Authors
Abstract(s)
Os biomarcadores, de uma forma geral, são utilizados para prever a resposta a um determinado tratamento, permitindo assim determinar grupos bem definidos de doentes, que podem ou não beneficiar de uma terapia particular. O objectivo primário das novas drogas anti-neoplásicas é terem como alvo a inibição directa de marcadores moleculares específicos expressos em células tumorais, de forma a melhorar as taxas de cura do cancro e a reduzir a citotoxicidade nas células normais. Recentes avanços na área da biologia molecular facilitaram a identificação de marcadores tumorais, que não só predizem o prognóstico e a resposta terapêutica, como podem eles próprios funcionar também como alvos terapêuticos.
O Trastuzumab, por exemplo, é um anticorpo monoclonal desenhado para tratar um determinado tipo de cancro da mama, cujas células tumorais sobre-expressam o fator de crescimento epidérmico humano de tipo 2 (HER2). No entanto, apesar da sua eficácia inicial, a resistência adquirida ao Trastuzumab desenvolve-se na maioria das pacientes com cancro da mama metastático, e um grande número nem nunca respondem, demonstrando resistência primária. Recentemente foi sugerido que níveis baixos de expressão da fosfatase PTEN podem resultar numa fosforilação aumentada da PI3K/Akt e consequente sinalização, assim como num bloqueio do efeito anti-proliferativo mediado pelo Trastuzumab. Aliás, tem sido demonstrado que pacientes com tumores deficientes em PTEN e com sobre-expressão de HER2 respondem pior à terapia com Trastuzumab. Em termos clínicos, a descoberta de que a expressão ou não de PTEN pode determinar a resposta dos tumores aos inibidores tirosina cinase é de extrema importância, não só porque irá permitir uma melhor seleção das pacientes, como também terá um efeito direto nos serviços de saúde.
Neste trabalho, verificou-se uma associação estatisticamente significativa entre a expressão proteica do PTEN numa série de carcinomas invasivos de mama com HER2 positivo e as taxas de resposta das pacientes tratadas com Trastuzumab. Demonstrou-se que a expressão negativa ou reduzida do PTEN está significativamente associada à positividade dos gânglios linfáticos, assim como à progressão da doença após tratamento. Curiosamente verificámos ainda que alguns casos apresentaram marcação nuclear intensa do PTEN, estando esta associada à expressão normal do PTEN no citoplasma, assim como a sua ausência estava associada à metastização ganglionar. Identificou-se ainda que a deleção do gene PTEN pode ser responsável pela perda de expressão do PTEN em alguns dos casos analisados.
Com base nestes resultados, podemos concluir que a expressão do PTEN pode selecionar os doentes que irão responder ou não à terapia com Trastuzumab nos tumores de mama que sobre-expressam HER2.
Biomarkers are used to predict the treatment response, allowing the selection of well-defined groups of patients who can benefit or not from a particular therapy. The primary objective of the new anti-neoplastic drugs is to target and inhibit specific molecular markers in tumor cells, in order to improve cancer treatment and to reduce cytotoxicity in normal cells. Recent progress in the area of molecular biology turned easier the identification of tumor markers that not only predict the prognosis and the therapeutic response, but can also work themselves as therapeutic targets. Trastuzumab, for example, is a monoclonal antibody designed to treat a specific type of breast cancer, which tumor cells over express the human epidermic growth factor receptor type 2 (HER2). However, despite initial efficacy, the acquired resistance to Trastuzumab develops in most of the patients with metastatic breast cancer, and some cases have primary resistance. Recently, it has been suggested that low levels of expression of the phosphatase PTEN can increase the phosphorylation of PI3K/Akt pathway and consequent signaling, as well as in a blockade of the anti-proliferative effect mediated by Trastuzumab. Indeed, it has been demonstrated that patients with PTEN defective tumors and with HER2 over expression respond worse to the therapy with Trastuzumab. In clinical terms, the discovery that PTEN expression will be able to determine tumor response to tyrosine kinase inhibitors is of extreme importance, not only because it will allow a better selection of patients, but also to an effect in the health services. In the present work, we found a statistically significant association between PTEN expression in a series of invasive breast carcinomas with HER2 over expression and the rates of response of patients treated with Trastuzumab. We demonstrated that negative or reduced PTEN expression is associated with lymph node metastasis, as well as with disease progression after treatment. We still identified that PTEN gene deletion can be responsible for the loss of PTEN expression in some of the analyzed cases. Curiously, we also demonstrated that, in some cases, there was PTEN strong nuclear expression, which was associated to normal PTEN cytoplasmic expression, as well as with negative lymph node invasion.Based on these results, we can conclude that PTEN expression can select the breast cancer patients that will benefit from Trastuzumab treatment in the HER2 over expressing tumors.
Biomarkers are used to predict the treatment response, allowing the selection of well-defined groups of patients who can benefit or not from a particular therapy. The primary objective of the new anti-neoplastic drugs is to target and inhibit specific molecular markers in tumor cells, in order to improve cancer treatment and to reduce cytotoxicity in normal cells. Recent progress in the area of molecular biology turned easier the identification of tumor markers that not only predict the prognosis and the therapeutic response, but can also work themselves as therapeutic targets. Trastuzumab, for example, is a monoclonal antibody designed to treat a specific type of breast cancer, which tumor cells over express the human epidermic growth factor receptor type 2 (HER2). However, despite initial efficacy, the acquired resistance to Trastuzumab develops in most of the patients with metastatic breast cancer, and some cases have primary resistance. Recently, it has been suggested that low levels of expression of the phosphatase PTEN can increase the phosphorylation of PI3K/Akt pathway and consequent signaling, as well as in a blockade of the anti-proliferative effect mediated by Trastuzumab. Indeed, it has been demonstrated that patients with PTEN defective tumors and with HER2 over expression respond worse to the therapy with Trastuzumab. In clinical terms, the discovery that PTEN expression will be able to determine tumor response to tyrosine kinase inhibitors is of extreme importance, not only because it will allow a better selection of patients, but also to an effect in the health services. In the present work, we found a statistically significant association between PTEN expression in a series of invasive breast carcinomas with HER2 over expression and the rates of response of patients treated with Trastuzumab. We demonstrated that negative or reduced PTEN expression is associated with lymph node metastasis, as well as with disease progression after treatment. We still identified that PTEN gene deletion can be responsible for the loss of PTEN expression in some of the analyzed cases. Curiously, we also demonstrated that, in some cases, there was PTEN strong nuclear expression, which was associated to normal PTEN cytoplasmic expression, as well as with negative lymph node invasion.Based on these results, we can conclude that PTEN expression can select the breast cancer patients that will benefit from Trastuzumab treatment in the HER2 over expressing tumors.