ERCC1 and Thymidylate Synthase as Prognostic ...

ERCC1 and Thymidylate Synthase as Prognostic Biomarkers in Malignant Mesothelioma Mezzapelle R1, Miglio U1, Rena O2, Mercalli F3, Veggiani C3, Paganotti A3, Buosi R4, Rinaldi M5, Bianchi ME6, Boldorini R1,3 1

Unit of Pathology, Department of Health Sciences, 4Unit of Oncology, Department of Translational Medicine, and 5Department of Pharmaceutical Science, University of Eastern Piedmont ‘A. Avogadro’, Novara 28100, Italy; 2Unit of Thoracic Surgery and 3Unit of Pathology, ‘Maggiore della Carità’ Hospital, Novara 28100, Italy; Division of Genetics and Cell Biology, San Raffaele University, 20132 Milano, Italy. The standard of care for malignant pleural mesothelioma (MPM) is a combination of platinum compounds and Pemetrexed. Still, the median survival of MPM patients is low (about 12 months). Excision Repair Cross Complementing Group 1 (ERCC1) acts by removing DNA adducts formed by platinum compounds, whereas Pemetrexed inhibits Thymidylate Synthase (TS), which is involved in DNA synthesis. Pleural biopsies were collected from 140 MPM patients (98 males and 42 females, mean age 68 years) before treatment initiation. Average disease specific survival was 13 months (range 1-60). mRNA was extracted from formalin fixed paraffin blocks, reverse transcribed and assayed by qRT-PCR. Immunohistochemistry with anti-ERCC1 and anti-TS mAbs was scored semi-quantitatively. Of 140 patients, 102 were treated, the remaining were not because of bad performance status or advanced age. Patients with low ERCC1 protein expression survived longer (24.3 vs 12.5 months, P=.03). Likewise, patients with low levels of TS mRNA had better survival (P=.01); there was no advantage, however, in the treated sub-group, suggesting that Pemetrexed treatment and low TS expression had no additive value. ERCC1 protein expression and TS gene expression, both seem important prognostic markers; we suggest their evaluation in routine biopsies from MPM patients.