Background RRM1, the regulatory subunit of ribonucleotide reductase,is involved in carcinogenesis, tumor progression, and the responseof non–small-cell lung cancer to treatment.
Methods We developed an automated quantitative determinationof the RRM1 protein in routinely processed histologic specimens.In these specimens, we measured the expression of RRM1 and twoother proteins that are relevant to non–small-cell lungcancer: the excision repair cross-complementation group 1 (ERCC1)protein and the phosphatase and tensin homologue (PTEN). Wecompared the results with the clinical outcomes in 187 patientswith early-stage non–small-cell lung cancer who had receivedonly surgical treatment.
Results RRM1 expression correlated with the expression of ERCC1(P<0.001) but not with the expression of PTEN (P=0.37). Themedian disease-free survival exceeded 120 months in the groupof patients with tumors that had high expression of RRM1 andwas 54.5 months in the group with low expression of RRM1 (hazardratio for disease progression or death in the high-expressiongroup, 0.46; P=0.004). The overall survival was more than 120months for patients with tumors with high expression of RRM1and 60.2 months for those with low expression of RRM1 (hazardratio for death, 0.61; P=0.02). Among these 187 patients, thesurvival advantage was limited to the 30% of patients with tumorsthat had a high expression of both RRM1 and ERCC1.
Conclusions RRM1 and ERCC1 are determinants of survival aftersurgical treatment of early-stage, non–small-cell lungcancer.
Lung cancer accounts for more than one fourth of all cancer-relateddeaths in the United States, despite improvements in diagnosisand management.1 Only recently have molecular markers becomeintegrated into decisions about the treatment of lung cancer,largely through the discovery of mutations in the epidermalgrowth factor receptor that are predictive of the response togefitinib and erlotinib.2,3,4 Other promising leads have notyet become clinically useful because of a lack of validationor complex technical requirements.5,6,7,8
RRM1, the gene that encodes the regulatory subunit of ribonucleotidereductase, is important in non–small-cell lung cancer.It is located on chromosome segment 11p15.5, a region with afrequent loss of heterozygosity in non–small-cell lungcancer.8,9,10 Low levels of expression of the gene are associatedwith poor survival among patients with non–small-celllung cancer.11 In genetically modified lung-cancer cells, anincrease in the expression of the RRM1 protein increases theexpression of the phosphatase and tensin homologue (PTEN), aninhibitor of cell proliferation; decreases the phosphorylationof focal adhesion kinase; and decreases cell migration and invasiveness.12Neoplastic mouse fibroblasts with increased expression of anRRM1 transgene have reduced metastatic potential,13 and in transgenicmice, high levels of RRM1 are associated with resistance tocarcinogen-induced lung tumors.14 RRM1 is also the predominantcellular determinant of the efficacy of the nucleoside analoguegemcitabine (2',2'-difluorodeoxycytidine).15,16,17 Gemcitabine,platinum analogues, and taxenes are the principal agents inchemotherapy for non–small-cell lung cancer.18,19,20,21
We describe a simple, automated, immunohistochemical methodfor the determination of RRM1 expression in tumors, the subcellularlocalization of RRM1, the association between the RRM1 proteinand its messenger RNA (mRNA), and the association of RRM1 withPTEN and with the excision repair cross-complementation group1 (ERCC1) protein in non–small-cell lung cancer. We alsodescribe the use of this method to validate RRM1 as a markerof the clinical outcome in a large cohort of patients with non–small-celllung cancer.
Methods
Patients
The patients were a subgroup of all patients who underwent thoracotomyfor resection of a primary lung cancer at the H. Lee MoffittCancer Center and Research Institute between 1991 and 2001.Patients were eligible for inclusion in the study if they hadan 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 witha previous nonlung cancer were included if the disease was deemedcured. Exclusion criteria were a previous lung cancer, preoperativechemotherapy or radiotherapy, and any previous radiotherapyto the chest. Staging studies had to include a physical examinationand computed tomography of the chest and upper abdomen. Noneof the patients underwent 18F-fluorodeoxyglucose positron-emissiontomography for staging, and none received any form of adjuvanttherapy. Sufficient amounts of tissue from the primary tumorhad 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 monthsfor 2 years, then visits every 6 months for 3 years, and thenannual visits. The follow-up results from outside physicianswere obtained by regular mail and telephone contacts. For dataon overall survival, the time from diagnosis to death was recorded.The vital status of the patients was verified with the use ofvital statistics records. For disease-free survival, the timefrom surgical resection to recurrence or death was recorded.Data for patients without tumor recurrence were censored atthe time of the last follow-up visit. Table 1 summarizes pertinentclinical information. The study was approved by the institutionalreview board of the University of South Florida.
Table 1. Characteristics of the 187 Patients in the Study Population.
In Situ Detection and Quantification of Protein Expression
A tissue microarray was constructed. Immunofluorescence combinedwith automated quantitative analysis (AQUA) was used to assessin situ expression of the target molecules.22 Antigens wereretrieved by incubating the tissue in a microwave oven.23 Optimalconcentrations of antiserum samples and antibodies were usedto detect RRM1, PTEN, ERCC1, and cytokeratin. Samples of antiserumto RRM1 fragments were generated from rabbits and affinity-purified.Commercial antibodies were used for the analysis of ERCC1 (Ab-2clone 8F1, MS-671-R7, Laboratory Vision), PTEN (A2B1, sc-7974,Santa Cruz Biotech), and cytokeratin (antihuman pancytokeratinAE1/AE3, M3515, and Z0622, Dako Cytomation). They were visualizedwith the use of fluorochrome-labeled antiserum samples. Thefinal slides were scanned with SpotGrabber (HistoRx), and imagedata were analyzed with AQUA (PM-2000, HistoRx). The final AQUAscores range from 0 (no expression) to 255 (maximal expression)(see the Supplementary Appendix, available with the full textof this article at www.nejm.org).
