BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients

We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response.

CÂNCER DE MAMA EM MULHERES JOVENS

Introdução: O câncer de mama (CM), acomete mais frequentemente mulheres acima de 50 anos que tenham entrado na menopausa, esse número representa uma pequena parcela dentre todos os casos. De 2 a 5% dos casos ocorrem antes dos 35 anos. Os estudos ainda divergem, porém, a maioria das vezes em mulheres jovens o CM está associado a um pior prognóstico, pois podem apresentar em associação clínica e patológica uma doença mais agressiva biologicamente. Tendem a ser hereditário, com mutações com os genes BRCA 1 e 2. O prognóstico menos favorável, os tratamentos tendem a ser agressivos. Objetivo: Revisão de literatura cientifica em relação ao Câncer de Mama em Mulheres Jovens. Material e métodos: US National Library of Medicine (PubMed) e Scientific Eletronic Library Online (SciELO) descritores: Breast Neoplasms, Young Adult, Adolescent e Immunophenotyping, com os Descritores em Ciências da Saúde (DeCS). Encontrados 235 artigos e após critérios de inclusão e exclusão, 6 artigos foram utilizados. Os utilizados para a inclusão: artigos em inglês, português ou espanhol, entre 2009 a 2021, disponíveis na íntegra para acesso online grátis. Resultado: Características clínicas de neoplasias mamárias em mulheres mais jovens diferem daquelas que surgiram mais tarde, a idade no diagnóstico do câncer de mama continua uma variável importante na determinação do prognóstico. Pacientes com menos de 40 anos, apresentam grau histológico alto, perfil imunoistoquímico desfavorável, taxa de mortalidade elevada em comparação as mulheres mais velhas, e são frequentemente classificados como câncer de mama triplo- negativo (TNBC, sigla em inglês), receptor de estrogênio (RE), receptor de progesterona (PR) e receptor-2 do fator de crescimento epidérmico humano (HER2-) negativos. Mulheres jovens são mais propensas a ter recorrências locais, diagnosticadas em um estágio avançado e terem sobrevida de 5 anos pior em comparado com suas contrapartes mais velhas na pré-menopausa. Conclusão: Carcinomas mamários de mulheres jovens possuem características clínicas, patológicas e moleculares mais agressivas, quando comparadas às mulheres de 50 anos. A sinalização oncogênica, é caracterizada por menor sensibilidade hormonal e maior expressão de HER-2 / receptor do fator de crescimento epidérmico (EGFR), e justifica estudos adicionais para oferecer este grupo de mulheres melhores prognósticos e opções preventivas e terapêuticas.

Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A Mini review

Background and aim The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual’s risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations. Methods Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review. Results Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.

Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials

Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.

POTENTIAL COUMARIN THIOSEMICARBAZONE HYBRIDS AS BRCA-1 MIMETICS FOR ER POSITIVE BREAST CANCER THERAPY: AN IN-SILICO APPROACH

The goal of this study is to find a novel class of BRCA-1 mimics for Estrogen Receptor α (ERα) breast cancer that works differently from conventional anti-estrogens. Breast Cancer Susceptibility Protein-1 (BRCA-1) is a protein was discovered to bind to ERα and decrease its function by a direct contact between regions inside BRCA1's amino terminus and the carboxy terminus of ERα. A novel class of hybrids with coumate and thiosemicarbazone scaffolds was created with the premise of developing small compounds that imitate the function of BRCA-1 to down regulate the ERα and inhibit the tumor activity of breast cancer cells. Using Schrodinger 2020-2, ADMET and in silico molecular docking tests of the proposed hybrids were performed on the BRCA-1 binding cavity of ERα. TSCO-XIV and TSCO-III are developed hybrids that have high docking scores and good binding interactions with important residues.