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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

	ABSTRACT

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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.

	INTRODUCTION

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The prognosis of advanced non-small cell lung cancer (NSCLC) is dismal. A recent Eastern Cooperative Oncology Group trial of 1155 patients showed no differences among cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel. Overall median time to progression was 3.6 months, and median survival was 7.9 months (1) . Although clear pharmacogenetic guidelines for personalized chemotherapy have not yet been exactly defined, the assessment of abnormalities in DNA repair pathways and enzymes involved in gemcitabine metabolism can help to distinguish between patients who are sensitive or resistant to gemcitabine or cisplatin.

Ribonucleotide reduction is the reaction whereby ribonucleotides, the precursors of RNA synthesis, are reduced to form deoxyribonucleotides, the precursors of DNA synthesis (2) . Ribonucleotide reductase converts ribonucleotide 5'-diphosphate to deoxyribonucleotide 5'-diphosphate, which is essential for DNA synthesis (Fig. 1) . Gemcitabine, an analogue of deoxycytidine (2',2'-difluorodeoxycytidine), is phosphorylated to the 5'-monophosphate form by deoxycytidine kinase. Subsequent phosphorylation by uridylate-cytidylate monophosphate kinase generates difluorodeoxycytidine 5'-diphosphate, which interferes with the function of ribonucleotide reductase and reduces the pool of deoxyribonucleotide 5'-diphosphate available for DNA synthesis (Ref. 3 ; fig. 1 ). Although RRM1 is a tumor suppressor gene (4) , up-regulation of human RRM1 has been observed during DNA repair after chemotherapy damage (5) . Overexpression of ribonucleotide reductase was observed in a gemcitabine-resistant human oropharyngeal carcinoma KB clone (6) and in a gemcitabine-resistant human leukemic cell line K562 (7) .

View larger version (14K): [in this window] [in a new window]   Fig. 1. Gemcitabine and cisplatin DNA damage. Gemcitabine metabolism competes with ribonucleotide 5'-diphosphate for incorporation into DNA. Ribonucleotide reductase converts ribonucleotide 5'-diphosphate to deoxyribonucleotide 5'-diphosphate, which is essential for DNA synthesis. Gemcitabine, an analogue of deoxycytidine (2',2'-difluorodeoxycytidine), is phosphorylated to the 5'-monophosphate form by deoxycytidine kinase. Subsequent phosphorylation by uridylate-cytidylate monophosphate kinase generates difluorideoxycytidine 5'-diphosphate, which interferes with the function of ribonucleotide reductase and reduces the pool of deoxyribonucleotide diphosphate available for DNA synthesis. Overexpression of ribonucleotide reductase abrogates gemcitabine depletion of deoxyribonucleotide diphosphate, leading to efficient DNA synthesis and repair.

To clarify the influence of RRM1 and ERCC1 on survival in patients treated with gemcitabine/cisplatin, we analyzed RRM1 and ERCC1 mRNA expression in tumors from 100 advanced NSCLC patients who were part of a larger randomized trial (16) , and we compared gemcitabine/cisplatin versus gemcitabine/cisplatin/vinorelbine versus sequential doublets of gemcitabine/vinorelbine followed by vinorelbine/ifosfamide.

	PATIENTS AND METHODS

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Patients.
A total of 100 tumor samples were analyzed to determine RRM1 and ERCC1 mRNA expression levels. They were obtained from 100 NSCLC patients derived from a group of 557 patients who were treated as part of a multicenter, randomized study (16) between September 1998 and July 2000. This study was carried out in accordance with the institutional review board at each participating institution, and written informed consent was obtained from all of the patients. The genetic analysis was carried out between July and September 2002, at which time 493 of 557 patients had died. For this reason, institutional review boards were informed that the genetic analysis was considered to be minimal-risk research, which would not affect the treatment administered and did not require a renewal of patient consent. Eligibility criteria for the randomized study included a histologically or cytologically confirmed diagnosis of advanced NSCLC with malignant pleural effusion or metastatic disease and the absence of prior chemotherapy. Patients were randomized to receive a maximum of six cycles of one of the following: cisplatin 100 mg/m² on day 1 plus gemcitabine 1250 mg/m² on days 1 and 8, every 21 days; triplets of cisplatin 100 mg/m² on day 1 plus gemcitabine 1000 mg/m² and vinorelbine 25 mg/m² on days 1 and 8, every 21 days; or sequential doublets of gemcitabine 1000 mg/m² and vinorelbine 30 mg/m² on days 1 and 8 for three cycles followed by vinorelbine 30 mg/m² on days 1 and 8 plus ifosfamide 3 g/m² on day 1 for three cycles.

