Predictive Biomarkers and Personalized Medicine Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin Paolo Andrea Zucali 1 , Elisa Giovannetti 6 , Annarita Destro 3 , Manlio Mencoboni 4 , Giovanni Luca Ceresoli 1 , Letizia Gianoncelli 1 , Elena Lorenzi 1 , Fabio De Vincenzo 1 , Matteo Simonelli 1 , Matteo Perrino 1 , Andrea Bruzzone 4 , Erik Thunnissen 7 , Gianni Tunesi 5 , Laura Giordano 2 , Massimo Roncalli 3 , Godefridus J. Peters 2 , and Armando Santoro 1 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 ¼ 0.027), longer progression-free survival (PFS; P ¼ 0.017), and longer overall survival (OS; P ¼ 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 ¼ 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. Clin Cancer Res; 17(8); 2581–90. Ó2011 AACR. Introduction Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. Its incidence is increasing throughout the world and is predicted to increase in the next 10 to 15 years in the Western European countries (1). The majority of patients (up to 80%) are diagnosed in stage III/IV, and systemic therapy represents the only potential treatment option for most cases (2). Two prognostic scor- ing systems have been reported (3, 4), but there are no clinical/biological markers that can be used to optimize the treatment. The combination of cisplatin and pemetrexed has recently become the standard of care in the first-line treat- ment of MPM; it has improved the response rate (RR; 41.3% vs. 16.7%; P < 0.0001), time to progression (TTP; 5.7 vs. 3.9 months; P ¼ 0.001), overall survival (OS; 12.1 vs. 9.3 months; P ¼ 0.020), and quality of life compared with cisplatin alone (5). Many patients with MPM are unfit to receive the cisplatin-based chemotherapy due to the increasing incidence of the disease in the elderly popula- tion and the poor performance status often observed at onset. Pemetrexed alone (6) or combined with carboplatin (7, 8) has been proposed as alternative treatment choices for these patients. Authors' Affiliations: Departments of 1 Oncology, 2 Biostatistics Unit, and 3 Pathology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan; Depart- ments of 4 Oncology and 5 Pathology, Ospedale Villa Scassi, Genova, Italy; Departments of 6 Oncology and, 7 Pathology, VU University Medical Cen- ter, Amsterdam, The Netherlands Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Paolo Andrea Zucali, Department of Medical Oncology and Haematology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano (Milan), Italy. Phone: þ390-282-244061; Fax: þ390- 282-244591. E-mail: paolo.zucali@humanitas.it doi: 10.1158/1078-0432.CCR-10-2873 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 2581 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/17/8/2581/2005299/2581.pdf by guest on 29 May 2023