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Ribonucleotide Reductase Messenger RNA Expression and Survival in Gemcitabine/Cisplatin-Treated Advanced Non-Small Cell Lung Cancer Patients

¹ Medical Oncology Service, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain;² Response Genetics Inc, Los Angeles, California;³ Medical Oncology Service, Hospital Arnau de Vilanova, Valencia, Spain;⁴ Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida;⁵ Facultat de Medicina, Autonomous University of Madrid, Madrid, Spain;⁶ Medical Oncology Service, Hospital General de Valencia, Valencia, Spain;⁷ Medical Oncology Service, Puerta de Hierro Hospital, Madrid, Spain;⁸ Medical Oncology Service, Hospital Clinico de Zaragoza, Zaragoza, Spain;⁹ Medical Oncology Service, Hospital de Leon, Leon, Spain; and¹⁰ Medical Oncology Service, Hospital Miguel Servet, Zaragoza, Spain

Purpose: No chemotherapy regimen, including the widely used combination of gemcitabine/cisplatin, confers significantly improved survival over any other in metastatic non-small cell lung cancer (NSCLC); however, the selection of patients according to key genetic characteristics can help to tailor chemotherapy. Ribonucleotide reductase subunit M1 (RRM1) is involved in DNA synthesis and repair and in gemcitabine metabolism, and the excision repair cross-complementing group 1 (ERCC1) gene has been related to cisplatin activity.

Experimental Design: Patients were part of a large randomized trial carried out from September 1998 to July 2000, comparing gemcitabine/cisplatin versus gemcitabine/cisplatin/vinorelbine versus gemcitabine/vinorelbine followed by vinorelbine/ifosfamide. We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded samples obtained from bronchoscopy by real-time quantitative reverse transcription-PCR. Results were correlated with survival using the Kaplan-Meier method.

Results: A total of 100 patients were assessed. There was a strong correlation between RRM1 and ERCC1 mRNA expression levels (Spearman r = 0.410; P < 0.001). In the gemcitabine/cisplatin arm, patients with low RRM1 mRNA expression levels had significantly longer median survival than those with high levels [13.7 versus 3.6 months; 95% confidence interval (CI), 9.6–17.8 months; P = 0.009]. Median survival was also significantly longer among patients with low mRNA expression levels of both RRM1 and ERCC1 (not reached), than among those with high levels of both genes (6.8 months; 95% CI, 2.6–11.1 months; P = 0.016).

Conclusions: RRM1 mRNA expression is a crucial predictive marker of survival in gemcitabine/cisplatin-treated patients. Genetic testing of RRM1 mRNA expression levels can and should be used to personalize chemotherapy.

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