Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma

M A Izquierdo, A G van der Zee, J B Vermorken, P van der Valk, J A Beliën, G Giaccone, G L Scheffer, M J Flens, H M Pinedo, P Kenemans

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

PURPOSE: 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.

IMPLICATIONS: 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.

Original languageEnglish
Pages (from-to)1230-7
Number of pages8
JournalJournal of the National Cancer Institute
Volume87
Issue number16
Publication statusPublished - 16 Aug 1995

Cite this

@article{8aaed43b30e44f3680ac01a33d0482bd,
title = "Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma",
abstract = "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.PURPOSE: 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.IMPLICATIONS: 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.",
keywords = "ATP-Binding Cassette Transporters, ATP-Binding Cassette, Sub-Family B, Member 1, Antibodies, Monoclonal, Biomarkers, Tumor, Drug Resistance, Multiple, Female, Gene Expression Regulation, Neoplastic, Humans, Immunoenzyme Techniques, Middle Aged, Multidrug Resistance-Associated Proteins, Neoplasm Proteins, Ovarian Neoplasms, Predictive Value of Tests, Prognosis, Retrospective Studies, Ribonucleoproteins, Survival Analysis, Treatment Outcome, Vault Ribonucleoprotein Particles, Journal Article, Research Support, Non-U.S. Gov't",
author = "Izquierdo, {M A} and {van der Zee}, {A G} and Vermorken, {J B} and {van der Valk}, P and Beli{\"e}n, {J A} and G Giaccone and Scheffer, {G L} and Flens, {M J} and Pinedo, {H M} and P Kenemans",
year = "1995",
month = "8",
day = "16",
language = "English",
volume = "87",
pages = "1230--7",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "16",

}

Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma. / Izquierdo, M A; van der Zee, A G; Vermorken, J B; van der Valk, P; Beliën, J A; Giaccone, G; Scheffer, G L; Flens, M J; Pinedo, H M; Kenemans, P.

In: Journal of the National Cancer Institute, Vol. 87, No. 16, 16.08.1995, p. 1230-7.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma

AU - Izquierdo, M A

AU - van der Zee, A G

AU - Vermorken, J B

AU - van der Valk, P

AU - Beliën, J A

AU - Giaccone, G

AU - Scheffer, G L

AU - Flens, M J

AU - Pinedo, H M

AU - Kenemans, P

PY - 1995/8/16

Y1 - 1995/8/16

N2 - 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.PURPOSE: 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.IMPLICATIONS: 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.

AB - 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.PURPOSE: 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.IMPLICATIONS: 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.

KW - ATP-Binding Cassette Transporters

KW - ATP-Binding Cassette, Sub-Family B, Member 1

KW - Antibodies, Monoclonal

KW - Biomarkers, Tumor

KW - Drug Resistance, Multiple

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunoenzyme Techniques

KW - Middle Aged

KW - Multidrug Resistance-Associated Proteins

KW - Neoplasm Proteins

KW - Ovarian Neoplasms

KW - Predictive Value of Tests

KW - Prognosis

KW - Retrospective Studies

KW - Ribonucleoproteins

KW - Survival Analysis

KW - Treatment Outcome

KW - Vault Ribonucleoprotein Particles

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

M3 - Article

VL - 87

SP - 1230

EP - 1237

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 16

ER -