Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer

Purpose: Overexpression of the excision repair cross-complementing 1 (ERCCl) gene, which is crucial in the repair of cisplatin (CDDP)-DNA adducts, is reported to negatively influence the effectiveness of CDDP-based therapy for gastric and ovarian cancers. Recent evidence indicates that Gemcitabine (Gem) may modulate ERCCl nucleotide excision repair activity, and down-regulation of DNA repair activity by ERCCl antisense RNA reportedly inhibits synergism of CDDP/Gem. We investigated whether ERCCl mRNA expression levels were associated with clinical outcomes after treatment with a combination Gem/CDDP regimen for patients with advanced stage non-small cell lung cancer (NSCLC). Experimental Design: Response and survival were correlated with the level of ERCCI expression in 56 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1250 mg/m(2) days 1 and 8 plus CDDP 100 mg/m(2) on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of ERCCl/beta-actin were measured using a quantitative reverse transcription-PCR (Taqman) system. Results: ERCCl expression was detectable in all tumors. There were no significant differences in ERCCl levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 44.7%. There were no significant associations between ERCCl expression and response. Median overall survival was significantly longer in patients with low ERCCl expression tumors (61.6 weeks; 95% confidence interval, 42.4-80.7 weeks) compared to patients with high expression tumors (20.4 weeks, 95% confidence interval, 6.9-33.9 weeks). ERCCl expression, Eastern Cooperative Oncology Group performance status, and presence of weight loss were significant prognostic factors for survival in a Cox proportional hazards multivariable analysis. Conclusions: These data suggest that ERCCI expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high ERCCI mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for ERCCI expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of ERCCl as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted.