[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology.

Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene (BRCA1/2). Hence, identifying HR-deficiencies by genomic analysis-for instance, BRCA1/2 used in triple-negative breast cancer-should be a part of the selection process for PARP inhibitor therapy. Published data suggest BRCA1/2 germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available BRCA1/2 analysis. In this review, we discuss [18F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.

Evaluation of Homologous Recombination Deficiency in Ovarian Cancer.

OPINION STATEMENT: Homologous recombination deficiency (HRD) is an important biomarker guiding selection of ovarian cancer patients who will derive the most benefit from poly(ADP-ribose) polymerase inhibitors (PARPi). HRD prevents cells from repairing double-stranded DNA damage with high fidelity, PARPis limit single-stranded repair, and together these deficits induce synthetic lethality. Germline or somatic BRCA mutations represent the narrowest definition of HRD, but do not reflect all patients who will have a durable PARPi response. HRD can also be defined by its downstream consequences, which are measured by different metrics depending on the test used. Ideally, all patients will undergo genetic counseling and germline testing shortly after diagnosis and have somatic testing sent once an adequate tumor sample is available. Should barriers to one test be higher, pursuing germline testing with reflex to somatic testing for BRCA wildtype patients or somatic testing first strategies are both evidence-based. Ultimately both tests offer complementary information, germline testing should be pursued for any patient with a history of ovarian cancer, and somatic testing is valuable at recurrence if not performed in the upfront setting. There is a paucity of data to suggest superiority of one germline or somatic assay; therefore, selection should optimize turnaround time, cost to patients, preferred result format, and logistical burden. Each clinic should implement a standard testing strategy for all ovarian cancer patients that ensures HRD status is known at the time of upfront chemotherapy completion to facilitate comprehensive counseling about anticipated maintenance PARPi benefit.

CA125 Levels in BRCA mutation carriers - a retrospective single center cohort study.

BACKGROUND: Ovarian cancer screening in BRCA1/2 mutation carriers utilizes assessment of carbohydrate antigen 125 (CA125) and transvaginal ultrasound (TVU), despite low sensitivity and specificity. We evaluated the association between CA125 levels, BRCA1/2 mutation status and menopausal status to provide more information on clinical conditions that may influence CA125 levels. METHODS: We retrospectively analyzed repeated measurements of CA125 levels and clinical data of 466 women at high risk for ovarian cancer. CA125 levels were compared between women with and without deleterious mutations in BRCA1/2. Pearson's correlation was used to determine the association between age and CA125 serum level. Differences in CA125 levels were assessed with the Mann-Whitney U test. The effect of BRCA1/2 mutation status and menopausal status on the change in CA125 levels was determined by Two-factor analysis of variance (ANOVA). RESULTS: The CA125 serum levels of premenopausal women (median, 13.8 kU/mL; range, 9.4 - 19.5 kU/mL) were significantly higher than in postmenopausal women (median, 10.4 kU/mL; range, 7.7 - 14.0 kU/mL; p < .001). There was no significant difference in the CA125 levels of BRCA mutation carriers and non-mutation carriers across all age groups (p = .612). When investigating the combined effect of BRCA1/2 mutation and menopausal status, variance analysis revealed a significant interaction between BRCA1/2 mutation status and menopausal status on CA125 levels (p < .001). There was a significant difference between the CA125 levels of premenopausal and postmenopausal women, with a large effect in BRCA mutation carriers (p < .001, d = 1.05), whereas in non-mutation carriers there was only a small effect (p < .001, d = 0.32). CONCLUSION: Our findings suggest that hereditary mutations in BRCA1/2 affect the decline of CA125 levels with increasing age. To prove a definite effect of this mutation on the CA125 level, prospective trials need to be conducted to define new cut-off levels of CA 125 in mutation carriers and optimize ovarian cancer screening.

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.

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.

International Tale on Gene Patents - between Medical and Legal Uncertainties / Cuento internacional sobre patentes genéticas: entre la incertidumbre médica y jurídica

This work is inspired by the international litigation chronicle of Myriad Genetics that remains of topical importance in the judicial and academic discourse regardless of the time that passed since. It discusses approaches of various jurisdictions to the problem of gene patenting as well as patenting of geneticdiagnostic testing. The article takes under scrutiny the judgments rendered in the U.S., Australia as well as the decisions by the European Patent Office and placesthem into interdisciplinary background of genetic science. The issue is significant, both theoretically and practically. Notwithstanding the expiration of patents that constituted the subject matter of the Myriad’s various lawsuits, the problem still remains currently relevant. Firstly, because the judgments in individual cases did not answer all the questions, but – in some way – only prepared a path for future decisions. Secondly, it is on account of new scientific breakthroughs in the area of human genetics. Consequently, the domain of genetic diagnostics is under continuous development and in the future may continue to reveal new scientific discoveries and (possibly) inventions. The lack of uniform and transparent rules in this field, and well-defined boundaries for potential monopolies constantly brings not only uncertainty for medical practitioners and scientists, but also real disadvantagesfor the patients. (AU)

Esta obra se inspira en la crónica del litigio internacional de Myriad Genetics, que sigue siendo de actualidad en el discurso judicial y académico a pesar del tiempotranscurrido desde entonces. En él se examinan los enfoques de diversas jurisdicciones sobre el problema de las patentes de genes, así como de las patentes de pruebas de diagnóstico genético. El artículo examina las sentencias dictadas en Estados Unidos y Australia, así como las decisiones de la Oficina Europea de Patentes, y las sitúa en el contexto interdisciplinario de la ciencia genética. La cuestión es importante, tanto desde el punto de vista teórico como práctico. A pesar de la expiración de las patentes que constituyeron el objeto de los diversos pleitos de Myriad, el problema siguesiendo de actualidad. En primer lugar, porque las sentencias dictadas en los casos individuales no respondieron a todas las preguntas, sino que –en cierto modo– sólo prepararon el camino para futuras decisiones. En segundo lugar, debido a los nuevosavances científicos en el ámbito de la genética humana. En consecuencia, el ámbito del diagnóstico genético está en continuo desarrollo y en el futuro puede seguirrevelando nuevos descubrimientos científicos y (posiblemente) invenciones. La falta de normas uniformes y transparentes en este ámbito y de límites bien definidos para los monopolios potenciales no sólo genera constantemente incertidumbre para losmédicos y científicos, sino también desventajas reales para los pacientes. (AU)

Clinical characteristics of patients with Breast and / or Ovarian Cancer with mutations in the BRCA1 and BRCA2 genes in Córdoba, Argentina / [Características clínicas de pacientes con Cáncer de Mama y / o Cáncer de Ovario con mutaciones en los genes BRCA1 y BRCA2 en Córdoba, Argentina.]

Introduction: Hereditary predisposition syndromes to cancer represent 5-10% of cancer cases, the most studied being HBOC produced by mutations in the BRCA1/2 genes. Objectives: To describe clinical, histopathological and PV characteristics in patients with HBOC in Córdoba, Argentina and compare it with those without BRCA1/2 mutations. Methods: Cross-sectional, correlational and observational analysis of patients from Córdoba. The ANOVA, Student's t test contingency tables and Fisher exact test were used the significance level was α = 0.05. Results: 155 women with BC, OC and BC/OC were studied. 40 BRCA1 / 2 mutations were identified. No differences were found in the age of diagnosis between patients with and without BRCA1/2 mutations. A significant association was found between VP in BRCA1/2 and the type of cancer (p = 0.003); all cases with BC/OC presented mutations in BRCA1/2. No significant association was found between mutated/non-mutated and personal history, family background, and ER-PR-HER2. 23.1% and 38.1% of BC cases were TN in individuals with VP in BRCA 1 and 2, respectively. The prevalence of mutations was 25.8% and the prevalence of novel PV was 10.0%. Conclusions: Patients with BC-VP BRCA1/2 are associated with ductal histology, and younger age of presentation with VP BRCA1. We did not find significant differences in the age at diagnosis of BC between patients with BRCA1 and BRCA2 mutations, a higher proportion of BC TN is observed than in the general population. In our sample, the prevalence of BRCA1/2 mutations among patients who meet criteria for HBOC is 25.8%, with 10% new pathogenic variant.

