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

• Published in: Gynecologic oncology 2004-04, Vol.93 (1), p.98-106
• Main Authors: Penson, Richard T, Oliva, Esther, Skates, Steven J, Glyptis, Tina, Fuller, Arlan F, Goodman, Annekathryn, Seiden, Michael V
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents, Phytogenic - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Chemotherapy; Female; Humans; Immunohistochemistry; MDR-1; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - surgery; P-gp; Paclitaxel - therapeutic use; Retrospective Studies; Survival Rate; Taxane
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2003.11.053

Objective. 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.