtipos básicos, determinados según características clínicas, histológicas y moleculares, los que se relacionan a estrategias terapéuticas. El CM triple negativo (CMTN) se caracteriza por su agresividad, recaída temprana y mayor tendencia a presentarse en etapas avanzadas. Frecuentemente afecta a mujeres jóvenes o con antecedentes familiares de CM u ovario. La única terapia sistémica aprobada para el CMTN es la quimioterapia; sin embargo, recientemente terapias moleculares con inhibidores de puntos de control inmune e inhibidores de la poli-adenosina difosfato ribosa polimerasa, han mostrado eficacia en pacientes seleccionados, y se han agregado al arsenal terapéutico para CMTN. Dada la aparición de estas nuevas estrategias, parece relevante entender la heterogeneidad de esta enfermedad, los mecanismos de acción de las nuevas terapias, resultados clínicos y criterios de selección de pacientes para terapias moleculares. Presentamos una revisión de la terapia sistémica actual del CMTN.

Breast cancer is the leading cause of cancer death in Chilean women and worldwide. It is a heterogeneous disease and four different subtypes have been identified based on clinical, histological and molecular features, which correlate with different treatment tumor sensitivity. Triple negative breast cancer is characterized by its aggressiveness, early relapse, and a greater tendency to present in advanced stages. It frequently affects young women, with cancer family history, especially breast or ovarian cancer. The approved systemic therapy for triple negative breast cancer is chemotherapy; however, recently, targeted therapies with checkpoint inhibitors and polyadenosine diphosphate ribose polymerase inhibitors have been shown to be effective in selected patients and have been added to the therapeutic arsenal for triple negative breast cancer. Given the appearance of these new strategies, it seems relevant to understand the heterogeneity of this disease, the mechanisms of action behind new therapies, clinical results, and the criteria to select patients for molecular therapies. We present a review of the current systemic therapy of this breast cancer subtype.