Effects of rosmarinic acid and doxorubicine on an ovarian adenocarsinoma cell line (OVCAR3) via the EGFR pathway

Purpose: We aimed to reveal the effects of rosmarinic acid (RA), which has come to the forefront with its antitumor and antioxidant properties in many studies recently in the ovarian adenocarcinoma cell line, on the epidermal growth factor receptor (EFGR) signaling pathway in the presence of doxorubicin (DOX). Methods: Ovarian adenocarcinoma cell line (OVCAR3) and human skin keratinocyte cell line human skin keratinocyte cell line (HaCaT) were used as control. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was applied to determine the effect of RA and DOX on the proliferation of OVCAR3 and HaCaT cells. Bcl2 expression and epidermal growth factor receptor (EGFR) and western blot analysis were performed to determine the expression levels of the markers. Results: It was determined that RA (IC50 = 437.6 µM) and DOX (IC50 = 0.08 µM) have the ability to inhibit the proliferation of OVCAR3 cells and induce apoptosis in a 72-hour time and dose-dependent manner. Western blot showed that the expression level of Bcl-2 and EGFR in OVCAR3 cells was down-regulated by RA and DOX. Conclusions: Apoptosis in OVCAR3 cells can potentially be induced by RA via the EGFR pathway, and RA may be a potent agent for cancer therapy.

Cytoplasmic-membrane egfr predicts expanded ras mutation status in colorectal carcinomas? / Egfr membrano-citoplasmático prediz mutação ras expandida no carcinoma colorretal?

ABSTRACT Background: Inhibitors of the epidermal growth factor (EGFR) represent an effective therapeutic option for patients with metastatic colorectal carcinoma, free of activating mutations in KRAS and NRAS. However, the research of mutations is of high cost and scarcely accessible. The expression of the EGFR by immunohistochemistry predicting the mutation status of the expanded RAS (KRAS and NRAS), may allow treatment by a diagnostic method less costly and more accessible. Aim: Investigate the correlation between the clinical-pathological data, the cytoplasmic-membrane expression of the EGFR and the mutational status of the expanded RAS. Method: A total of 139 patients with colorectal carcinoma from the archives of Instituto Goiano de Oncologia e Hematologia were evaluated. Results: Mutation of the expanded RAS was detected in 78 (56.1%) cases. The EGFR expression was stratified in 23 (16.5%) "positive", 49 (35.2%) "negative" and 67 (48.2%) "uncertain". No significant correlation was found between the mutational status of the RAS and the EGFR expression in comparison to age, gender, location, histological type, histological grade and stage. From 23 "positive" cases, 21 (91.3%) showed wild-type RAS gene, and 49 "negative", 41 (83.7%) presented mutation, resulting in a strong association between EGFR "positive", "negative" groups and the mutational status of the RAS (p<0.001), with 86.1% of accuracy. Conclusions: The cytoplasmic-membrane analysis of the EGFR expression stratified into "positive", "negative" and "uncertain" predicts mutational status of the RAS in 51.7% of the cases (p<0.001), with 86.1% of accuracy.

RESUMO Racional: Inibidores do fator de crescimento epidermal (EGFR) representam opção de terapia efetiva para o câncer colorrectal metastático, na ausência de ativação de mutações KRAS e NRAS. Entretanto, a pesquisa de mutações é cara e pouco acessível. A expressão de EGFR por imuno-histoquímica predizendo o status mutacional do RAS expandido (KRAS e NRAS) poderia permitir o tratamento por método diagnóstico menos caro e mais acessível. Objetivo: Investigar a correlação entre os dados clinicopatológicos, a expressão de EGFR na membrana citoplasmática e o status mutacional do RAS expandido. Método: Estudo retrospectivo de acurácia envolvendo 139 pacientes com carcinoma colorretal. Resultado: A mutação do RAS expandido foi detectada em 78 (56,1%) casos. A expressão de EGFR foi estratificada em 23 (16,5%) casos "positivos", 49 (35,2%) casos "negativos" e 67 (48,2%) "duvidosos". Não houve correlação significante entre o status mutacional do RAS e a expressão de EGFR em relação a idade, gênero, local do tumor, tipo histológico, grau histológico e estádio clínico. Em 23 casos "positivos", 21 (91,3%) mostraram gene RAS tipo selvagem, e em 49 "negativos", 41 (83,7%) apresentaram mutação, resultando em forte associação entre grupos EGFR "positivo" ou "negativo" e o status mutacional do RAS (p<0.001), com 86,1% de acurácia. Conclusão: A análise da expressão de EGFR na membrana citoplasmática estratificada em "positivo", "negativo" e "duvidoso" prediz o status mutacional do RAS em 51,7% dos casos (p<0.001), com 86,1% de acurácia.

Study of EGFR mutations in head and neck squamous cell carcinomas

Introduction Squamous carcinoma is the commonest malignancy of the head and neck region. It is associated with high morbidity and mortality. Epidermal growth factor receptor (EGFR) regulates downstream signaling pathways through its tyrosine kinase (TK) domains that play a role in cell proliferation and survival. EGFR mutations have been found to occur between exons 18 to 21 on chromosome 7. Limited studies are available on EGFR-TK mutations in the head and neck squamous cell carcinoma (HNSCC) globally. This study explores EGFR mutations in 30 HNSCC cases presenting to a tertiary care hospital over a period of two years. Material and Methods Fresh tumor tissue was collected from the resection specimens of cases of primary HNSCC. Cases with pre-operative therapy were not included. Parameters in the form of patients' age, gender, smoking/tobacco intake, site of the lesion were recorded. Tumor parameters after histopathological examination were recorded in the form of TNM stage, tumor grade. DNA was extracted from fresh tissue of all the cases. EGFR Mutation Analysis Kit assay was used to detect mutations of the EGFR gene. PCR was run and results were analyzed. Results EGFR Mutations were found in 6.7%of the patients. There was no significant association of the EGFR Mutation with the studied parameters. Conclusion EGFR mutations are present in a subset of patients of HNSCC. Patients having these mutations may benefit from targeted therapy with tyrosine kinase inhibitors.

Epidermal growth factor receptor regulates fibrinolytic pathway elements in cervical cancer: functional and prognostic implications

Epidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in tumor progression. In the present study, we employed cBioPortal platform (http://www.cbioportal.org/), cancer cell lines, and an in vivo model of immunocompromised mice to evaluate a possible cooperation between EGFR signaling, uPA, and TM expression/function in the context of cervical cancer. cBioPortal analysis revealed that EGFR, uPA, and TM are positively correlated in tumor samples of cervical cancer patients, showing a negative prognostic impact. Aggressive human cervical cancer cells (CASKI) presented higher gene expression levels of EGFR, uPA, and TM compared to its less aggressive counterpart (C-33A cells). EGFR induces uPA expression in CASKI cells through both PI3K-Akt and MEK1/2-ERK1/2 downstream effectors, whereas TM expression induced by EGFR was dependent on PI3K/Akt signaling alone. uPA induced cell-morphology modifications and cell migration in an EGFR-dependent and -independent manner, respectively. Finally, treatment with cetuximab reduced in vivo CASKI xenografted-tumor growth in nude mice, and decreased intratumoral uPA expression, while TM expression was unaltered. In conclusion, we showed that EGFR signaling regulated expression of the fibrinolytic system component uPA in both in vitro and in vivo settings, while uPA also participated in cell-morphology modifications and migration in a human cervical cancer model.

Association of tumor mutation burden and epidermal growth factor receptor inhibitor history with survival in patients with metastatic stage III/IV non-small-cell lung cancer: A retrospective study

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.

Tratamientos de primera línea para pacientes estadio IV con adenocarcinoma pulmonar de mutación EGFR / First-line treatments for stage IV patients with EGFR-mutated lung adenocarcinoma

Lung cancer is one of the leading causes of death in the world. Current treatments act directly on the signal transduction pathways in cancer cells, mainly. One of the main pathways is associated with the Epidermal Growth Factor (EGFR), whose mutations leads to uncontrolled cell proliferation and a higher rate of cell invasion. Activating mutations in the EGFR gene, which includes deletions in exon 19 and the L858R mutation in exon 21, were detected in most patients with non-small cell lung cancer (NSCLC). Studies of EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as Gefitinib, Erlotinib and Afatinib, compared with platinum-based treatments, showed that EGFR-TKIs produce increased disease-free survival, although only in patients whose cancers harbor activating mutations in the EGFR gene. Clinical trials also demonstrated that EGFR-TKIs are effective as first-line therapies in stage IV pulmonary adenocarcinoma. Here, the main aspects of the activation of the EGFR pathway in NSCLC will be reviewed, highlighting the importance for health professionals of correctly identifying activating mutations in the EGFR gene and acting quickly at the molecular level based on aforementioned treatments. (AU)

Comparação entre expressão de receptores hormonais e de HER-2 entre células tumorais circulantes e metástases de câncer de mama / Comparison of hormonal receptor expression and HER2 status in circulating tumor cells and breast cancer metastases

Introdução: O câncer de mama é a neoplasia mais comum em mulheres. A maioria deles é diagnosticada em estágios iniciais, quando o tratamento visa a cura. Mas apesar dos avanços no tratamento, metástases à distância podem ocorrer. A biópsia das lesões metastáticas é recomendada para confirmar o status do receptor de estrogênio (RE), receptor de progesterona (RP) e receptor do fator de crescimento epidérmico humano 2 (HER2), por ocorrerem discrepâncias nesses padrões entre tumores primários e metástases em até 40% dos casos. As células tumorais circulantes (CTCs) estão relacionadas às evoluções clínicas do câncer de mama e podem potencialmente desempenhar um papel substituto aos procedimentos invasivos de rebiópsia de metástase. A tecnologia ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, França) não é usualmente empregada para detectar CTCs em pacientes com câncer de mama, embora seja reconhecida como uma ferramenta útil em alguns outros tumores. Existem dados emergentes de que a caracterização da expressão proteica das CTC pode refinar seu valor prognóstico. Sabe-se que o fator de transformação de crescimento (TGF-ß) desempenha um papel na progressão e invasividade do câncer de mama. Objetivos: Comparar a expressão de RE, RP e HER2 em tumores primários, CTCs, metástases e avaliar a expressão do receptor TGF-ß tipo 1 (TGF-ß RI) em CTCs como fator prognóstico para sobrevida global. Metodologia: Estudo realizado no A.C.Camargo Cancer Center, Brasil. As amostras de sangue foram coletadas antes da biópsia guiada por tomografia computadorizada de lesões metastáticas suspeitas e processadas pela metodologia ISET®. Os níveis de expressão proteica das CTCs foram comparados aos de tumores primários e metástases e correlacionados aos resultados clínicos. Todos os dados clínicopatológicos foram obtidos dos prontuários médicos. Resultados: Dos 39 pacientes inicialmente incluídos, 27 tiveram tanto a biópsia de metástases quanto a coleta de sangue e foram considerados para análise. As taxas de concordância para a expressão de RE, RP e HER2 entre tumores primários e metástases foram altas. Não foi observada nenhuma perda de expressão de HER2 nas metástases e os tumores triplo negativos mantiveram o mesmo padrão em todas as metástases (p <0,0001). Quando as metástases e CTCs foram classificadas como triplo negativo (TN) ou não ­ TN, as CTCs determinaram alta especificidade (93%), acurácia (84,2%) e valor preditivo negativo (88%). A sobrevida global mediana de pacientes sem expressão de TGF-ß RI em CTCs foi de 42,6 x 20,8 meses para os positivos, clinicamente relevante, porém sem significância estatística (p> 0,05). Conclusões: No câncer de mama, o papel das CTCs detectadas pelo ISET® ainda não está estabelecido. Com este estudo, sugerimos que esta metodologia possa ser útil para avaliar metástases em casos de tumores não TN, assim como a expressão de TGF-ß RI em CTCs, o que pode impactar a sobrevida. Devido à limitação da amostra, estudos futuros devem se concentrar em subtipos específicos de câncer de mama, ampliando a coorte.

