Prevalência da mutação de gene ESR1 em pacientes com câncer de mama receptor hormonal positivo resistentes à terapia endócrina neoadjuvante

Introdução: Mutações no gene ESR1 (ESR1m) são importante mecanismo de resistência à terapia endócrina em câncer de mama receptor de estrogênio positivo (RE+) e vêm sido reconhecidas como biomarcadores prognósticos e preditivos, assim como um potencial alvo terapêutico. Entretanto, as pesquisas publicadas descrevem ESR1m como um potencial mecanismo de resistência adquirida no contexto de doença metastática. O papel de ESR1m como potencial mecanismo de resistência intrínseca no contexto de doença inicial não foi estudada. O escore PEPI é um índice que avalia o perfil de sensibilidade ou resistência à terapia endócrina neoadjuvante. O objetivo deste estudo foi avaliar a prevalência de ESR1m em amostras tumorais de pacientes com câncer de mama RE+ com perfil de resistência à terapia endócrina neoadjuvante com inibidores de aromatase. Resultados: Uma coorte prospectiva de mulheres na pós-menopausa com câncer de mama RE+ HER2-negativo estádio II-III tratadas com hormonioterapia neoadjuvante foi conduzida. Pacientes receberam tratamento com anastrozol por um período mínimo de três meses. Amostras tumorais de pacientes com um perfil de resistência endócrina primária (definida como escore PEPI maior ou igual a 4) foram selecionados e analisados quanto à presença de mutações no gene ESR1. ESR1m foram avaliadas em amostras de tecido tumoral incluídas em blocos de parafina utilizando a técnica de reação PCR quantitativo. As mutações em hotspots nos códons 380, 537 e 538 do gene ESR1 foram analisadas. Resultados: Cento e vinte e sete pacientes foram incluídas na coorte, das quais 100 (79%) completaram a neoadjuvância, foram operadas e tiveram o escore PEPI calculado. Dentre estas pacientes, o escore PEPI variou entre 0 e 3 em 70% (70/100) e foi igual ou maior a 4 em 30% (30/100). Vinte e três pacientes foram incluídas na análise. ESR1m não foram identificadas em nenhuma das amostras dos 23 pacientes com câncer de mama em estádio inicial resistentes a hormonioterapia neoadjuvante. Conclusão: As evidências atuais suportam a noção que existem diferentes mecanismos de resistência intrínseca ou adquirida à terapia endócrina em câncer de mama. Nosso estudo sugere que mutações no gene ESR1m não se desenvolvem em um período curto de tempo e não representam um mecanismo comum de resistência endócrina intrínseca. Portanto, ESR1m devem ser consideradas um mecanismo de resistência adquirida no contexto de câncer metastático. Pesquisas buscando identificar mecanismos de resistência endócrina intrínseca devem ser estimuladas uma vez que não existem biomarcadores com implicações na prática clínica nesta área.Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive (ER+) advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. However, published data described ESR1m as a mechanism of secondary endocrine resistance in patients with metastatic breast cancer. The role of ESR1m as a potential mechanism of primary endocrine resistance as well as whether it also occurs in tumors that are resistant to ET used early-stage disease as (neo)adjuvant has not been adequately studied. The preoperative endocrine prognostic index (PEPI) is a surrogate of endocrine sensitivity and can identify a subgroup of patients with primary resistance to ET. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer that were resistant to neoadjuvant aromatase inhibitor therapy. Methods: We followed a prospective cohort of postmenopausal patients with ER+ HER2- stages II-III breast cancer treated with neoadjuvant endocrine therapy (NET). Patients were treated with anastrozole for a recommended period of at least three months. Tumor samples from patients with a pattern of primary endocrine-resistant tumors (defined as a PEPI score of 4 or more) were selected and analyzed for the presence of ESR1m. ESR1m were evaluated in formalin-fixed paraffin-embedded breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Results: One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), and 30% (30/100) had a PEPI score of 4 or more and were selected. Twenty-three patients were included in the analysis. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET, Discussion: Growing evidence supports the notion that there are different mechanisms of primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET

Abordagem Multidisciplinar Em Hormonioterapia Neoadjuvante No Câncer De Mama: Uma Revisão

Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HRþ) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemo-therapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2þ) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HRþ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field.38261562

The somatic mutation profile of estrogen receptor-positive HER2-negative metastatic breast cancer in Brazilian patients

BackgroundBreast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly originated from developed nations. There are still limited data on the molecular epidemiology of MBC in low- and middle-income countries. This study aims to evaluate the prevalence of mutations in the PI3K-AKT pathway and other actionable drivers in estrogen receptor (ER)+/HER2- MBC among Brazilian patients treated at a large institution representative of the nation’s demographic diversity.MethodsWe conducted a retrospective observational study using laboratory data (OC Precision Medicine). Our study included tumor samples from patients with ER+/HER2- MBC who underwent routine tumor testing from 2020 to 2023 and originated from several Brazilian centers within the Oncoclinicas network. Two distinct next-generation sequencing (NGS) assays were used: GS Focus (23 genes, covering PIK3CA, AKT1, ESR1, ERBB2, BRCA1, BRCA2, PALB2, TP53, but not PTEN) or GS 180 (180 genes, including PTEN, tumor mutation burden [TMB] and microsatellite instability [MSI]).ResultsEvaluation of tumor samples from 328 patients was undertaken, mostly (75.6%) with GS Focus. Of these, 69% were primary tumors, while 31% were metastatic lesions. The prevalence of mutations in the PI3K-AKT pathway was 39.3% (95% confidence interval, 33% to 43%), distributed as 37.5% in PIK3CA and 1.8% in AKT1. Stratification by age revealed a higher incidence of mutations in this pathway among patients over 50 (44.5% vs 29.1%, p=0.01). Among the PIK3CA mutations, 78% were canonical (included in the alpelisib companion diagnostic non-NGS test), while the remaining 22% were characterized as non-canonical mutations (identifiable only by NGS test). ESR1 mutations were detected in 6.1%, exhibiting a higher frequency in metastatic samples (15.1% vs 1.3%, p=0.003). Additionally, mutations in BRCA1, BRCA2, or PALB2 were identified in 3.9% of cases, while mutations in ERBB2 were found in 2.1%. No PTEN mutations were detected, nor were TMB high or MSI cases.ConclusionWe describe the genomic landscape of Brazilian patients with ER+/HER2- MBC, in which the somatic mutation profile is comparable to what is described in the literature globally. These data are important for developing precision medicine strategies in this scenario, as well as for health systems management and research initiatives

Prevalência da mutação de gene ESR1 em pacientes com câncer de mama receptor hormonal positivo resistentes à terapia endócrina neoadjuvante

Introdução: Mutações no gene ESR1 (ESR1m) são importante mecanismo de resistência à terapia endócrina em câncer de mama receptor de estrogênio positivo (RE+) e vêm sido reconhecidas como biomarcadores prognósticos e preditivos, assim como um potencial alvo terapêutico. Entretanto, as pesquisas publicadas descrevem ESR1m como um potencial mecanismo de resistência adquirida no contexto de doença metastática. O papel de ESR1m como potencial mecanismo de resistência intrínseca no contexto de doença inicial não foi estudada. O escore PEPI é um índice que avalia o perfil de sensibilidade ou resistência à terapia endócrina neoadjuvante. O objetivo deste estudo foi avaliar a prevalência de ESR1m em amostras tumorais de pacientes com câncer de mama RE+ com perfil de resistência à terapia endócrina neoadjuvante com inibidores de aromatase. Resultados: Uma coorte prospectiva de mulheres na pós-menopausa com câncer de mama RE+ HER2-negativo estádio II-III tratadas com hormonioterapia neoadjuvante foi conduzida. Pacientes receberam tratamento com anastrozol por um período mínimo de três meses. Amostras tumorais de pacientes com um perfil de resistência endócrina primária (definida como escore PEPI maior ou igual a 4) foram selecionados e analisados quanto à presença de mutações no gene ESR1. ESR1m foram avaliadas em amostras de tecido tumoral incluídas em blocos de parafina utilizando a técnica de reação PCR quantitativo. As mutações em hotspots nos códons 380, 537 e 538 do gene ESR1 foram analisadas. Resultados: Cento e vinte e sete pacientes foram incluídas na coorte, das quais 100 (79%) completaram a neoadjuvância, foram operadas e tiveram o escore PEPI calculado. Dentre estas pacientes, o escore PEPI variou entre 0 e 3 em 70% (70/100) e foi igual ou maior a 4 em 30% (30/100). Vinte e três pacientes foram incluídas na análise. ESR1m não foram identificadas em nenhuma das amostras dos 23 pacientes com câncer de mama em estádio inicial resistentes a hormonioterapia neoadjuvante. Conclusão: As evidências atuais suportam a noção que existem diferentes mecanismos de resistência intrínseca ou adquirida à terapia endócrina em câncer de mama. Nosso estudo sugere que mutações no gene ESR1m não se desenvolvem em um período curto de tempo e não representam um mecanismo comum de resistência endócrina intrínseca. Portanto, ESR1m devem ser consideradas um mecanismo de resistência adquirida no contexto de câncer metastático. Pesquisas buscando identificar mecanismos de resistência endócrina intrínseca devem ser estimuladas uma vez que não existem biomarcadores com implicações na prática clínica nesta área.Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive (ER+) advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. However, published data described ESR1m as a mechanism of secondary endocrine resistance in patients with metastatic breast cancer. The role of ESR1m as a potential mechanism of primary endocrine resistance as well as whether it also occurs in tumors that are resistant to ET used early-stage disease as (neo)adjuvant has not been adequately studied. The preoperative endocrine prognostic index (PEPI) is a surrogate of endocrine sensitivity and can identify a subgroup of patients with primary resistance to ET. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer that were resistant to neoadjuvant aromatase inhibitor therapy. Methods: We followed a prospective cohort of postmenopausal patients with ER+ HER2- stages II-III breast cancer treated with neoadjuvant endocrine therapy (NET). Patients were treated with anastrozole for a recommended period of at least three months. Tumor samples from patients with a pattern of primary endocrine-resistant tumors (defined as a PEPI score of 4 or more) were selected and analyzed for the presence of ESR1m. ESR1m were evaluated in formalin-fixed paraffin-embedded breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Results: One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), and 30% (30/100) had a PEPI score of 4 or more and were selected. Twenty-three patients were included in the analysis. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET, Discussion: Growing evidence supports the notion that there are different mechanisms of primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET

Overall survival and progression-free survival with endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: review

We reviewed randomized phase II/III trials comparing first- or second-line endocrine therapy as monotherapy or in combination with targeted therapies for treatment of postmenopausal patients with hormone receptor-positive advanced breast cancer. First-line was defined as treatment for endocrine therapy-naïve advanced breast cancer or advanced disease treated with endocrine therapy in the adjuvant/neoadjuvant setting. Second-line was defined as endocrine therapy for advanced breast cancer following disease progression on endocrine therapy for advanced disease. Publications reporting progression-free survival (PFS)/time to progression (TTP) or overall survival (OS) for FDA-approved agents anastrozole, exemestane, fulvestrant 250 mg, fulvestrant 500 mg, letrozole (0.5 and 2.5 mg), megestrol acetate, and tamoxifen as monotherapy, or in combination with everolimus, palbociclib or ribociclib, were assessed. First-line monotherapy with anastrozole, fulvestrant 500 mg or letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; however, only fulvestrant 500 mg improved OS. For endocrine therapy in combination with targeted therapies, palbociclib plus letrozole 2.5 mg, and ribociclib plus letrozole 2.5 mg significantly improved PFS versus letrozole 2.5 mg alone first-line. For second-line monotherapies, exemestane, fulvestrant 500 mg and letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; only fulvestrant 500 mg and letrozole 2.5 mg improved OS. For second-line combination therapies, everolimus plus exemestane, and palbociclib plus fulvestrant 500 mg, improved PFS versus endocrine therapy alone. In both first- and second-line settings, aromatase inhibitors demonstrated PFS benefits versus comparator endocrine therapy; however, fulvestrant 500 mg was the only endocrine therapy included in our review to show both PFS and OS advantages compared with other endocrine therapies. Targeted agents in combination with endocrine therapy have demonstrated PFS improvements both first- and second-line; OS data are awaited

Bleomycin-Induced Lung Injury

Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and Hodgkin’s lymphoma. The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. The mechanism of bleomycin-induced pneumonitis (BIP) involves oxidative damage, relative deficiency of the deactivating enzyme bleomycin hydrolase, genetic susceptibility, and the elaboration of inflammatory cytokines. Ultimately, BIP can progress to lung fibrosis. The diagnosis of BIP is established by the combination of systemic symptoms, radiological and histological findings, and respiratory function tests abnormalities, while other disorders should be excluded. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there is no effective therapy for the disease. In general, the clinical picture is extremely complex. A greater understanding of the BIP pathogenesis may lead to the development of new agents capable of preventing or even treating the injury already present. Physicians who prescribe bleomycin must be aware of the potential pulmonary toxicity, especially in the presence of risk factors. This review will focus on BIP, mainly regarding recent advances and perspectives in diagnosis and treatment