Laboratory Methods.
Malignant cells were selectively procured from serial microdissected tissue sections of 10 µm stained with nuclear Fast Red. RNA isolation from paraffin-embedded specimens was performed according to a proprietary procedure (United States patent number 6,248,535). After RNA isolation, cDNA was prepared from each sample as described previously (17) . Relative cDNA quantitation for RRM1, ERCC1, and an internal reference gene (ß-actin) was done using a fluorescence-based, real-time detection method (ABI PRISM 7700 Sequence Detection System; TaqMan; Applied Biosystems, Foster City, CA), as described previously (17) . Primers and probe sequences and PCR conditions used for gene expression analysis have previously been described in detail (15 , 17) . The GenBank accession numbers are L10342 for RRM1 human genomic DNA and NT_028310 for a genomic clone (contig) on chromosome 11. The GenBank accession numbers are M13194 for ERCC1 human genomic DNA and NT_011109 for a genomic clone (contig) on chromosome 19. The threshold cycle (C_T) was the fractional cycle number at which the fluorescence generated by cleavage of the probe exceeded a fixed level above baseline. The relative amount of tissue target mRNA standardized against the amount of ß-actin mRNA was expressed as -C_T = - (C_{T(target gene-1)} - C_T(ß-actin)). The ratio of the number of target mRNA copies to the number of ß-actin mRNA copies was then calculated as 2^-CT x K, where K is a constant. Significant contamination with genomic DNA was excluded by amplifying non-reverse-transcribed RNA.

Statistical Analysis.
Quantitative PCR analyses yield values that are expressed as ratios between two absolute measurements (gene of interest:internal reference gene). The maximal ² method of Halpern was adapted to determine which cutoff value best dichotomized patients into low-expression and high-expression RRM1 and ERCC1 subgroups. Proportions were compared by use of Fisher’s exact test. The Kaplan-Meier method was used to calculate survival and time to progression, and the Brookmeyer-Crowley method was used for the 95% CI. Vertical lines on survival curves indicate the SE of survival probability. Univariate analyses of survival and time to progression according to levels of RRM1 and ERCC1 and other factors (age, disease stage, performance status, and chemotherapy) were performed using a two-sided log-rank test. Because of the small sample size, bootstrap-like simulations were used to confirm results obtained from the log-rank test; Ps were determined for the statistical differences in median survival values when comparing RRM1 and ERCC1 mRNA expression levels. Multiple logistic-regression analysis was used to determine risk factors for time to progression. Spearman correlation coefficients were calculated to assess associations between the mRNA expression levels of RRM1 and ERCC1. Differences of P 0.05 were considered statistically significant. Calculations were performed with the SPSS software package, version 10.0.5 (SPSS Inc, Chicago, IL). Bootstrap analyses and graphics were performed with the S Plus 6 statistical package.

	RESULTS

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Patient Characteristics.
A total of 81 of 100 patients were assessable for RRM1 and ERCC1 mRNA expression levels. The remaining patients were not quantifiable because of fibrotic or necrotic tumor tissue. The clinical characteristics of patients in the three arms were similar (Table 1) . The median age was 59 years; 77 were male; 77% of patients had a performance status of 1. Forty-two % of patients had a weight loss of more than 5% in the previous 6 months. Eighty-five % had stage IV disease. Forty-three % had lung, 27% bone, 24% adrenal, and 18% liver metastases; other metastatic sites were observed at lower frequencies. Median survival for all 81 patients was 10.2 months; survival rate at 1 year was 41.3% and at 2 years was 18%. Median survival was 12.8 months in the gemcitabine/cisplatin arm, 11.1 months in the gemcitabine/cisplatin/vinorelbine arm, and 7.5 months in the sequential doublet arm (P = 0.600). Median time to progression was 7 months for the gemcitabine/cisplatin arm, 9 months for the gemcitabine/cisplatin/vinorelbine arm, and 5 months for the sequential doublet arm (P = 0.030).

Clinical Outcome According to Biological Markers.
Table 2 shows median survival and time to progression in the three treatment arms according to biological markers. Median survival was significantly longer in the gemcitabine/cisplatin arm among patients with low RRM1 levels. Median survival was 13.7 months (95% CI, 9.6–17.8 months) for patients with low levels and 3.6 months (95% CI, 0–8.1 months) for those with high levels (P = 0.009; Fig. 2A ). There was a tendency towards longer median survival and time to progression in the gemcitabine/cisplatin arm among patients with low ERCC1 levels, although the difference was not statistically significant. Median survival was 13.7 months (95% CI, 0.3–27 months) for patients with low levels and 9.5 months (95% CI, 6.3–12.8 months) for those with high levels (P = 0.190; Fig. 3A ). Figure 4 shows median survival and time to progression for each of the treatment arms according to levels of both RRM1 and ERCC1. Median survival was significantly longer in the gemcitabine/cisplatin arm among patients with low levels of both RRM1 and ERCC1. Median survival has not been reached for these patients, whereas patients with high levels of both genes had a median survival of 6.8 months (95% CI, 2.6–11.1 months). Patients with low levels of one gene and high levels of the other had a median survival of 8.3 months (95% CI, 0–21.7 months; P = 0.020; Table 2 ; Fig. 4A ). No other significant differences in median survival were observed according to gene expression levels (Table 2 ; Figs. 2 3 4 ).

View larger version (24K): [in this window] [in a new window]   Fig. 2. Kaplan-Meier estimates of survival and time to progression according to ribonucleotide reductase subunit M1 (RRM1) mRNA expression, as measured by quantitative PCR. A, survival for patients treated with gemcitabine plus cisplatin. B, survival for patients treated with gemcitabine plus cisplatin plus vinorelbine. C, survival for patients treated with gemcitabine plus vinorelbine followed by vinorelbine plus ifosfamide. D, time to progression for patients treated with gemcitabine plus cisplatin. E, time to progression for patients treated with gemcitabine plus cisplatin plus vinorelbine. F, time to progression for patients treated with gemcitabine plus vinorelbine followed by vinorelbine plus ifosfamide. Vertical lines, the SE of survival probability.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Kaplan-Meier estimates of survival and time to progression according to excision repair cross-complementing 1 (ERCC1) mRNA expression, as measured by quantitative PCR. A, survival for patients treated with gemcitabine plus cisplatin. B, survival for patients treated with gemcitabine plus cisplatin plus vinorelbine. C, survival for patients treated with gemcitabine plus vinorelbine followed by vinorelbine plus ifosfamide. D, time to progression for patients treated with gemcitabine plus cisplatin. E, time to progression for patients treated with gemcitabine plus cisplatin plus vinorelbine. F, time to progression for patients treated with gemcitabine plus vinorelbine followed by vinorelbine plus ifosfamide. Vertical lines, the SE of survival probability.

View larger version (34K): [in this window] [in a new window]   Fig. 4. Kaplan-Meier estimates of survival and time to progression according to ribonucleotide reductase subunit M1 (RRM1) and excision repair cross-complementing 1 (ERCC1) mRNA expression, as measured by quantitative PCR. A, survival for patients treated with gemcitabine plus cisplatin. B, survival for patients treated with gemcitabine plus cisplatin plus vinorelbine. C, survival for patients treated with gemcitabine plus vinorelbine followed by vinorelbine plus ifosfamide. D, time to progression for patients treated with gemcitabine plus cisplatin. E, time to progression for patients treated with gemcitabine plus cisplatin plus vinorelbine. F, time to progression for patients treated with gemcitabine plus vinorelbine followed by vinorelbine plus ifosfamide. Vertical lines, the SE of survival probability.

Significant differences in time to progression were observed only in the gemcitabine/cisplatin arm. Median time to progression was significantly longer in the gemcitabine/cisplatin arm among patients with low RRM1 levels. Median time to progression was 8.4 months (95% CI, 5.3–11.3 months) for patients with low levels and 2.7 months (95% CI, 2.5–2.9 months) for those with high levels (P = 0.020; Fig. 2D ). No significant differences in time to progression were observed in the other two treatment arms according to RRM1 levels (Table 2 ; Fig. 2, E and F ). Time to progression in the gemcitabine/cisplatin arm was 8.4 months (95% CI, 4.5–12.2 months) for patients with low ERCC1 levels and 5.1 months (95% CI, 1–9.3 months) for those with high levels (P = 0.070; Fig. 3D ). No significant differences were observed according to ERCC1 levels in the other treatment arms (Table 2 ; Fig. 3, B, C, E, and F ). Time to progression was significantly longer in the gemcitabine/cisplatin arm among patients with low levels of both RRM1 and ERCC1. Time to progression for these patients was 11 months (95% CI, 4.2–17.8 months), whereas patients with high levels of both genes had a time to progression of 2.7 months (95% CI, 2.6–2.9 months). Patients with low levels of one gene and high levels of the other had a time to progression of 5.1 months (95% CI, 3.3–6.9 months) (P = 0.030; Table 2 ; Fig. 4D ). No other significant differences were observed according to combined RRM1 and ERCC1 levels (Table 2 ; Fig. 4, B, C, E, and F ).

The logistic regression analysis of factors predictive of disease progression indicated that high RRM1 levels increased the risk of disease progression 4-fold for patients treated with gemcitabine/cisplatin (odds ratio, 4.3; 95% CI, 1.4–13.1; P = 0.009). However, the addition of vinorelbine to this combination significantly decreased the risk of disease progression for patients with high RRM1 levels (odds ratio, 0.25; 95% CI, 0.09–0.73; P = 0.01).

	DISCUSSION

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Pooled data on older randomized trials of cisplatin-based chemotherapy versus supportive care showed a hazard ratio of 0.73 in favor of chemotherapy, but with only a slight absolute improvement in 1-year survival of 10% (from 5% to 15%) and an increase in median survival of 1.5 months (18) . However, in more recent randomized trials, paclitaxel, gemcitabine, docetaxel, or vinorelbine in combination with a platinum compound have shown an absolute improvement of 15–20% for chemotherapy over best supportive care. One-year survival for best supportive care was 11–17% versus 30–35% for chemotherapy, and median survival improved by 3–4 months (19 , 20) . Although no single chemotherapy combination has demonstrated a clear overall superiority to any other in survival benefit (1 , 21) or in quality of life (21) in metastatic NSCLC, Fossella et al. (22) have recently shown an increase in median survival with docetaxel/cisplatin over vinorelbine/cisplatin.

We have previously observed that overexpression of ERCC1 (15) or RRM1 (23) is each separately correlated with strikingly shorter survival in gemcitabine/cisplatin (but not in vinorelbine/cisplatin)-treated stage IV NSCLC patients (23) . The present study is the first to report both a high correlation between ERCC1 and RRM1 mRNA levels and a specific effect of RRM1 expression on survival in gemcitabine/cisplatin-treated stage IV NSCLC.

The first suggestions of a relation between dysregulation of gene expression and differential cisplatin sensitivity are now emerging. Up-regulation of BRCA1, which is involved in transcription-coupled NER (24) , confers cisplatin resistance (25) . An association between the degree of BRCA1 expression and taxane sensitivity in an inducible breast cancer model cell line has also been reported (26) , and decreased BRCA1 mRNA expression enhanced cisplatin sensitivity and resistance to antimicrotubule agents (27) . Collectively, these preclinical and clinical findings indicate that antimicrotubule/cisplatin combinations could be active in NER-efficient tumors (those with high RRM1 levels). This hypothesis should be tested in tailored chemotherapy trials, in both early and advanced NSCLC, in which RRM1 could be used as a surrogate of NER functional status. Patients with low RRM1 levels could receive gemcitabine/cisplatin, whereas those with higher RRM1 levels could receive an antimicrotubule/cisplatin combination.

	ACKNOWLEDGMENTS

 
The following consultants and their colleagues entered patients on this study: Ulpiano Jimenez (Hospital Princesa, Madrid, Spain), Alfredo Carrato (Hospital de Elche, Elche, Spain), Pilar Garrido (Hospital Ramon y Cajal, Madrid, Spain), Amelia Insa (Hospital Clinico de Valencia, Valencia, Spain), Manuel Domine (Fundacion Jimenez Diaz, Madrid, Spain), Enriqueta Felip (Hospital Vall d’Hebron, Barcelona, Spain), Guillermo Lopez-Vivanco (Hospital Cruces, Bilbao, Spain), and Inmaculada Maestu (Hospital Virgen de los Lirios, Alcoy, Alicante, Spain). We are also grateful to Maria Sanchez-Ronco for assistance with the statistical analyses, and to Lourdes Franquet and Renée O’Brate for assistance with the manuscript.

	FOOTNOTES

 
Grant support: This research was funded in part by a grant from Eli Lilly and Company (master agreement 2001–2003) and in part by grants from Red Temática de Investigación Cooperativa de Centros de Cáncer and from Red Respira.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Rafael Rosell, Chief, Medical Oncology Service, Hospital Germans Trias i Pujol, Institut Català d’Oncologia, Ctra Canyet, s/n, 08916 Badalona (Barcelona), Spain. Phone: 34-93-497-89-25; Fax: 34-93-497-89-50; E-mail: rrosell{at}ns.hugtip.scs.es

Received 9/ 4/03; revised 10/14/03; accepted 10/17/03.

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