Introduction: Breast cancer (BC) is the most common neoplasm in women. Most of BC are diagnosed in early stages, when treatment aims cure. Despite advances in BC treatment, distant metastases may develop. Biopsy of metastatic lesions is recommended to confirm estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, due to discrepancies in these patterns between primary tumors/metastasis in up to 40% of cases. Circulating Tumor Cells (CTCs) are related to breast cancer outcomes and could potentially play a role surrogating invasive procedures of metastasis rebiopsy. ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, France) technology is not currently employed to detect CTCs in breast cancer patients, although recognized as a useful tool in some other tumors. There are emerging data that characterization of CTC protein expression can refine its prognostic value. Transforming growth factor (TGF)-ß play a role in progression/invasiveness of BC. Objectives: To compare ER, PR and HER2 expression in primary tumors, CTCs, metastases and to evaluate TGF-ß type 1 receptor (TGF- ß RI) expression in CTCs as prognostic factor for overall survival. Methods: Study conducted at the A.C.Camargo Cancer Center, Brazil. Blood samples were processed in ISET® before computed tomography­guided biopsy of suspected metastatic lesions. Protein expression levels in CTCs were compared to those in primary tumors/metastases and correlated to clinical outcomes. All clinicopathological data were obtained from medical records. Results: From the 39 patients initially included, 27 had both biopsy of metastases and blood collection and were considered for analysis. Concordance rates for ER, PR and HER2 expression between primary tumors/metastases were high. No loss of HER2 expression at any metastasis site and retention of the same pattern in all triplenegative (TN) tumors (p <0.0001) were observed. When metastases/CTCs were classified as TN/non­TN, CTCs showed high specificity (93%), accuracy (84.2%) and negative predictive value (88%). The median overall survival of patients with no TGF-ß RI expression in CTCs was 42.6 x 20.8 months for positive ones, clinically relevant but not statistically significant (p>0.05). Conclusions: In BC, the role of CTCs detected by ISET® is not yet established. Here, we could suggest that this methodology may be useful to evaluate metastasis in non-TN cases as also TGF-ß RI expression in CTCs, which may impact survival. Due to sample limitation, future studies must focus on specific subtypes of BC, expanding the cohort.

Prevalência do rearranjo do gene ROS1 em carcinoma de pulmão de células não pequenas não escamoso, EGFR e ALK negativo: análise de uma coorte brasileira / Prevalence of ROS1 gene rearrangements in EGFR-Negative and ALK-negative nonsquamous NSCLC: analysis of a Brazilian cohort

Introdução: A prevalência do câncer de pulmão tem aumentado cerca de 2% ao ano e é considerado um problema de saúde pública mundial, sendo a principal causa de morte por câncer entre homens e mulheres. O Câncer de Pulmão de Células Não Pequenas (CPCNP) representa 85-90% dos cânceres de pulmão. A detecção do rearranjo do gene ROS1, considerada um importante fator preditivo para direcionamento terapêutico, constitui uma etapa crítica no tratamento de CPCNP. Objetivo: Avaliar a prevalência do rearranjo do gene ROS1 em pacientes portadores de CPCNP não escamoso, sem mutação de EGFR ou rearranjo de ALK, diagnosticados na Região da Foz do Rio Itajaí, Estado de Santa Catarina, Brasil, no período de 02/01/2019 a 27/07/2020. Materiais e Métodos: Estudo observacional, retrospectivo e prospectivo, descrito e analítico com 95 pacientes que possuíam material de biópsia suficiente para a realização de novas análises e que não apresentavam mutação de EGFR ou rearranjo de ALK. Os pacientes com imuno-histoquímica positiva para a proteína ROS1 foram testados pelo método de FISH, utilizando-se uma sonda de DNA do tipo break-apart para o gene ROS1. Foi realizada uma análise descritiva da amostra, e os resultados foram apresentados em números absolutos e porcentagens, representados por tabelas. O teste de qui-quadrado (χ2) foi empregado para comparação das frequências entre os grupos analisados. Resultados: 52,6% foram pacientes do sexo masculino; a idade mediana foi de 64 anos; 54,7% declararam-se tabagistas; 40,0% apresentavam doença estágio IV; 29,5% apresentaram tumores com alta expressão de PD-L1. Quanto a expressão de ROS1 por imuno-histoquímica: 89,5% foram identificados como ROS1+ em 0% das células tumorais, 4,2% como ROS1+ em <70% das células, e 6,3% como ROS1+ em ≥70% das células do tumor; portanto, 10,5% apresentaram resultados positivos para expressão de ROS1. Estes pacientes foram submetidos à análise de rearranjo de ROS1 pelo método de FISH e 7 (7,4%) apresentaram resultados positivos. Conclusão: Na população estudada, a análise pelo método de FISH mostrou uma prevalência de 7,4% para rearranjos do gene ROS1

Introduction: Lung cancer prevalence has been increasing at rate of 2% per year and is considered a major public health concern worldwide, being the main cause of cancer death among women and men. Non-small cell lung cancer (NSCLC) represents 85-90% of total lung cancer. Detecting the rearrangement of the ROS1 gene is critical to the treatment of NSCLC. Objective: To assess the prevalence of the ROS1 gene rearrangement in patients diagnosed with non-squamous NSCLC patients diagnosed between January 2019 to July 2020 at Foz do Rio Itajaí, in the state of Santa Catarina, Brazil. Materials and Methods: This is a retrospective and prospective observational study Ninety-five NSCLC whose tumors were negative for EGFR mutation and ALK rearrangement and who had enough tumor tissue to carry out additional molecular analysis. Patients whose tumors were positive for ROS1 by immune-histochemistry were tested using by FISH using a break-apart DNA probe (Abbot Molecular) for the ROS1 gene. A descriptive analysis was performed and results were presented as absolute frequencies and percentages and depicted in charts. Frequencies were compared with the chi-squared test (χ2). Results: 52,6% were male, mean and median age were 65,10 and 64 years, respectively. 54,7% self-declared as smokers; 40,0% had stage IV disease; 29,5% had tumours with high expression of PD-L1. Regarding the expression of ROS1 by immunohistochemistry: 89,5% were identified as ROS1+ in 0% of cells, 4,2% as ROS1+ in <70% of cells, and 6,3% as ROS1+ in ≥70% of the cells; therefore, 10,5% displayed positive results for the expression of ROS1+. These tumors were subjected to the analysis of ROS1 rearrangement by FISH and 7 (7,4%) were positive. Conclusion: We observed 7,4% prevalence for ROS1 gene rearrangements in this pre-selected population

