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 tr eatment of ovarian carcinoma. None of the earlier-identified resistanc e mechanisms, such as overexpression of the MDR1 gene product, P-glyco protein (Pgp), has been shown to be a major determinant of clinical re sponse to chemotherapy and survival for ovarian cancer patients. The m ultidrug resistance-associated protein (Mrp) and the lung resistance p rotein (Lrp, also called the p110 major vault protein), are newly desc ribed 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 ch emotherapy and survival. Methods: Fifty-seven banked frozen specimens, previously collected and frozen at the time of diagnosis from an equa l number of patients with International Federation of Gynecology and O bstetrics (FIGO) stage III or IV ovarian carcinoma, were immunostained for Pgp (with monoclonal antibodies [MAbs] MRK-16 and JSB-1), Mrp (wi th MAb MRPrI), and Lrp (with MAb LRP-56). AH patients had received pla tinum- or alkylating-based chemotherapy after debulking surgery. Clini copathologic parameters determined at diagnosis were retrospectively a ssessed for their relationship with Pgp, Mrp, and Lrp expression. Resp onse 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-tai led. Results: Nine (16%), 39 (68%), and 44 (77%) of the 57 tumor speci mens examined showed positive immunostaining for Pgp, Mrp, and Lrp, re spectively. Positive immunostaining for these proteins was not associa ted with any other prognostic factor examined. No association was foun d between Pgp and Mrp expression and response to chemotherapy and surv ival. In contrast, patients with Lrp-positive tumors had poorer respon se to chemotherapy (P = .004) and shorter progression-free (P = .003) and overall (P = .007) survival than Lrp-negative patients. Multivaria te analysis of Lrp expression, FIGO stage, residual turner after initi al surgery, tumor grade, and presence or absence of ascites showed tha t only Lrp status was independently related to both progression-free s urvival and overall survival. Conclusions: Positive Lrp immunostaining in advanced ovarian carcinoma appears to be an indicator of poor resp onse to standard chemotherapy (platinum or alkylating agents) and of a dverse prognoses. Implications: The functional characterization of Lrp and related proteins may reveal new approaches to modulate Lrp-associ ated drug resistance. A large prospective study is warranted to confir m the prognostic value of Lrp.