Introducción: Los síndromes de predisposición hereditaria al cáncer representan un 5-10% de los casos de cáncer, el más estudiado es HBOC producido por mutaciones en los genes BRCA1/2. Objetivos: Describir características clínicas, histopatológicas y VP en pacientes con HBOC en Córdoba, Argentina y compararla con aquellas sin mutaciones en BRCA1/2. Métodos: Análisis transversal, correlacional y observacional de pacientes de Córdoba. Se utilizó la prueba ANOVA, t de Student, tablas de contingencia y prueba exacta de Fisher, el nivel de significancia fue α=0,05. Resultados: Se estudiaron 155 mujeres con CM, CO y CM/CO. Se identificaron 40 mutaciones en BRCA1/2. No se encontraron diferencias en edad de diagnóstico entre pacientes con y sin mutaciones en BRCA1/2. Se encontró asociación significativa entre VP en BRCA1/2 y el tipo de cáncer (p=0,003); todos los casos con CM/CO presentaron mutaciones en BRCA1/2. No se encontró asociación significativa entre mutados/no mutados y AP, AF, RE-RP-HER2. El 23.1% y 38.1% de los casos de CM fueron TN en individuos con VP en BRCA 1 y 2 respectivamente. La prevalencia de mutaciones fue 25,8% y la prevalencia de VP noveles del 10,0%. Conclusiones: Las pacientes con CM-VP BRCA1/2 están asociadas con histología ductal, y menor edad de presentación con VP BRCA1. No encontramos diferencias significativas en edad de diagnóstico del CM entre pacientes con mutaciones BRCA1 y BRCA2, se observa una mayor proporción CM TN que en la población en general. En nuestra muestra, la prevalencia de mutaciones en BRCA1/2 entre los pacientes que reúnen criterios para HBOC es del 25,8%, con 10% de VP noveles.

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.

[Treatment of metastatic pancreatic cancer]. / Therapie des metastasierten Pankreaskarzinoms.

Pancreatic cancer is the 4th most common cause of cancer death in Germany and continues to be associated with a poor prognosis. A prerequisite for chemotherapy or radiotherapy is always the pathohistological (or cytological) confirmation of the tumor disease. Molecular diagnostics include analysis of DNA mismatch repair in the tumor and of the germline mutations in BRCA 1/2 (gBRCA mutation). Systemic chemotherapy remains the mainstay in the management of locally advanced and metastatic disease. If a gBRCA mutation is detected, platinum-based therapy should be used. Patients with good performance status benefit from second-line therapy. Immunotherapy with checkpoint inhibitors (not yet approved) may be considered in pretreated patients with evidence of deficient DNA mismatch repair or microsatellite instability.

Sex Differences in Attitudes Toward Marriage and Childbearing Based on the Assumption of Being BRCA1/2 Mutation Carriers Among Young People.

PURPOSE: This study investigated changes in attitudes toward marriage and childbearing assuming a BRCA1/2 mutation carrier status among healthy, unmarried individuals in Korea. METHODS: A nationally representative sample of healthy, unmarried individuals aged 20-39 years was surveyed. A questionnaire on marriage and childbearing intentions was administered to the participants before and after providing them with information on BRCA1/2 mutation carriers' breast and ovarian cancer risks and their autosomal dominant inheritance pattern. The participants were asked about their attitudes toward childbearing through preimplantation genetic diagnosis (PGD). RESULTS: Of the participants who initially wanted to marry, the assumption that they or their partners had BRCA1/2 mutation caused 25.3% to no longer want to get married and 36.2% to change their attitude from wanting to bear children to no longer wanting them. Females were more likely than males to change their attitudes toward marriage and childbearing. The participants who had negative attitudes toward genetic testing were more likely to change their attitudes regarding marriage and childbearing than those who were favorable toward both disclosure and testing. More than 50% of the participants who did not want children were willing to bear children through PGD when it was assumed that they were BRCA mutation carriers. CONCLUSION: On the assumption of being carriers, general, young, and healthy females were more likely than males to negatively change their attitudes toward marriage and childbearing. Public education on the implications of living with mutation carriers and reproductive options may be required.

Low BRCA1 and BRCA2 Germline Mutation Rates in a French-Canadian Population with a Diagnosis of Epithelial Tubo-Ovarian Carcinoma.

OBJECTIVE: Universal genetic testing has become increasingly important in the management of epithelial tubo-ovarian and peritoneal carcinoma. Worldwide, reported incidences of deleterious BRCA mutations vary between 12% and 15%. We sought to evaluate the incidence in our population, given its specific genetic background (French-Canadian ancestry). METHOD: Mainstream genetic testing was implemented in our service in May 2017 and offered to all patients with epithelial tubo-ovarian or peritoneal carcinomas, except mucinous and borderline tumours. Data were prospectively collected in a database and retrospectively analyzed. RESULTS: We tested 222 patients in our centre, of whom 183 (82.4%) had high-grade serous carcinoma (HGSC). Overall, 139 patients had no identified mutation (62.6%). Deleterious BRCA1 and BRCA2 mutations were found in 12 patients (5.4%): 6 had BRCA1, and 6 BRCA2 mutations; 11 of these patients had HGSC. Other non-BRCA mutations (ATM, RAD51C, RAD51D, BRIP1, CDH1, MRE11, MSH6, MUTYH, PALB2, and PMS2) were observed in an additional 20 patients (9.0%), of whom 18 had HGSC. A total of 63 different variants of unknown significance (VUS) were found, of which 4 were in the BRCA1 and BRCA2 genes. Deleterious mutations were not identified in clear cell carcinomas, and only 1 was found in low-grade serous carcinoma. CONCLUSION: In our French-Canadian population, the incidence of deleterious germline BRCA mutations was surprisingly low at 5.4%-less than half that reported in the literature. This may affect patient response to poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy. Mainstream genetic testing was successfully implemented in our service and facilitated access to genetic testing in our patient population.

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples.

OBJECTIVE: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. METHODS: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. RESULTS: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. CONCLUSION: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience.

Breast cancer is a multifaceted disease that currently represents a leading cause of death in women worldwide. Over the past two decades (1998-2020), the National Health Laboratory Service's Human Genetics Laboratory in central South Africa screened more than 2,974 breast and/or ovarian cancer patients for abnormalities characteristic of the widely known familial breast cancer genes, Breast Cancer gene 1 (BRCA1) and Breast Cancer gene 2 (BRCA2). Patients were stratified according to the presence of family history, age at onset, stage of the disease, ethnicity and mutation status relative to BRCA1/2. Collectively, 481 actionable (likely-to pathogenic) variants were detected in this cohort among the different ethnic/racial groups. A combination of old (pre-2014) and new (post-2014) laboratory techniques was used to identify these variants. Additionally, targeted genotyping was performed as translational research revealed the first three recurrent South African pathogenic variants, namely BRCA1 c.1374del (legacy name 1493delC), BRCA1 c.2641G>T (legacy name E881X) and BRCA2 c.7934del (legacy name 8162delG). This initial flagship study resulted in a cost-effective diagnostic test that enabled screening of a particular ethnic group for these variants. Since then, various non-Afrikaner frequent variants were identified that were proven to represent recurrent variants. These include BRCA2 c.5771_5774del (legacy name 5999del4) and BRCA2 c.582G>A, both Black African founder mutations. By performing innovative translational research, medical science in South Africa can adopt first-world technologies into its healthcare context as a developing country. Over the past two decades, the progress made in the public sector enabled a pivotal shift away from population-directed genetic testing to the screening of potentially all breast and ovarian cancer patients, irrespective of ethnicity, family history or immunohistochemical status. The modifications over the years complied with international standards and guidelines aimed at universal healthcare for all. This article shares all the cohort stratifications and the likely-to pathogenic variants detected.

Familial breast cancer, pregnancy and cardiotoxicity associated with the use of doxorubicin and reaction with trastuzumab.

