Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response and survival in ovarian cancer patients: a study in serial samples.
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.
Penson
Richard T
RT
Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
Oliva
Esther
E
Skates
Steven J
SJ
Glyptis
Tina
T
Fuller
Arlan F
AF
Goodman
Annekathryn
A
Seiden
Michael V
MV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000601:surgery; D017239:Paclitaxel / Q000627:therapeutic use*; D012189:Retrospective Studies; D015996:Survival Rate
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel