Thymidylate synthase and excision repair cross-complementing group-1 as predictors of responsiveness in mesothelioma patients treated with pemetrexed/carboplatin

Paolo Andrea Zucali, Elisa Giovannetti, Annarita Destro, Manlio Mencoboni, Giovanni Luca Ceresoli, Letizia Gianoncelli, Elena Lorenzi, Fabio De Vincenzo, Matteo Simonelli, Matteo Perrino, Andrea Bruzzone, Erik Thunnissen, Gianni Tunesi, Laura Giordano, Massimo Roncalli, Godefridus J. Peters, Armando Santoro

Research output: Contribution to journalArticlepeer-review

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 the 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 done by PCR and immunohistochemistry [with the H-score (histologic 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 progression-free survival (PFS;P = 0.017), and longer overall survival (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 developing 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, lowTS 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.

Original languageEnglish
Pages (from-to)2581-2590
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
Publication statusPublished - Apr 15 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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