Custo-efetividade do erlotinibe comparado ao gefitinibe para CPNPC com mutações EGFR no Inca / Cost-effectiveness of erlotinib compared to gefitinib for NSCLC with EGFR mutations at the Inca

Objetivo: O câncer de pulmão (CP), segundo dados da Organização Mundial de Saúde, é a neoplasia mais frequente e mais letal em homens e a segunda nas mulheres em todo o mundo. O CP compreende vários tipos histológicos, incluindo câncer de pulmão de pequenas células e os diferentes tipos de câncer de pulmão de não pequenas células (CPNPC). Esse subtipo representa cerca de 80% dos casos e compreende principalmente o adenocarcinoma. A terapia de escolha para tratamento de CPNPC com mutação no receptor do fator de crescimento epidérmico (EGFR) são os inibidores de tirosina quinase (ITKs), como erlotinibe e gefitinibe. Neste artigo avaliamos o custo-efetividade do erlotinibe comparado ao gefitinibe no tratamento de CPNPC. Métodos: Foi realizada uma análise de custo-efetividade sob a perspectiva de um hospital federal do Sistema Único de Saúde (SUS). Em um modelo de árvore de decisão, foram aplicados os desfechos de efetividade e segurança dos ITKs. Os dados clínicos foram extraídos de prontuários e os custos diretos, consultados em fontes oficiais do Ministério da Saúde. Resultados: O custo de 10 meses de tratamento, englobando o valor dos ITKs, procedimentos e manejo de eventos adversos, foi de R$ 63.266,76 para o erlotinibe e de R$ 39.594,72 para o gefitinibe. Os medicamentos apresentaram efetividade estatisticamente equivalente e diferença estatisticamente significativa para o desfecho de segurança, no qual o gefitinibe obteve melhor resultado. Conclusão: O gefitinibe, nesse contexto, é a tecnologia dominante quando os custos de tratamento são associados aos de manejo de eventos adversos.

Objective: According to the World Health Organization (WHO), lung cancer (LC) is the most common and lethal neoplasm in men and the second most common in women worldwide. The LC comprises several histological types, including small cell lung cancer and the different types of non-small cell lung cancer (NSCLC). This subtype represents about 80% of the cases and mainly comprises adenocarcinoma. The therapy of choice for epidermal growth factor receptor (EGFR) mutant NSCLC are tyrosine kinase inhibitors (TKI), like erlotinib and gefitinib. In this article, we evaluate the cost-effectiveness of erlotinib in comparison to gefitinib. Methods: A cost-effectiveness analysis was performed from the perspective of a Sistema Único de Saúde (SUS) federal hospital. In a decision tree model, the effectiveness and safety outcomes of TKIs were applied. The clinical data were extracted from the medical records and the direct costs consulted in official sources of the Ministry of Health. Results: The cost of 10 months of processing, encompassing the TKI value, procedures and resources of adverse events was R$ 63.266,76 for the year and R$ 39.594,72 for gefitinib. Forging cards have equal and statistically significant effectiveness for the safety outcome. Conclusion: Gefitinib, in this context, is a dominant technology when process costs are associated with those of managing adverse event.

Distinct models to assess the cost-effectiveness of EGFR-tyrosine kinase inhibitors for the treatment of metastatic non-small cell lung cancer in the context of the Brazilian Unified Health Care System / Diferentes modelos para avaliar a relação custo-efetividade de inibidores de tirosina quinase do EGFR no tratamento do câncer de pulmão não pequenas células metastático no contexto do Sistema Único de Saúde

ABSTRACT Objective: Lung cancer is an important health problem due to its high incidence and mortality. The treatment of metastatic disease improved after the molecular pathways of cancer came to be known. However, targeted therapy is unavailable to many patients treated within the Brazilian Sistema Único de Saúde (SUS, Unified Health Care System). Our objective was to assess the cost-effectiveness of erlotinib, gefitinib, and afatinib versus that of chemotherapy for the treatment of non-small cell lung cancer in the context of the SUS. Methods: Different analytical models were developed based on data in the literature. The outcomes were presented in quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) per QALY gained. All costs related to treatment and supportive therapies were included in the models. Results: In one model, data from retrospective studies showed 2.01 life-years saved and a mean QALY gain of 1.169. The ICER per QALY gained ranged from R$48,451.29 (for gefitinib) to R$85,559.22 (for erlotinib). In another model, data from a meta-analysis showed −0.01 life-years saved and a mean QALY gain of 0.178. The ICER per QALY gained ranged from R$27,028.30 (for gefitinib) to R$75,203.26 (for erlotinib). Conclusions: There is no ideal analytical model for the SUS. However, targeted therapy with EGFR-tyrosine kinase inhibitors has been shown to be cost-effective in various scenarios. The adoption of drug price discounts will improve the cost-effectiveness of treatment.

RESUMO Objetivo: O câncer de pulmão é um importante problema de saúde pela sua alta incidência e mortalidade. O tratamento da doença metastática melhorou após o conhecimento de vias moleculares tumorais. Contudo, a terapia-alvo está indisponível para muitos pacientes do Sistema Único de Saúde (SUS). Nosso objetivo foi avaliar a relação custo-efetividade de erlotinibe, gefitinibe e afatinibe vs. quimioterapia no tratamento do câncer de pulmão não pequenas células no contexto do SUS. Métodos: Foram desenvolvidos modelos analíticos distintos baseados em dados da literatura. Os desfechos foram apresentados em quality-adjusted life years (QALY, anos de vida ajustados pela qualidade) e incremental cost-effectiveness ratio (ICER, relação custo-efetividade incremental). Todos os custos relacionados ao tratamento e terapias de suporte foram incluídos nos modelos. Resultados: No primeiro modelo, dados de estudos retrospectivos apontaram 2,01 anos de vida salvos e uma média de ganho de QALY de 1,169. O ICER variou entre R$ 48.451,29 (gefitinibe) e R$ 85.559,22 (erlotinibe). No segundo modelo, dados de uma meta-análise evidenciaram −0,01 ano de vida salvos e uma média de ganho de QALY de 0,178. O ICER foi de R$ 27.028,30 (gefitinibe) a R$ 75.203,26 (erlotinibe). Conclusões: Não existe um modelo analítico ideal para o SUS. Contudo, diferentes cenários disponíveis na literatura mostram que a terapia-alvo com o uso dessas drogas é custo-efetiva. A adoção de descontos nos preços dos medicamentos melhorará a relação custo-efetividade do tratamento.

