Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response and survival in ovarian cancer patients: a study in serial samples.

ABSTRACT

OBJECTIVES: The role of MDR1 in clinical paclitaxel resistance remains poorly characterized. This study sought to identify the incidence and significance of P-glycoprotein (P-gp) over-expression on survival, tumor response to paclitaxel and the effect of prior cytotoxic exposure on P-gp expression in patients with paired primary and recurrent ovarian cancer samples. METHODS: Retrospective survival analysis. P-gp expression was evaluated immunohistochemically with antibodies c494 and c219. RESULTS: Thirty-two patients were identified from the tumor registry. Median interval between primary and secondary surgery was 17.9 (5.7-40.9) months. Only five primary tumors (16%) demonstrated +++ staining for P-gp. First-line treatment contained paclitaxel in 17 patients (53%) and 26 patients (81%) had been exposed to P-gp exportable chemotherapy before second surgery. Only seven of the recurrent tumors (22%) were +++. Only one of seven (14% (95% CI 0-46%)) recurrent tumors with ++ or +++ staining responded to subsequent paclitaxel, while 8 of 10 (80% (CI 46-100%)) recurrent tumors with 0/+ staining responded (P = 0.025). In multivariate analysis of outcome following second surgery, response to paclitaxel (P = 0.004) and P-gp over-expression (P < 0.001) were significant predictors of survival. CONCLUSIONS: De novo strong P-gp over-expression is uncommon, appears to change little over time or with prior exposure to chemotherapy. However, P-gp over-expression is a significant prognostic factor, and at the time of disease, relapse is inversely correlated with tumor response to paclitaxel.