PO-497 Microtubule regulatory proteins as predictive biomarkers of taxane-based chemoresistance in breast cancer?

Abstract

IntroductionNeo-adjuvant chemotherapy combining taxanes and anthracyclines represents an interesting option for a number of breast cancer patients. However, the proportion of patients who achieve a pathological complete response (pCR) after treatment remains low, reaching 15%–20% in the whole population. Thus, identifying predictive biomarkers of drug resistance is necessary to select the patients who are most likely to benefit from chemotherapy. Taxanes (paclitaxel, docetaxel) are potent stabilisers of the microtubule cytoskeleton, which functions are tightly regulated by a panel of MT-associated proteins and mitotic kinases. In the present study, we evaluated whether taxane resistance in breast cancer may be associated with alterations of genes encoding MT-regulatory proteins.Material and methodsExpression levels of 411 MT-related genes were analysed from Affymetrix U133 microarray of breast tumours from three independent multicentered clinical trials, namely REMAGUS-02 (115 patients), REMAGUS-04 (142 patients) and MD Anderson (133 patients). Only patients treated with neoadjuvant taxane-based chemotherapy were included in this study. Expression level of MT-related genes in tumours was compared with the ability to achieve pCR.Results and discussionsBy comparing expression levels of 411 MT-related genes in three independent cohorts of breast cancer patients treated with taxane-based neo-adjuvant chemotherapy, we have identified a total of 94 MT-related genes that are differentially expressed in tumours with pCR. Among those, 18 MT-related genes are common to the three cohorts. Interestingly, all these genes appear as potential prognostic biomarkers of overall survival. Ongoing studies aim at functionally validating these candidates using siRNA screening in two different breast cancer cell lines.ConclusionThis study should lead to the identification of novel predictive biomarkers to select breast cancer patients who are likely to benefit from taxane-based chemotherapy. This should also pave the way for future targeted treatments of chemoresistant breast tumours.