PD6-1-2: ERCC1 and TOPOIIa mRNA levels predict response to platinum/etoposide chemotherapy and survival of small-cell lung cancer patients.

Abstract

ERCC1 and TOPOIIa mRNA levels predict response to platinum/ etoposide chemotherapy and survival of small-cell lung cancer patients. Selvaggi, Giovanni1 Ceppi, Paolo2 Giai Levra, Matteo1 Novello, Silvia1 Longo, Marina1 Cappia, Susanna2 Papotti, Mauro2 Volante, Marco2 Scagliotti, Giorgio V.1 1 Thoracic Oncology at Ospedale San Luigi, University of Torino, Orbassano, Italy 2 Pathology at Ospedale San Luigi, University of Torino, Orbassano, Italy Background: This study was designed to evaluate the predictive role of mRNA quantification of three genes potentially related to platinum/ etoposide therapy in small-cell lung cancer (SCLC): ERCC1, RRM1 and TOPOIIα. Methods: A retrospective analysis was therefore performed on 103 consecutive patients with either limited stage (LS) or extensive stage (ES) SCLC. Total RNA was extracted from microdissected sections of 103 formalin-fixed, paraffin embedded pre-treatment biopsies of SCLC patients. Relative quantification for ERCC1, RRM1 and TOPOIIα plus an internal reference gene (b-actin) was done by Real Time PCR using intron-spanning primers. ERCC1 was evaluated also by immunohistochemistry (IHC) with a semi-quantitative score. Results: Eighty-five samples (83%) were successfully amplified by Real Time PCR and a gene expression level was detectable in all samples. Out of these 85 cases, 45 (53%) had LS SCLC and 40 (47%) ES SCLC; overall response rate (RR) to chemotherapy was 65% (56 cases), median survival was 9.9 months. IHC staining of ERCC1 was positive in 2 out of 85 patients with no correlation with clinico-pathological factors. A significant correlation emerged between ERCC1 and RRM1 mRNA levels (Rs=0.34, p=0.001). Low TOPOIIα expression was associated to increased RR in LS patients (p=0.025) and TOPOIIα levels were lower in patients who had a complete response than in patients with either partial responses or no response (p=0.01). At univariate analysis LS patients with low ERCC1 mRNA levels had longer median survival (14.9 months vs. 9.9 months, p=0.01), while RRM1 and TOPOIIα levels showed no significant influence on survival. At multivariate analysis, ERCC1 was confirmed as an independent prognostic factors for survival in LS patients, together with performance status (PS) and response to chemotherapy. No significant prognostic role was found for ERCC1, RRM1 and TOPOIIα in patients with ES SCLC. Conclusions: Pharmacogenomics have been widely studied in advanced NSCLC, while poor efforts have so far been devoted on such topic in SCLC. ERCC1 and TOPOIIα mRNA levels could represent new reliable markers to predict response to treatment and clinical outcome in subgroups of SCLC patients. The path to the individualization of therapy through selection of patients based on pharmacogenomic data should be pursued to improve prognosis of SCLC. PD6-1-3 SCLC, Mon, 16:00 17:30