Concomitant using of topical carrageenan-kappa and oral vitamin D against 7, 12-dimethylbenz[a]anthracene induced-oral cancer in rats: A synergism or an antagonism effects / Uso concomitante de carragenina tópica e vitamina D oral contra câncer de boca em ratos induzido por 7, 12-dimetilbenz(a) antraceno: efeitos sinérgicos ou antagonistas

Objective: κ-carrageenan is a food stabilizer agent which has an antiproliferative effect, while vitamin D is a prohormone acts on the nuclear receptor and has a cytotoxic against cancer. This study aimed to show the synergistic effect of using topical κ-carrageenan and oral administration of the vitamin D on the 7, 12-dimethylbenz[a] anthracene (DMBA)-induced oral cancer. Material and Methods: fifty four male albino rats were randomly divided into seven groups: Acetonetreated served as control (Group I), vitamin D (5000UI)-treated (Group II), κ-carrageenan (1%)- treated (Group III), DMBA (0.5%)-treated (Group IV), Acetone, κ-carrageenan and DMBA were administered topically on both cheeks and palate, five times weekly for 12 weeks, while the vitamin D was administered orally twice weekly for 12 weeks. Groups V, VI, and VII were animals treated with vitamin D, κ-carrageenan, and both vitamin D and κ-carrageenan for 8 weeks after induction of oral cancer. At the end of the study, blood samples were obtained by cardiac puncture for determination of TNF-α and EGFR. Results: In the groups III and IV, serum EGFR showed significant low levels compared with Group I. In the Group VII, serum EGFR showed a significantly (p=0.014) low level compared with Group IV (614.3±69.7 pg/ml versus 882.4±45.6 pg/ml, respectively). Higher percentages of high levels of TNF-α were observed in the Groups VI and VII, while a lower percentage of EGFR was observed in the Group VI. Conclusion: both κ-carrageenan and vitamin D have antiproliferative effect against DMBAinducing oral cancer by increasing the levels of TNF-α and suppressing the signaling pathway of EGFR. Concomitant using κ-carrageenan and vitamin D reduces the antiproliferative effect of each other.(AU)

Objetivo: κ-carragenina é um agente estabilizador de alimentos que tem efeito um antiproliferativo, enquanto a vitamina D é um pró-hormônio que atua sobre o receptor nuclear e possui efeito citotóxico contra o câncer. Este estudo teve como objetivo mostrar o efeito sinérgico do uso de κ-carragenina tópica e administração oral da vitamina D no câncer de boca induzido por 7, 12-dimetilbenz[a]antraceno (DMBA). Material e Métodos: cinquenta e quatro ratos albinos machos foram divididos aleatoriamente em sete grupos: tratado com acetona como controle (Grupo I), tratado com vitamina D (5000UI) (grupo II), tratado com κ-carragenina (1%) (grupo III), DMBA (0,5%) tratado (Grupo IV), acetona, κ-carragenina e DMBA foram administrados topicamente nas bochechas e no palato, cinco vezes por semana durante 12 semanas, enquanto a vitamina D foi administrada por via oral duas vezes por semana durante 12 semanas. Os grupos V, VI e VII foram animais tratados com vitamina D, κ-carragenina e No final do estudo, foram obtidas amostras de sangue por punção cardíaca para determinação do TNF-α e EGFR. Resultados: Nos grupos III e IV, o EGFR sérico mostrou níveis baixos significativos em comparação com o Grupo I. No grupo VII, o EGFR sérico mostrou um nível significativamente baixo (p = 0,014) em comparação com o Grupo IV (614,3 ± 69,7 pg / ml versus 882,4 ± 45,6 pg / ml, respectivamente). Maiores porcentagens de TNF-α foram observadas nos Grupos VI e VII, enquanto uma menor porcentagem de EGFR foi observada no Grupo VI. Conclusão: Tanto a κ-carragenina quanto a vitamina D têm efeito antiproliferativo contra o câncer de boca induzido por DMBA aumentando os níveis de TNF-α e suprimindo a via de sinalização do EGFR. O uso concomitante de κ-carragenina e a vitamina D reduz o efeito antiproliferativo um do outro (AU)

Potential life years not saved due to lack of access to anti-EGFR tyrosine kinase inhibitors for lung cancer treatment in the Brazilian public healthcare system: Budget impact and strategies to improve access. A pharmacoeconomic study

ABSTRACT BACKGROUND: Lung cancer is the fourth most common cancer in Brazil. In the 2000s, better understanding of molecular pathways led to development of epidermal growth factor receptor (EGFR)-targeted treatments that have improved outcomes. However, these treatments are unavailable in most Brazilian public healthcare services (Sistema Único de Saúde, SUS). OBJECTIVE: To assess the potential number of years of life not saved, the budget impact of the treatment and strategies to improve access. DESIGN AND SETTING: Pharmacoeconomic study assessing the potential societal and economic impact of adopting EGFR-targeted therapy within SUS. METHODS: We estimated the number of cases eligible for treatment, using epidemiological data from the National Cancer Institute. We used data from a single meta-analysis and from the Lung Cancer Mutation Consortium (LCMC) study as the basis for assessing differences in patients' survival between use of targeted therapy and use of chemotherapy. The costs of targeted treatment were based on the national reference and were compared with the amount reimbursed for chemotherapy through SUS. RESULTS: There was no life-year gain with EGFR-targeted therapy in the single meta-analysis (hazard ratio, HR, 1.01). The LCMC showed that 1,556 potential life-years were not saved annually. We estimated that the annual budget impact was 125 million Brazilian reais (BRL) with erlotinib, 48 million BRL with gefitinib and 52 million BRL with afatinib. Their incremental costs over chemotherapy per life-year saved were 80,329 BRL, 31,011 BRL and 33,225 BRL, respectively. A drug acquisition discount may decrease the budget impact by 30% (with a 20% discount). A fixed cost of 1,000 BRL may decrease the budget impact by 95%. CONCLUSION: Reducing drug acquisition costs may improve access to EGFR-targeted therapy for lung cancer.

