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

Abstract

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 crosscomplementing 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.

Expression of excision repair cross-complementation group 1 protein predicts poor outcome in advanced non-small cell lung cancer patients treated with platinum-based doublet chemotherapy

“…Several studies reported the correlation between ERCC1 expression and resistance to platinum-based chemotherapy or outcome in advanced NSCLC [14,[25][26][27][28][29][30]. High expression of ERCC1 mRNA was significantly associated with poor survival in patients with advanced NSCLC who underwent palliative chemotherapy with gemcitabine/cisplatin or gemcitabine alone [28][29][30].…”

“…High expression of ERCC1 mRNA was significantly associated with poor survival in patients with advanced NSCLC who underwent palliative chemotherapy with gemcitabine/cisplatin or gemcitabine alone [28][29][30]. Moreover, a recently published study using a patient cohort from the International Adjuvant Lung Cancer Trial showed that NSCLC patients with positive ERCC1 in immunohistochemical staining did not benefit from cisplatin-based combination chemotherapy, while adjuvant chemotherapy significantly improved OS in patients with negative ERCC1 [26].…”

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine

“…Ribonucleotide reductase subunit M1 mRNA expression by quantitative PCR significantly influenced time to progression and survival in stage IV NSCLC patients treated with gemcitabine/ cisplatin (Rosell et al, 2003). Two subsequent studies confirmed that RRM1 mRNA expression levels were able to identify stage IV NSCLC patients likely to have good or poor survival when treated with gemcitabine/cisplatin (Rosell et al, 2004;Ceppi et al, 2006).…”

RRM1 *151A>T, RRM1 ‐756T>C, and RRM1 ‐585T>Gis associated with increased susceptibility of lung cancer in Chinese patients

“…Many recent works have mainly focused on whether RRM1 can be used as a molecular predictor in lung cancer by different methods of biomarker analysis, including quantitative real‐time PCR analysis, immunohistochemistry, western blot analysis, and automated quantitative analysis 7, 20, 21, 22. A meta‐analysis of 18 studies evaluating a gemcitabine‐based regimen in patients with advanced NSCLC ( n  = 1243) was recently published 21.…”

“…This is the rate‐limiting step in deoxyribonucleotide formation, and the only known enzyme that converts ribonucleotides to deoxyribonucletides, which is required for DNA polymerization and repair. Furthermore, RRM1 is the molecular target of gemcitabine, and its mRNA expression levels are related to the efficacy of gemcitabine therapy 7, 8. The RRM1 polymorphism – 37 C<A and haplotype – was shown to be associated with susceptibility to gemcitabine in cancer patients including lung cancer 9, 10.…”