INTRODUCTION: Breast Cancer (BC) is a neoplasm with the highest prevalence in women in Brazil and worldwide. Pregnancy-associated with BC is defined as that which occurs during pregnancy or within 1 to 2 years postpartum. The objective is to present a clinical case of a young patient with a history of familial BC who had cancer during pregnancy. The patient had cardiotoxicity after using doxorubicin and trastuzumab. CASE REPORT: She was a young patient within infiltrating ductal carcinoma in the right breast She was diagnosed within nine weeks of gestation and submitted to neoadjuvant chemotherapy with AC protocol (doxorubicina and cyclophosphamide) and mastectomy. Developed left atrial overload after treatment and still responding to hypersensitivity to trastuzumab. MANAGEMENT AND OUTCOME: The patient presented an alteration in the electrocardiogram (ECG) after the use of doxorubicin. The exam was repeated and the ECG was normal. Trastuzumab was started after delivery and the patient had a hypersensitivity reaction. Administration of trastuzumab was stopped and hydrocortisone was administered. The patient showed improvement in symptoms with cessation of trastuzumab. DISCUSSION: Although anthracycline-induced cardiotoxicity and hypersensitivity reactions to trastuzumab are common reactions, there are few studies on the effects of these drugs in patients with Gestational breast cancer (GBC). Monitoring cardiotoxicity in breast cancer treatment in pregnant patients is essential to avoid two complications: for the pregnant woman and the fetus.

Influence of cellular models and individual factor in the biological response to chest CT scan exams.

BACKGROUND: While computed tomography (CT) exams are the major cause of medical exposure to ionising radiation, there is increasing evidence that the potential radiation-induced risks must be documented. We investigated the impact of cellular models and individual factor on the deoxyribonucleic acid double-strand breaks (DSB) recognition and repair in human fibroblasts and mammary epithelial cells exposed to current chest CT scan conditions. METHOD: Twelve human primary fibroblasts and four primary human mammary epithelial cell lines with different levels of radiosensitivity/susceptibility were exposed to a standard chest CT scan exam using adapted phantoms. Cells were exposed to a single helical irradiation (14.4 mGy) or to a topogram followed, after 1 min, by one single helical examination (1.1 mGy + 14.4 mGy). DSB signalling and repair was assessed through anti-γH2AX and anti-pATM immunofluorescence. RESULTS: Chest CT scan induced a significant number of γH2AX and pATM foci. The kinetics of both biomarkers were found strongly dependent on the individual factor. The topogram may also influence the biological response of radiosensitive/susceptible fibroblasts to irradiation. Altogether, our findings show that a chest CT scan exam may result in 2 to 3 times more unrepaired DSB in cells from radiosensitive/susceptible patients. CONCLUSIONS: Both individual and tissue factors in the recognition and repair of DSB after current CT scan exams are important. Further investigations are needed to better define the radiosensitivity/susceptibility of individual humans.

[PARP Inhibitors: From the Mechanism of Action to Clinical Practice]. / Inibidores da PARP: do mecanismo de ação à prática clínica.

Repairing damage and errors that occur in the DNA molecule is essential to maintain the integrity of the genome and cell viability. Deficits in DNA repair mechanisms lead to an increased risk of genetic instability and contribute to neoplastic transformation. Poly (ADP-ribose) polymerases (PARP) are a group of enzymes that play a key role in signalling and repairing DNA errors. The inhibition of its activity is a therapeutic strategy that takes advantage of the mechanism of synthetic lethality and that can be used in the treatment of tumours with specific defects in DNA repair pathways, namely in tumours with mutations in the tumour suppressor genes BRCA1 and BRCA2. There are several PARP inhibitors (iPARP), already approved by the USA Food and Drug Administration and the European Medicines Agency used in the treatment of breast, ovarian, pancreatic and prostate cancer. However, as with other target therapies, despite being well tolerated and widely used in the clinical practice, iPARP resistance is common and can be developed through various molecular mechanisms. In this article, we intend to make an updated review on iPARP and its main role in tumour cells, highlighting the several resistance mechanisms that have been recently revealed, as well as the current clinical applications and toxicity associated with this target therapy.

A reparação dos danos que ocorrem na molécula de ADN é fundamental para manter a integridade do genoma e a viabilidade celular. Défices nos mecanismos de reparação desta molécula cursam com um aumento do risco para instabilidade genética e contribuem para a transformação neoplásica. As poly (ADP-ribose) polymerases (PARP) são um grupo de enzimas que apresentam um papel chave na sinalização e reparação dos erros no ADN. A inibição da sua atividade é uma estratégia terapêutica que tira partido do mecanismo de letalidade sintética e que pode ser usada no tratamento de tumores com defeitos específicos nas vias de reparação de ADN, nomeadamente em tumores com mutações nos genes supressores tumorais BRCA1 e BRCA2. Existem vários inibidores das PARP (iPARP) já aprovados pela Food and Drug Administration dos Estados Unidos da América e pela Agência Europeia do Medicamento e utilizados no tratamento do cancro da mama, ovário, pâncreas e próstata. No entanto, tal como acontece com outras terapias alvo, a resistência aos iPARP é comum apesar de bem tolerados e amplamente utilizados na prática clínica, e pode desenvolver-se através de vários mecanismos moleculares. Neste artigo, pretendemos realizar uma revisão atualizada sobre os iPARP e o seu principal modo de ação em células tumorais, dando a conhecer os vários mecanismos de resistência que têm sido recentemente revelados, assim como as atuais aplicações clínicas e a toxicidade associada a esta terapia alvo.

Afrontamiento de la mastectomía preventiva en mujeres con riesgo de cáncer de mama hereditario / Coping with prophylactic mastectomy in women at risk of hereditary breast cancer

Objetivo: explorar las vivencias y el afrontamiento de las mujeres intervenidas de mastectomía preventiva ante el riesgo de cáncer de mama hereditario. Método: estudio cualitativo descriptivo con abordaje fenomenológico realizado con un muestreo de conveniencia y complementado por bola de nieve. Se llevaron a cabo entrevistas semiestructuradas en profundidad a mujeres con riesgo de cáncer de mama hereditario sometidas a mastectomía preventiva. El análisis de datos se efectuó según la propuesta de Miles y Huberman. Resultados: participaron nueve mujeres. Un 55,6% tenía entre 40 y 50 años y un 66,7% había sido diagnosticada antes de los 40 y tenía mutación BRCA2. Las mujeres demandaron un mayor conocimiento acerca del cáncer de mama hereditario y de la cirugía en sí, especialmente de la previsión del dolor y la interferencia en las actividades de la vida diaria. Expresaron también haber recibido la noticia con preocupación y contrariedad, ya que se debían someter a cirugía estando sanas. Las estrategias de afrontamiento más habituales fueron el acompañamiento de familiares y amistades, el deporte y la realización del tatuaje del pezón. Destacaron la importancia de la humanización de los cuidados y la comunicación activa de sus especialistas, y la importancia de recursos como asociaciones, banco de imágenes o terapia psicológica para facilitar el afrontamiento. Conclusiones: la mastectomía preventiva genera un gran impacto en las mujeres. Para mejorar su afrontamiento es necesario proporcionar un trato humanizado, transmitir información veraz y de calidad, ofrecer cuidados en función de sus necesidades promoviendo su autonomía y proporcionar apoyo emocional.(AU)

Objective: to explore the experiences and coping strategies of women undergoing prophylactic mastectomy when faced with the risk of hereditary breast cancer. Method: a descriptive qualitative study with phenomenological approach conducted with convenience sampling and complemented by snowball sampling. In-depth semistructured interviews were conducted with women at risk of hereditary breast cancer who had undergone prophylactic mastectomy. There was data analysis according to the Miles and Huberman’s model. Results: the study included nine women; 55.6% were between 40 and 50 years old and had been diagnosed before they were 40 and presented BRCA2 mutation. Women demanded higher knowledge about hereditary breast cancer and the surgery, particularly regarding estimated pain and interference in daily life activities. They also expressed concern and distress when receiving the news, because they had to undergo surgery while healthy. The most usual coping strategies were support by relatives and friends, sports, and nipple tattooing. They highlighted the importance of humanized care and active communication by specialists, as well as the importance of resources such as associations, image banks, or psychological therapy to enable coping. Conclusions: prophylactic mastectomy generates a high impact on women. For an improvement in coping, it is necessary to provide humanized care, to convey truthful and quality information, to offer care based on their needs encouraging autonomy, and to provide emotional support.(AU)

Comparing breast cancer imaging characteristics of CHEK2 with BRCA1 and BRCA2 gene mutation carriers.

PURPOSE: Breast cancer gene (BRCA) 1 and 2 mutations are frequently studied gene mutations (GM); the incidence of checkpoint kinase 2 (CHEK2) is increasing. We describe the imaging features of breast cancer (BC) in CHEK2 mutations, compared to BRCA 1 and 2 using mammography, ultrasound (US) and magnetic resonance imaging (MRI). METHOD: Inclusion criteria were primary BC in GM carriers, treated in the same hospital. Age at diagnosis, histology, hormone receptor and human epidermal growth factor receptor 2 (HER2) status were retrieved. Mammography descriptors were mass, asymmetry and suspicious microcalcifications. The enhancement pattern (MRI), shape and border, architectural distortion, the presence of a hyperechoic rim and cystic complex structure (US) were documented. Analyses were performed using SAS software (version 9.4). Fishers' exact test was used to test associations between two categorical variables. RESULTS: In 191 women, 233 malignant lesions were diagnosed (78 in BRCA1, 109 in BRCA2, 46 in CHEK2). In CHEK2 carriers, mammographically, suspicious microcalcifications (54%) were more prevalent (BRCA2 (48%) and BRCA1 carriers (33%)) (p-value = 0.057) compared to mass lesions (35%). On US, lesions were most frequently ill-defined (86%) (p = 0.579) and irregular (94.5%) (p = 0.098) compared to BRCA2 (77% and 80% resp.) and BRCA1 carriers (71% and 72% resp.). On MRI, mass lesions showed a type 3 curve in CHEK2 (67%) compared to BRCA1 (36%) and BRCA2 (50%) (p = 0.056). CONCLUSIONS: Malignant radiological characteristics of breast cancer, more specifically suspicious microcalcifications, were more frequently seen in CHEK2 and BRCA2 compared to BRCA1 mutation carriers (without a significant difference) indicating the importance of mammography in follow-up of CHEK2 carriers.

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.

Histological Findings of Mammary Gland Development and Risk of Breast Cancer in BRCA1 Mutant Mouse Models.

PURPOSE: The breast cancer susceptibility gene, BRCA1, is involved in normal development and carcinogenesis of mammary glands. Here, we aimed to evaluate the relationship between histological findings of mammary gland development and breast cancer risk in BRCA1 mutant mice. METHODS: Five BRCA1 mutant mice and five non-mutant FVB/NJ mice were used for each group of 1-month-old (pubertal), 3-month-old (fertile), and 8-month-old (menopausal) mice. In another experiment, 15 BRCA1 mutant mice were followed up to 8 months after birth and classified into tumor-bearing (11 mice) and tumor-free (4 mice) groups. Excised mammary gland tissues were stained with Carmine Alum, and the number of terminal end buds (or alveolar buds), branching density, and duct elongation were measured using image analysis programs. Differences between the two groups were assessed using paired t-test. RESULTS: One-month-old BRCA1 mutant mice showed a higher number of terminal end buds (23.8 ± 1.0 vs. 15.6 ± 0.8, p = 0.0002), branching density (11.7 ± 0.4 vs. 9.6 ± 0.5%, p = 0.0082), and duct elongation (9.7 ± 0.7 vs. 7.3 ± 0.4 mm, p = 0.0186) than controls. However, there was no difference between the 3- and 8-month-old groups. In BRCA1 mutant mice, the tumor-bearing group showed a significantly higher number of alveolar buds (142.7 ± 5.5 vs. 105.5 ± 5.4, p = 0.0008) and branching density (30.0 ± 1.0 vs. 24.1 ± 1.1%, p = 0.008) than the tumor-free group; however, duct elongation was not different (23.9 ± 0.6 vs. 23.6 ± 0.6 mm, p = 0.8099) between the groups. CONCLUSION: BRCA1 mutant mice exhibited early pubertal mammary gland development and delayed age-related mammary gland involution was associated with breast cancer. Our results may have clinical implications for predicting breast cancer risk and developing prevention strategies for BRCA1 mutation carriers.