A prospective study assessing feasibility of performing percutaneous nephrolithotomy in chronic kidney disease patients - What factors affect the outcome?

ABSTRACT Objectives To primarily evaluate the functional outcomes of PCNL for bilateral renal calculi/calculi in solitary functioning kidney with Chronic Kidney Disease(CKD). To identify factors affecting the renal replacement therapy following PCNL. Materials and Methods Patients with bilateral renal calculi/calculi in solitary kidney and CKD (eGFR<60/s.creatinine>2) and Good Performance Status [Eastern Cooperative Oncology Group (ECOG): 0-2] were included in the study. Results A total of 60 patients with CKD who had bilateral renal calculi/calculi in solitary functioning kidney underwent PCNL. At 6 months, eGFR improved or stabilized in 45 (75%) patients, while in 15 (25%) patients eGFR deteriorated. A total of 5 (14.28%) and 2 (25%) patients of CKD stage 4 and 5 respectively had improvement in eGFR as well as CKD stage. Fourteen (82.35%), 21 (60%), 3 (37.5%) patients of CKD stage 3, 4, 5 had improvement in eGFR but not significant enough to cause stage migration. Again 3 (17.65%) , 9 ( 40%) and 3 (37.5%) patients of CKD stage 3, 4, 5 had reduction in eGFR but not significant enough to cause stage migration. None of the patients had worsening of CKD stage. Preoperative CKD stage and eGFR were compared with measurements made at the final follow up visit (6 months). Conclusion Our results indicate that most patients of renal calculi with CKD show improvement or stabilization of renal function with aggressive stone removal. Improvement is more in patients who have mild to moderate CKD. Aggressive management of comorbidities, peri-operative UTI and complications may delay or avoid progression of CKD status in such patients.

Astemizole, an inhibitor of ether-à-go-go-1 potassium channel, increases the activity of the tyrosine kinase inhibitor gefitinib in breast cancer cells

Abstract Background Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression. Objective We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells. Materials and Methods The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using dose-response curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cytometry. Results Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle. Conclusions Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.

Immunoexpression of TS, p53, COX2, EGFR, MSH6 and MLH1 biomarkers and its correlation with degree of differentiation, tumor staging and prognostic factors in colorectal adenocarcinoma: a retrospective longitudinal study

ABSTRACT BACKGROUND: There are cases of colorectal tumors that, although small, show more aggressive evolution than large tumors. This motivated us to study whether there are any proteins capable of alerting about these changes. The aim here was to correlate the immunoexpression of the TS, p53, COX2, EGFR, MSH6 and MLH1 biomarkers in tumors in patients with colorectal adenocarcinoma, with the degree of cell differentiation, tumor staging and clinical-pathological prognostic factors. DESIGN AND SETTING: Retrospective observational study at a public tertiary-level hospital. METHODS: We analyzed tissue-microarray paraffin blocks of tumor tissues that had been resected from 107 patients. We used Fisher's exact test to study associations between tumor differentiation/staging and the immunoexpression of biomarkers. We also used Kaplan-Meier estimation, the log-rank test and the adjusted Cox regression model to investigate the patients' overall survival (in months) according to biomarkers and disease-free interval. RESULTS: The degree of tumor differentiation and tumor staging were not associated with the biomarkers, except in cases of patients in stages III or IV, in which there was a correlation with MLH1 expression (P=0.021). Patient survival and disease-free interval were not associated with the biomarkers. CONCLUSION: There were no associations between the degree of tumor differentiation, staging, length of survival or disease-free interval and the immunoexpression of the TS, p53, COX2, EGFR or MSH6 tumor markers. In advanced cases of colorectal adenocarcinoma (stages III and IV), there was a higher percentage of MLH1-negative results.

Prognostic utility of epidermal growth factor receptor (EGFR) expression in prostatic acinar adenocarcinoma

Background: Epidermal growth factor receptor (EGFR) is potential prognostic biomarker expressed in many human cancers. Prognostic significance of EGFR immunohistochemical expression has not been established in prostatic acinar adenocarcinoma, therefore we aimed to evaluate the frequency of expression of EGFR in prostatic adenocarcinoma and its association with other prognostic parameters. Methods: The study included 123 cases of biopsy proven prostatic acinar adenocarcinoma treated at Liaquat National hospital, Karachi from January 2013 till December 2017. Paraffin blocks of all cases were retrieved; sections were cut and stained with haematoxylin and eosin. Pathologic characteristics including tumor quantification, WHO grade group, gleason score, perineural and lymphovascular invasion were evaluated. EGFR immunohistochemistry (IHC) was performed on all tissue blocks. Results: Mean age of the patients included in the study was 69.05±8.68years. High gleason scores i.e. 8 & 9 were noted in 22% (27 cases) and 22.8% (28 cases) respectively. Similarly, 22.8% (28 cases) showed WHO grade group 5. 52.8% (65 cases) had > 50% tissue involvement by carcinoma and perineural invasion was seen in 37.4% (46 cases). Positive EGFR expression was noted in 18.7% (23 cases), while 81.3% (100 cases) showed negative EGFR expression. Significant association of EGFR expression was noted with gleason score (p-value = < 0.001), WHO grade (p = < 0.001), tumor quantification (p =0.007) and perineural invasion (p = < 0.001). Moreover, significant association of EGFR expression was also seen with disease recurrence and Her2neu over expression. Patients with low gleason scores (score 6 and 7) and lower grade group (1, 2 & 3) were less likely to have positive EGFR expression as compared to patients with high gleason score (score 9) and higher grade group (5). Similarly, patients with perineural invasion were more likely to have positive EGFR expression. Conclusion: We found a relatively low EGFR expression in our patients with prostatic adenocarcinoma; however, its association with poor prognostic parameters like high gleason score, higher grade group, perineural invasion, higher tissue involvement by cancer and disease recurrence signifies its importance as a prognostic parameter in prostatic acinar adenocarcinoma (AU)

