TS AND ERCC1 PREDICTIVE VALUE IN MESOTHELIOMA

Clin Cancer Res. 2011 Jan 24. [Epub ahead of print]

THYMIDYLATE SYNTHASE AND EXCISION REPAIR-CROSS-COMPLEMENTING GROUP-1 AS PREDICTORS OF RESPONSIVENESS IN MESOTHELIOMA PATIENTS TREATED WITH PEMETREXED-CARBOPLATIN.

Zucali PA, Giovannetti E, Destro A, Mencoboni M, Ceresoli GL, Gianoncelli L, Lorenzi E, De Vincenzo F, Simonelli M, Perrino M, Bruzzone A, Thunnissen E, Tunesi G, Giordano L, Roncalli M, Peters GJ, Santoro A.

Medical Oncology and Hematology, Istituto Clinico Humanitas IRCCS.

Abstract

PURPOSE: The pemetrexed/platinum-agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize treatment. This retrospective study aimed to assess the role of excision-repair-cross-complementing group-1 (ERCC1) and thymidylate-synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting.Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein-expression was performed by PCR and immunohistochemistry (using the H-score) in tumor specimens from 126 MPM patients, including 99 carboplatin/pemetrexed-treated patients.
RESULTS: A significant correlation between low TS protein-expression and disease-control (DC) to carboplatin/pemetrexed therapy (p=0.027), longer PFS (p=0.017), and longer OS (p=0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of progressive disease (p=0.022), shorter PFS (p<0.001) and shorter OS (p<0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS-H-score confirmed their independent prognostic role for DC, PFS and OS. No significant associations were found among ERCC1 protein-expression, TS and ERCC1 polymorphisms and clinical outcome.
CONCLUSIONS: In our series of carboplatin/pemetrexed-treated MPM patients, low TS-protein and mRNA-levels were significantly associated to DC, improved PFS and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted.