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Low ERCC1 Expression Correlates with Prolonged Survival after Cisplatin plus Gemcitabine Chemotherapy in Non-Small Cell Lung Cancer¹

University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033 [R. V. N. L., J. B., P. V. D.]; University of California, Davis Cancer Center, Sacramento, California 95817 [D. G., P. H. G.]; Hospital Arnau de Vilanova, 46015 Valencia, Spain [V. A.]; Hospital General de Valencia, 46014 Valencia, Spain [C.C.]; Fundación Jiménez Diaz, 28005 Madrid, Spain [M. D.]; Institut Català d’Oncologia, 08907 Bellvitge, Barcelona, Spain [F. C.]; Hospital Germans Trias i Pujol, Badalona, s/n 08916 Barcelona, Spain [J. M. S., M. T., R. R.]; Free University of Madrid, 28029 Madrid, Spain [J. J. S.]; and Response Genetics, Los Angeles, California 90033 [K. D. D.]

Purpose: Overexpression of the excision repair cross-complementing 1 (ERCC1) 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 ERCC1 nucleotide excision repair activity, and down-regulation of DNA repair activity by ERCC1 antisense RNA reportedly inhibits synergism of CDDP/Gem. We investigated whether ERCC1 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 ERCC1 expression in 56 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1250 mg/m² days 1 and 8 plus CDDP 100 mg/m² on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of ERCC1/ß-actin were measured using a quantitative reverse transcription-PCR (Taqman) system.

Results: ERCC1 expression was detectable in all tumors. There were no significant differences in ERCC1 levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 44.7%. There were no significant associations between ERCC1 expression and response. Median overall survival was significantly longer in patients with low ERCC1 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). ERCC1 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 ERCC1 expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high ERCC1 mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for ERCC1 expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of ERCC1 as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted.