Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma.
BACKGROUND
Drug resistance is a major impediment to the successful treatment of ovarian carcinoma. None of the earlier-identified resistance mechanisms, such as overexpression of the MDR1 gene product, P-glycoprotein (Pgp), has been shown to be a major determinant of clinical response to chemotherapy and survival for ovarian cancer patients. The multidrug resistance-associated protein (Mrp) and the lung resistance protein (Lrp, also called the p110 major vault protein), are newly described proteins associated with multidrug resistance in vitro.


OBJECTIVE
The aim of this retrospective study was to investigate the expression of Mrp and Lrp, in addition to Pgp, in advanced ovarian carcinoma and to determine whether such expression was predictive of response to chemotherapy and survival.


METHODS
Fifty-seven banked frozen specimens, previously collected and frozen at the time of diagnosis from an equal number of patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian carcinoma, were immunostained for Pgp (with monoclonal antibodies [MAbs] MRK-16 and JSB-1), Mrp (with MAb MRPrl), and Lrp (with MAb LRP-56). All patients had received platinum- or alkylating-based chemotherapy after debulking surgery. Clinicopathologic parameters determined at diagnosis were retrospectively assessed for their relationship with Pgp, Mrp, and Lrp expression. Response to treatment and survival were compared between Pgp, Mrp, and Lrp expression groups. Qualitative variables were analyzed using Fisher's exact test or the chi-squared test. All reported P values are two-tailed.


RESULTS
Nine (16%), 39 (68%), and 44 (77%) of the 57 tumor specimens examined showed positive immunostaining for Pgp, Mrp, and Lrp, respectively. Positive immunostaining for these proteins was not associated with any other prognostic factor examined. No association was found between Pgp and Mrp expression and response to chemotherapy and survival. In contrast, patients with Lrp-positive tumors had poorer response to chemotherapy (P = .004) and shorter progression-free (P = .003) and overall (P = .007) survival than Lrp-negative patients. Multivariate analysis of Lrp expression, FIGO stage, residual tumor after initial surgery, tumor grade, and presence or absence of ascites showed that only Lrp status was independently related to both progression-free survival and overall survival.


CONCLUSIONS
Positive Lrp immunostaining in advanced ovarian carcinoma appears to be an indicator of poor response to standard chemotherapy (platinum or alkylating agents) and of adverse prognoses.


CONCLUSIONS
The functional characterization of Lrp and related proteins may reveal new approaches to modulate Lrp-associated drug resistance. A large prospective study is warranted to confirm the prognostic value of Lrp.
Izquierdo
M A
MA
Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
van der Zee
A G
AG
Vermorken
J B
JB
van der Valk
P
P
Beliën
J A
JA
Giaccone
G
G
Scheffer
G L
GL
Flens
M J
MJ
Pinedo
H M
HM
Kenemans
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D018528:ATP-Binding Cassette Transporters / Q000032:analysis*; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000032:analysis*; D018432:Drug Resistance, Multiple; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000032:analysis*; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D012261:Ribonucleoproteins / Q000032:analysis*; D016019:Survival Analysis; D016896:Treatment Outcome; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012261:Ribonucleoproteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein