Original Article
DNA Synthesis and Repair Genes RRM1 and ERCC1 in Lung Cancer
N Engl J Med 2007; 356:800-808February 22, 2007
- Abstract
Background
RRM1, the regulatory subunit of ribonucleotide reductase, is involved in carcinogenesis, tumor progression, and the response of non–small-cell lung cancer to treatment.
Methods
We developed an automated quantitative determination of the RRM1 protein in routinely processed histologic specimens. In these specimens, we measured the expression of RRM1 and two other proteins that are relevant to non–small-cell lung cancer: the excision repair cross-complementation group 1 (ERCC1) protein and the phosphatase and tensin homologue (PTEN). We compared the results with the clinical outcomes in 187 patients with early-stage non–small-cell lung cancer who had received only surgical treatment.
Results
RRM1 expression correlated with the expression of ERCC1 (P<0.001) but not with the expression of PTEN (P=0.37). The median disease-free survival exceeded 120 months in the group of patients with tumors that had high expression of RRM1 and was 54.5 months in the group with low expression of RRM1 (hazard ratio for disease progression or death in the high-expression group, 0.46; P=0.004). The overall survival was more than 120 months for patients with tumors with high expression of RRM1 and 60.2 months for those with low expression of RRM1 (hazard ratio for death, 0.61; P=0.02). Among these 187 patients, the survival advantage was limited to the 30% of patients with tumors that had a high expression of both RRM1 and ERCC1.
Conclusions
RRM1 and ERCC1 are determinants of survival after surgical treatment of early-stage, non–small-cell lung cancer.
Media in This Article
Figure 1
Immunoblots of Lung-Cancer Cell Lines.Figure 2
Confocal Microscopy of RRM1, ERCC1, and PTEN Expression in Cell Line NCI-H23.Article Activity
- Article
Lung cancer accounts for more than one fourth of all cancer-related deaths in the United States, despite improvements in diagnosis and management.1 Only recently have molecular markers become integrated into decisions about the treatment of lung cancer, largely through the discovery of mutations in the epidermal growth factor receptor that are predictive of the response to gefitinib and erlotinib.2-4 Other promising leads have not yet become clinically useful because of a lack of validation or complex technical requirements.5-8
RRM1, the gene that encodes the regulatory subunit of ribonucleotide reductase, is important in non–small-cell lung cancer. It is located on chromosome segment 11p15.5, a region with a frequent loss of heterozygosity in non–small-cell lung cancer.8-10 Low levels of expression of the gene are associated with poor survival among patients with non–small-cell lung cancer.11 In genetically modified lung-cancer cells, an increase in the expression of the RRM1 protein increases the expression of the phosphatase and tensin homologue (PTEN), an inhibitor of cell proliferation; decreases the phosphorylation of focal adhesion kinase; and decreases cell migration and invasiveness.12 Neoplastic mouse fibroblasts with increased expression of an RRM1 transgene have reduced metastatic potential,13 and in transgenic mice, high levels of RRM1 are associated with resistance to carcinogen-induced lung tumors.14 RRM1 is also the predominant cellular determinant of the efficacy of the nucleoside analogue gemcitabine (2′,2′-difluorodeoxycytidine).15-17 Gemcitabine, platinum analogues, and taxenes are the principal agents in chemotherapy for non–small-cell lung cancer.18-21
We describe a simple, automated, immunohistochemical method for the determination of RRM1 expression in tumors, the subcellular localization of RRM1, the association between the RRM1 protein and its messenger RNA (mRNA), and the association of RRM1 with PTEN and with the excision repair cross-complementation group 1 (ERCC1) protein in non–small-cell lung cancer. We also describe the use of this method to validate RRM1 as a marker of the clinical outcome in a large cohort of patients with non–small-cell lung cancer.
Methods
Patients
The patients were a subgroup of all patients who underwent thoracotomy for resection of a primary lung cancer at the H. Lee Moffitt Cancer Center and Research Institute between 1991 and 2001. Patients were eligible for inclusion in the study if they had an adenocarcinoma, squamous-cell carcinoma, or large-cell carcinoma; had undergone a complete resection of the tumor (R0 resection); and had stage I disease by pathological staging. Patients with a previous nonlung cancer were included if the disease was deemed cured. Exclusion criteria were a previous lung cancer, preoperative chemotherapy or radiotherapy, and any previous radiotherapy to the chest. Staging studies had to include a physical examination and computed tomography of the chest and upper abdomen. None of the patients underwent 18F-fluorodeoxyglucose positron-emission tomography for staging, and none received any form of adjuvant therapy. Sufficient amounts of tissue from the primary tumor had to be available for construction of tissue microarrays. We identified 187 patients who met these criteria.
Follow-up data for overall survival, disease-free survival, and sites of tumor recurrence were obtained at regular intervals. We recommended that patients have follow-up visits every 3 months for 2 years, then visits every 6 months for 3 years, and then annual visits. The follow-up results from outside physicians were obtained by regular mail and telephone contacts. For data on overall survival, the time from diagnosis to death was recorded. The vital status of the patients was verified with the use of vital statistics records. For disease-free survival, the time from surgical resection to recurrence or death was recorded. Data for patients without tumor recurrence were censored at the time of the last follow-up visit. Table 1Table 1
Characteristics of the 187 Patients in the Study Population. summarizes pertinent clinical information. The study was approved by the institutional review board of the University of South Florida.In Situ Detection and Quantification of Protein Expression
A tissue microarray was constructed. Immunofluorescence combined with automated quantitative analysis (AQUA) was used to assess in situ expression of the target molecules.22 Antigens were retrieved by incubating the tissue in a microwave oven.23 Optimal concentrations of antiserum samples and antibodies were used to detect RRM1, PTEN, ERCC1, and cytokeratin. Samples of antiserum to RRM1 fragments were generated from rabbits and affinity-purified. Commercial antibodies were used for the analysis of ERCC1 (Ab-2 clone 8F1, MS-671-R7, Laboratory Vision), PTEN (A2B1, sc-7974, Santa Cruz Biotech), and cytokeratin (antihuman pancytokeratin AE1/AE3, M3515, and Z0622, Dako Cytomation). They were visualized with the use of fluorochrome-labeled antiserum samples. The final slides were scanned with SpotGrabber (HistoRx), and image data were analyzed with AQUA (PM-2000, HistoRx). The final AQUA scores range from 0 (no expression) to 255 (maximal expression) (see the Supplementary Appendix, available with the full text of this article at www.nejm.org).
RNA Isolation and Gene-Expression Analysis
Fresh-frozen and formalin-fixed, paraffin-embedded tumor specimens were obtained from 44 patients. The fresh-frozen specimens were processed for RNA isolation, and quantitative, real-time, reverse-transcriptase polymerase chain reaction (RT-PCR)–based expression analysis for the RRM1, PTEN, and ERCC1 genes and for 18S–ribosomal RNA as previously described.11,24
Statistical Analysis
The average values for the AQUA scores from triplicate readings were calculated for each gene and treated as independent continuous variables. The RNA-based gene-expression analysis was likewise treated as an independent continuous variable. Correlation coefficients between gene-expression variables and among the genes were calculated as continuous variables according to Spearman's rank-correlation coefficient (rho), and two-tailed significance levels were calculated. We made an a priori decision to classify gene-expression values as high or low, using the sample median for the analysis of survival; this classification was done with the use of Kaplan–Meier estimates and the log-rank test. The primary objective was to determine the association between RRM1 expression in the tumor and survival. Secondary objectives were to assess the associations between the expression of RRM1 and ERCC1, between RRM1 and PTEN, and between mRNA and protein levels of RRM1. The associations between gene expression and discrete clinical values were analyzed with the use of the Wilcoxon rank-sum test for variables with two categories and the Kruskal–Wallis test for variables with more than two categories. A Cox regression analysis was performed to assess the effect of gene expression, with adjustment for tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, sex, and smoking status.
Results
Expression of RRM1 and Its Corresponding mRNA
Samples of antiserum to RRM1 peptides were generated and designated R1AS-1 to R1AS-10. Specificity for the RRM1 protein was shown, and immunoreactivity was found in the nuclear extracts of lung-cancer cell lines (Figure 1Figure 1
Immunoblots of Lung-Cancer Cell Lines.). With the use of confocal microscopy, RRM1 staining showed a coarse nuclear pattern (Figure 2Figure 2Confocal Microscopy of RRM1, ERCC1, and PTEN Expression in Cell Line NCI-H23.). ERCC1 and PTEN were included in the analysis because previous data had suggested a positive correlation in the levels of expression among these genes. ERCC1 was predominantly located in the nucleus and had a fine granular pattern, whereas PTEN was mostly located in the cytoplasm.Using the AQUA technique, we assessed RRM1 expression with R1AS-6 and R1AS-10 in a microarray. This array contained triplicates of 25 specimens of a variety of human tissues, including 12 non–small-cell lung-cancer specimens. In all tissues, RRM1 expression showed a granular nuclear pattern, and analysis of both antiserum samples confirmed the results obtained in the cell lines (Figure 2). The gene-expression scores ranged from 20.3 to 200.5 (median, 114.1; mean, 111.0) for R1AS-6 and from 36.1 to 182.7 (median, 85.4; mean, 93.5) for R1AS-10. RRM1 expression was highest in the small intestine, renal cortex, and stomach and lowest in the epidermis, larynx, and trachea.
Tumor specimens from 44 patients were available for the analysis of RRM1 protein and RNA. With the R1AS-6 antiserum sample, there was significant correlation between the RRM1 protein and its mRNA (Spearman's rho=0.41, P=0.004). The same 44 specimens were also analyzed for ERCC1 and PTEN and mRNA. There was no significant correlation between protein and mRNA expression for ERCC1 (rho=0.1, P>0.30) or for PTEN (rho=0.1, P>0.30).
RRM1 and Survival after Surgical Resection
We constructed a tissue microarray with the use of triplicate 0.6-mm cores from formalin-fixed and paraffin-embedded specimens of the primary tumor. The analysis of RRM1 expression by AQUA with R1AS-6 was performed on specimens obtained from 187 patients who had undergone complete surgical resection for stage I non–small-cell lung cancer and had not received chemotherapy or radiation therapy before resection. R1AS-6 was selected instead of R1AS-10 because of its better correlation with the expression of RRM1 RNA and its greater dynamic range of expression. In addition, the specific staining conditions were better suited to the simultaneous identification of nuclei, cytokeratin, and RRM1. The AQUA score ranged from 8.3 to 96.2 (median, 40.5; mean, 43.2) for all specimens. The median value for RRM1 expression was chosen a priori to divide the patient groups into a high-expression group and a low-expression group.
The median disease-free survival for patients with tumors that had low levels of RRM1 (gene-expression score, <40.5) was 54.5 months (95% confidence interval [CI], 32.9 to 74.2). For patients with tumors that had high levels of RRM1 (gene-expression score, >40.5), the median disease-free survival was more than 120.0 months. This difference was statistically significant (P=0.004; hazard ratio for low vs. high expression, 2.2) (Figure 3AFigure 3
Kaplan–Meier Estimates of Disease-free Survival and Overall Survival among 187 Patients with Completely Resected, Stage I Non–Small-Cell Lung Cancer, According to RRM1 Expression Level.). The median overall survival was 60.2 months (95% CI, 47.3 to 88.2) for patients with tumors with low levels of RRM1 and more than 120 months for those with high levels of RRM1. This difference was significant (P=0.02; hazard ratio for death for patients with RRM1 levels, 1.6) (Figure 3B). In a multivariate analysis that included RRM1 expression, tumor stage, ECOG performance status, sex, and smoking status, RRM1 was the only variable that was significantly associated with disease-free survival (P=0.03); the association with overall survival, however, was not statistically significant (P=0.11).There was no significant association between RRM1 expression and tumor stage, histologic type, or age, sex, ECOG performance status, absence or presence of weight loss, and smoking status (Table 1).
