Clinical impact of ERCC1 and TOPOIIα gene expression in small-cell lung cancer patients treated with platinum/etoposide

Abstract

2526 Background: Platinum/etoposide is a commonly used regimen both in limited (LS) and extensive stage (ES) small-cell lung cancer (SCLC). The study was aimed at testing retrospectively the predictive role of mRNA quantification of genes correlated to platinum/etoposide therapy: ERCC1, RRM1 and TOPOIIa. Methods: Total RNA was extracted from microdissected sections of 103 formalin-fixed, paraffin embedded bronchial biopsies. Relative quantification for ERCC1, RRM1 and TOPOIIa and an internal reference gene (β- Actin) was performed by Real-Time PCR using intron-spanning primers. ERCC1 expression was also evaluated by immunohistochemistry using a semi-quantitative score. Results: Eighty-five samples (83%) were successfully amplified. Overall median survival (MS) was 9.9 months, 45 patients had LS (MS=13.1 months) and 40 had ES (MS=7.1 months). Fifty-six (65%) had an objective (complete or partial) response to treatment. Immunohistochemical staining of ERCC1 evidenced a positivity in 2 out of 85 patients with no correlation with clinico-pathological factors. By contrast, a gene expression level was detectable in all samples and a significant correlation between ERCC1 and RRM1 levels (Rs=0.34, p=0.0011) was found. By segregating patients according to response to treatment, it was found that lower TOPOIIa expression was associated to a better response in LS patients (p=0.025) and, more interestingly, those who had a complete response had low TOPOIIa levels than both partial and non-responsive patients (p=0.015). By adopting cut-offs according to median values, univariate analysis of survival by Kaplan-Meier method showed that LS patients with low ERCC1 had a significantly longer survival (MS 14.9 vs. 9.9 months, p=0.012), while RRM1 and TOPOIIa levels showed no influence on outcome. In multivariate analysis, ERCC1 was an independent prognostic factor for survival of LS patients, together with PS and response to therapy. No significant role was found for ERCC1, RRM1 and TOPOIIa in patients with ES. Conclusions: ERCC1 and TOPOIIa represent reliable candidate markers in predicting clinical outcome and response to treatment in LS SCLC patients, who may benefit from a better individualized therapy. [Table: see text]