Correlation of multidrug-resistance gene (MDR1) expression levels and outcome to adjuvant cisplatin/MTX based chemotherapy in patients enrolled in the AUO-AB 05/95 phase III trial

Abstract

5026 Background: The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. MDR1 mRNA levels have been shown to influence metabolism of cancer drugs. We tested whether MDR1 gene expression is associated with outcome in patients with locally advanced bladder cancer. Methods: 221 formalin fixed paraffin embedded (FFPE) tumor samples from patients with locally advanced and/or lymph node-positive bladder cancer enrolled for adjuvant therapy in the AUO-AB 05/95 phase III trial (Lehmann et al, J Clin Oncol. 2005;23:4963–4974) were analyzed (110 pts treated with cisplatin/MTX, 101 pts treated with MTX, vinblastine, epirubicin, and cisplatin, M-VEC).FFPE tissues were dissected using laser-captured microdissection and analyzed for MDR1 and ERCC1 mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: MDR1 was significantly correlated to progression free and overall survival. We included tumor stage (pT), lymph node status (pN) and the blood vessel invasion along with the measured gene expression in a stepwise multivariate Cox proportional hazards regression model. The overall model fit had a significance level of p = 0.0001 (<0.05). The relative risk for shorter survival in patients with High MDR1 expression was 2.8. Regarding survival MDR1 was strongly associated to ERCC1 expression in patients with M-VEC treatment. Conclusions: These results suggest that MDR1 gene expression levels predict response and overall survival in patients with locally advanced urothelial cancer enrolled in AUO-AB 05/95. MDR1 gene expression levels may allow the selection of patients who benefit likely from adjuvant cisplatin/MTX based chemotherapy. Further studies are warranted to study this association. [Table: see text]