Cost effectiveness analysis of plasma genotyping versus tumor genotyping in detection of advanced non-small-cell lung cancer with epidermal growth factor receptor and T790M mutation under the Brazilian private healthcare system perspective / Custo-efetividade do uso da biópsia líquida versus biópsia tecidual para detecção de câncer de pulmão de não pequenas células avançado com receptor do fator de crescimento epidérmico e mutação T790M sob a perspectiva do sistema suplementar de saúde do Brasil

Objective: Comparing the costs and effectiveness of plasma genotyping versus tumor genotyping for detecting the T790M mutation in advanced non-small cell lung cancer (NSCLC) with a mutation in the epidermal growth factor receptor (EGFR) and that progressed after use of an EGFR tyrosine kinase inhibitor (EGFR-TKI), from the perspective of the private healthcare system in Brazil. Methods: Patients with a post-EGFR-TKI T790M mutation are eligible for a second-line treatment with a third-generation EGFR-TKI (osimertinib). In order to estimate the costs associated with the diagnosis method for the T790M mutation, a decision tree model has been used. Resource use was estimated by a team of experts, and the direct costs were estimated based on official databases. Results: Plasma genotyping provided a R$391 reduction per patient, due to the reduced cost with complications; it prevented 40.96% of the patients from undergoing an invasive procedure and 31.91% of the patients from having any kind of complication. Conclusion: Data found support a new paradigm for treating the resistance to EGFR-TKIs, with plasma genotyping as the first diagnostic choice, what can help to define the treatment and to reduce the costs of Brazilian private healthcare system.

Objetivo: Comparar os custos e efetividade da biópsia líquida versus biópsia tecidual para detecção da mutação T790M no câncer de pulmão de não pequenas células (CPNPC) avançado com mutação no receptor do fator de crescimento epidérmico (EGFR) e que progrediram após o uso de um inibidor do sítio da tirosina cinase associada ao EGFR (EGFR-TKI), sob a perspectiva do sistema suplementar de saúde do Brasil. Métodos: Pacientes com mutação EGFR-T790M pós-EGFR-TKI são elegíveis ao tratamento de segunda linha com um EGFR-TKI de terceira geração (osimertinibe). Para a estimativa dos custos relacionados ao método de diagnóstico de mutação T790M, foi elaborado um modelo de árvore de decisão. A utilização de recursos foi estimada por painel de especialistas e os custos diretos foram estimados utilizando-se bases de dados oficiais. Resultados: A biópsia líquida proporcionou redução de R$ 391 por paciente, devido a uma redução no custo com complicações; evitou que 40,96% dos pacientes passassem por um procedimento invasivo e que 31,95% dos pacientes tivessem algum tipo de complicação. Conclusão: Os dados observados embasam um novo paradigma para o manejo da resistência aos EGFR-TKIs, com genotipagem pelo plasma como primeira opção diagnóstica, o que pode auxiliar na melhor definição do tratamento e reduzir custos ao sistema de saúde suplementar brasileiro.

Expresión del receptor de factor de crecimiento epidérmico en cáncer de ovario / Expression of the epidermal growth factor receptor in ovarian cancer

El cáncer de ovario es una de las neoplasias más letales dentro de los cánceres ginecológicos con altos niveles de resistencia a los tratamientos habituales. La identificación de blancos tumorales para terapias biológicas responde a la necesidad de desarrollar nuevas estrategias terapéuticas contra este tipo de tumor. Diferentes estudios han demostrado que existe asociación entre la expresión del ligando de EGF, así como sus receptores y el pronóstico de las pacientes con cáncer de ovario. Altos niveles de EGFr se asocian a proliferación, invasión, metástasis y resistencia a la quimioterapia. El uso de productos anti-EGF, como la vacuna CIMAvax-EGF, podría resultar beneficioso en el tratamiento del cáncer de ovario, lo que constituye una opción terapéutica para estas pacientes(AU)

Ovarian cancer is one of the most lethal neoplasms in gynecological cancers having high levels of resistance to the usual treatments.Identifying tumor targets for biological therapies responds to the need to develop new therapeutic strategies against this type of tumor. Different studies have shown that there is an association between EGF ligand expression, as well as receptors and prognosis of patients with ovarian cancer. High levels of EGFr are associated with proliferation, invasion, metastasis and resistance to chemotherapy. High levels of EGFr are associated with proliferation, invasion, metastasis and resistance to chemotherapy.The use of anti-EGF products, such as the CIMAvax-EGF vaccine, could be beneficial in the treatment of ovarian cancer, which constitutes a therapeutic option for these patients(AU)

Efficacy of targeted therapy for advanced renal cell carcinoma: A systematic review and meta-analysis of randomized controlled trials

ABSTRACT We conducted a systematic review and meta-analysis of the literature on the efficacy of the targeted therapies in the treatment of advanced RCC and, via an indirect comparison, to provide an optimal treatment among these agents. A systematic search of Medline, Scopus, Cochrane Library and Clinical Trials unpublished was performed up to Jan 1, 2015 to identify eligible randomized trials. Outcomes of interest assessing a targeted agent included progression free survival (PFS), overall survival (OS) and objective response rate (ORR). Thirty eligible randomized controlled studies, total twentyfourth trails (5110 cases and 4626 controls) were identified. Compared with placebo and IFN-α, single vascular epithelial growth factor (receptor) tyrosine kinase inhibitor and mammalian target of rapamycin agent (VEGF(r)-TKI & mTOR inhibitor) were associated with improved PFS, improved OS and higher ORR, respectively. Comparing sorafenib combination vs sorafenib, there was no significant difference with regard to PFS and OS, but with a higher ORR. Comparing single or combination VEGF(r)-TKI & mTOR inhibitor vs BEV + IFN-α, there was no significant difference with regard to PFS, OS, or ORR. Our network ITC meta-analysis also indicated a superior PFS of axitinib and everolimus compared to sorafenib. Our data suggest that targeted therapy with VEGF(r)-TKI & mTOR inhibitor is associated with superior efficacy for treating advanced RCC with improved PFS, OS and higher ORR compared to placebo and IFN-α. In summary, here we give a comprehensive overview of current targeted therapies of advanced RCC that may provide evidence for the adequate targeted therapy selecting.

Impacto na Sobrevida Livre de Progressão pela Falta de Acesso a Inibidores de EGFR em Carcinoma de Pulmão de Células não Pequenas no Sistema de Saúde Público Brasileiro / Impact that Lack of Access to EGFR Inhibitors has on Progression-Free Survival in Non-Small Cell Lung Cancer treated via the Public Health Care System in Brazil / Impacto en la Sobrevida Libre de Progresión por la Falta de Acceso a los Inhibidores de EGFR en el Carcinoma de Pulmón de Células no Pequeñas en el Sistema de Salud Pública Brasileña

Introdução: O advento de terapias-alvo antirreceptor do fator de crescimento epidérmico (anti-EGFR) impactou na sobrevida dos pacientes com câncer de pulmão de células não pequenas avançado e portadores de mutação no EGFR, que são tratados no Sistema Único de Saúde Brasileiro (SUS). Objetivo: Estimar o impacto da falta de acesso a terapias anti-EGFR na sobrevida livre de progressão (SLP) desses pacientes. Método: Por meio da base de dados do Instituto Nacional de Câncer José Alencar Gomes da Silva e de estudos que descrevem a prevalência de mutação em EGFR na população brasileira, foi estimado o número de pacientes com adenocarcinoma de pulmão avançado, portadores de mutação EGFR, candidatos à terapia-alvo no ano de 2017. Para a estimativa de efetividade, quatro diferentes esquemas de tratamentos foram considerados: quimioterapia, erlotinib, afatinib e gefitinib. O número de pacientes livres de progressão de doença, após dois anos, foi estimado com base nos resultados para SLP em ensaios clínicos randomizados. Resultados: Foram estimados 1.735 pacientes com adenocarcinoma de pulmão metastático portadores de mutações ativadoras de EGFR no Brasil para o ano de 2017. Projetou-se que, caso fossem tratados com quimioterapia, apenas 71 estariam livres de progressão após 24 meses do início do tratamento. Em contrapartida, com o uso de inibidores de tirosina-quinase anti-EGFR, a expectativa seria de 312 pacientes livres de doença para erlotinib, 377 para gefitinib e 388 para afatinib. Conclusão: Apesar de recomendadas internacionalmente, as terapias anti-EGFR não são disponibilizadas no SUS, sendo oferecida aos pacientes apenas a quimioterapia. Isso problematiza a situação de falta de acesso no âmbito do SUS e embasa, localmente, a discussão acerca da incorporação dessas terapias no âmbito público.

Introduction: The advent of targeted anti-epidermal growth factor receptor (anti-EGFR) therapies have improved survival in patients with metastatic non-small cell lung cancer that carry the EGFR mutation, including those treated via the Brazilian Sistema Único de Saúde (SUS, Unified Health Care System). Objective: To estimate the impact that lack of access to anti-EGFR therapies has on progression-free survival (PFS) among such patients. Method: On the basis of epidemiologic data obtained from the José Alencar Gomes da Silva National Cancer Institute and from studies reporting the prevalence of the EGFR mutation in the Brazilian population, we estimated the number of patients with advanced lung adenocarcinoma and the EGFR mutation who were candidates for targeted therapy in 2017. To estimate effectiveness, we evaluated four different treatments: chemotherapy, erlotinib, afatinib, and gefitinib. The number of patients with PFS after 2 years of follow-up was estimated on the basis of the results of randomized clinical trials. Results: We evaluated 1,735 patients with EGFR mutation-positive metastatic lung adenocarcinoma in Brazil in 2017. We estimated that, if treated with chemotherapy, only 71 of those patients would be free of progression after 24 months. In contrast, if all of the patients were treated with anti-EGFR tyrosine kinase inhibitors, the expectation was that PFS would be achieved in 312 patients for erlotinib, 377 for gefitinib, and 388 for afatinib. Conclusion: Although recommended by international guidelines, anti-EGFR therapies are not available via the SUS, which offers only chemotherapy. This complicates the problem of lack of access in the SUS and promotes local discussion in the public sphere about the incorporation of these therapies.

Introducción: El advenimiento de terapias objetivo anti receptor del factor de crecimiento epidérmico (EGFR) impactó en la supervivencia de los pacientes con cáncer de pulmón de células no pequeñas avanzado y portadores de mutación en el EGFR, que son tratados en el sistema único de salud brasileño (SUS). Objetivo: Estimar el impacto de la falta de acceso a terapias anti-EGFR en la sobrevida libre de progresión (SLP) de esos pacientes. Método:A través de la base de datos del Instituto Nacional de Cáncer José Alencar Gomes da Silva y de estudios que describen la prevalencia de mutación de EGFR en la población brasileña, se estima el número de pacientes con adenocarcinoma de pulmón avanzado portadores de mutación EGFR candidatos a la terapia objetivo en el año de Para la estimación de efectividad, cuatro diferentes esquemas de tratamientos fueron considerados: quimioterapia, erlotinib, afatinib y gefitinib. El número de pacientes libres de progresión de la enfermedad después de dos años se calculó sobre la base de los resultados para SLP en los ensayos clínicos aleatorizados. Resultados: Se estimó 1.735 pacientes con adenocarcinoma de pulmón metastático, portadores de mutaciones activadoras de EGFR en Brasil para el año 2017. Se proyectó que si se tratar con quimioterapia sólo 81 estarían libres de progresión después de 24 meses. En contrapartida, con el uso de inhibidores de tirosina quinasa anti-EGFR, la expectativa sería de 312 pacientes libres de enfermedad para erlotinib, 377 para gefitinib y 388 para afatinib. Conclusión: A pesar de ser recomendadas internacionalmente, las terapias anti-EGFR no están disponibles en el SUS, siendo ofrecido a los pacientes sólo quimioterapia. Esto problematiza claramente la situación de falta de acceso en el ámbito del SUS y basan, localmente, la discusión sobre la incorporación de estas terapias en el ámbito público.