Association of RRM1 Expression with ERCC1 and PTEN Expression
AQUA scores for RRM1, PTEN, and ERCC1 expression in 184 patients were available. The scores for RRM1 were not correlated with those for PTEN (rho=−0.07, P>0.37), and PTEN expression was not significantly associated with survival (P=0.08 for disease-free survival, and P=0.11 for overall survival). However, the AQUA scores were significantly correlated with ERCC1 (rho=0.3, P<0.001) (Figure 4Figure 4
Scatter Plot Comparing RRM1 and ERCC1 Protein Expression.), and ERCC1 expression was associated with survival (P=0.11 for disease-free survival and P=0.01 for overall survival). We grouped the 184 patients with scores for both proteins into four categories. With the median scores for RRM1 and ERCC1 used as cutoff values (Figure 4), 55 patients had tumors with high expression of both proteins (high/high), 54 had low expression of both (low/low), 38 had high RRM1 expression and low ERCC1 expression (high/low), and 37 had low RRM1 and high ERCC1 (low/high). Kaplan–Meier survival curves were generated (Figure 5Figure 5
Disease-free Survival and Overall Survival among 184 Patients with AQUA Scores for RRM1 and ERCC1.), and the log-rank test was used to test for significant differences among these groups. Patients in the high/high group had a median disease-free survival and a median overall survival of more than 120 months, which were significantly longer than those for the patients in the other groups (P=0.01 for disease-free survival, and P=0.02 for overall survival). The outcomes for patients in the high/low group (disease-free survival, 56.0 months; overall survival, 80.0 months), the low/high group (disease-free survival, 51.0 months; overall survival, 56.8 months), and the low/low group (disease-free survival, 61.4 months; overall survival, 66.5 months) were similar (P>0.51 for disease-free survival, and P>0.73 for overall survival).Discussion
RRM1 is involved in tumor invasiveness and metastasis.12,13 PTEN, a bifunctional phosphatase that regulates cellular signaling, survival, and migration,25 is thought to mediate these effects of RRM1. The increased expression of RRM1 decreases the formation of metastases, inhibits the development of carcinogen-induced lung tumors, and prolongs survival in tumor-bearing mice.12-14 An association between high expression of RRM1, as determined by quantitative, real-time RT-PCR, and prolonged survival has been reported in patients with non–small-cell lung cancer.11 Similar data were reported for ERCC1.24 Results from small data sets have suggested coordinate expression of RRM1 and ERCC1 in non–small-cell lung cancer.17,26 Recent data have provided evidence of a strong association between the expression of nuclear ERCC1, as measured by visual immunohistochemical scoring, and clinical outcome.27
Analysis of the RRM1 protein in non–small-cell lung-cancer specimens has not been possible to date because of technical limitations. Our study showed that the RRM1 protein in non–small-cell lung-cancer cells is nuclear, highly correlated with ERCC1 expression, and significantly associated with disease-free and overall survival. Our data show that the coordinate high expression of RRM1 and ERCC1 defines a subgroup of patients with an excellent outcome. These patients accounted for approximately 30% of our patients (55 of 184) who underwent potentially curative lung-cancer surgery. Although the high expression of either protein alone was associated with a good prognosis, coexpression of the two proteins characterized the group with an excellent outcome (Figure 5).
The apparent lack of an association between RRM1 and PTEN contrasts with the previously reported positive correlation between these genes at the RNA level.11 This discrepancy may be due to differential, post-translational processing or compartmentalization for PTEN and RRM1 or to technical issues.28,29
Previously, the determination of RRM1 expression was technically difficult. However, with the development of an immunohistochemical technique and the integration of a fully automated and quantitative system, the gene-expression analysis for RRM1 and ERCC1 is now objective, reliable, and reproducible.22
This technical development is important in the context of recent data showing that high levels of expression of RRM1 and ERCC1 are predictive of the resistance of non–small-cell lung cancer to gemcitabine and platinum.17 Moreover, there are encouraging preliminary data from trials using RNA-based expression analysis of these genes for decision making about treatment.30,31 Given that high levels of expression of both genes are associated with long survival among patients with completely resected lung cancer and are also associated with a poor response to chemotherapy containing gemcitabine and platinum, a trial comparing the current standard of care with adjuvant treatment selected on the basis of RRM1 and ERCC1 expression appears to be warranted.
Supported in part by grants (R01-CA102726 and R21-CA110487) from the National Cancer Institute and from donations by Ann and David Murphey and Amy and James Shimberg.
Dr. Bepler reports having a patent application pending on the use of RRM1 with or without ERCC1 as a prognostic marker of outcome in cancer and for the prediction of response to therapy. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Address reprint requests to Dr. Bepler at the H. Lee Moffitt Cancer Center and Research Institute, MRC-4W, Rm. 4046, 12902 Magnolia Dr., Tampa, FL 33612-9497, or at beplerg@moffitt.usf.edu.
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