A expressão do PTEN como mecanismo de resistência ao Trastuzumab em carcinomas da mama com sobre-expressão do HER2

Abstract

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.

Date of Award	May 2012
Original language	Portuguese
Awarding Institution	Universidade Católica Portuguesa
Supervisor	Fernandes Carlos de Landér Schmitt (Supervisor) & Joana Cancela de Amorim Falcão Paredes (Co-Supervisor)