RNA Isolation and Gene-Expression Analysis
Fresh-frozen and formalin-fixed, paraffin-embedded tumor specimenswere obtained from 44 patients. The fresh-frozen specimens wereprocessed for RNA isolation, and quantitative, real-time, reverse-transcriptasepolymerase chain reaction (RT-PCR)–based expression analysisfor the RRM1, PTEN, and ERCC1 genes and for 18S–ribosomalRNA as previously described.11,24
Statistical Analysis
The average values for the AQUA scores from triplicate readingswere calculated for each gene and treated as independent continuousvariables. The RNA-based gene-expression analysis was likewisetreated as an independent continuous variable. Correlation coefficientsbetween gene-expression variables and among the genes were calculatedas continuous variables according to Spearman's rank-correlationcoefficient (rho), and two-tailed significance levels were calculated.We made an a priori decision to classify gene-expression valuesas high or low, using the sample median for the analysis ofsurvival; this classification was done with the use of Kaplan–Meierestimates and the log-rank test. The primary objective was todetermine the association between RRM1 expression in the tumorand survival. Secondary objectives were to assess the associationsbetween the expression of RRM1 and ERCC1, between RRM1 and PTEN,and between mRNA and protein levels of RRM1. The associationsbetween gene expression and discrete clinical values were analyzedwith the use of the Wilcoxon rank-sum test for variables withtwo categories and the Kruskal–Wallis test for variableswith more than two categories. A Cox regression analysis wasperformed to assess the effect of gene expression, with adjustmentfor tumor stage, Eastern Cooperative Oncology Group (ECOG) performancestatus, sex, and smoking status.
Results
Expression of RRM1 and Its Corresponding mRNA
Samples of antiserum to RRM1 peptides were generated and designatedR1AS-1 to R1AS-10. Specificity for the RRM1 protein was shown,and immunoreactivity was found in the nuclear extracts of lung-cancercell lines (Figure 1). With the use of confocal microscopy,RRM1 staining showed a coarse nuclear pattern (Figure 2). ERCC1and PTEN were included in the analysis because previous datahad suggested a positive correlation in the levels of expressionamong these genes. ERCC1 was predominantly located in the nucleusand had a fine granular pattern, whereas PTEN was mostly locatedin the cytoplasm.
RRM1 was visualized in cell line NCI-H23 with the use of the designated antiserum samples and the only commercially available antibody, mouse clone AD203 (Chemicon). Adsorption of the antiserum samples with the respective peptide used for their generation resulted in the disappearance of the RRM1 band. None denotes no peptide blockage, 6 denotes blockage with peptide 6, 7 denotes blockage with peptide 7, and 10 denotes blockage with peptide 10 (Panel A). Nuclear and cytosolic extracts were prepared from cell lines H23-Ct and H23-R1 and probed with the use of R1AS-6, R1AS-10, and commercial ERCC1 and PTEN antibodies. Oct-1 was used as a nuclear marker and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a cytoplasmic marker (Panel B).
Figure 2. Confocal Microscopy of RRM1, ERCC1, and PTEN Expression in Cell Line NCI-H23.
Panels A and B show nuclei labeled with 4',6-diamidine-2-phenylindole (DAPI, blue). RRM1 was visualized with the use of R1AS-6 labeled with Alexa 488 (green). ERCC1 and PTEN were visualized with the use of commercial antibodies labeled with Alexa 555 (red). During the interphase, RRM1 is only nuclear, ERCC1 is predominantly nuclear, and PTEN is predominantly cytoplasmic. Panel C shows multitarget immunofluorescence labeling of formaldehyde-fixed and paraffin-embedded histologic sections of lung cancer. The nuclei are blue, RRM1 is green, and the tumor cytoplasm is red. RRM1 is located in the nucleus and displays a granular pattern.
Using the AQUA technique, we assessed RRM1 expression with R1AS-6and R1AS-10 in a microarray. This array contained triplicatesof 25 specimens of a variety of human tissues, including 12non–small-cell lung-cancer specimens. In all tissues,RRM1 expression showed a granular nuclear pattern, and analysisof both antiserum samples confirmed the results obtained inthe cell lines (Figure 2). The gene-expression scores rangedfrom 20.3 to 200.5 (median, 114.1; mean, 111.0) for R1AS-6 andfrom 36.1 to 182.7 (median, 85.4; mean, 93.5) for R1AS-10. RRM1expression 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 analysisof RRM1 protein and RNA. With the R1AS-6 antiserum sample, therewas significant correlation between the RRM1 protein and itsmRNA (Spearman's rho=0.41, P=0.004). The same 44 specimens werealso analyzed for ERCC1 and PTEN and mRNA. There was no significantcorrelation 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 triplicate0.6-mm cores from formalin-fixed and paraffin-embedded specimensof the primary tumor. The analysis of RRM1 expression by AQUAwith R1AS-6 was performed on specimens obtained from 187 patientswho had undergone complete surgical resection for stage I non–small-celllung cancer and had not received chemotherapy or radiation therapybefore resection. R1AS-6 was selected instead of R1AS-10 becauseof its better correlation with the expression of RRM1 RNA andits greater dynamic range of expression. In addition, the specificstaining conditions were better suited to the simultaneous identificationof nuclei, cytokeratin, and RRM1. The AQUA score ranged from8.3 to 96.2 (median, 40.5; mean, 43.2) for all specimens. Themedian value for RRM1 expression was chosen a priori to dividethe patient groups into a high-expression group and a low-expressiongroup.
The median disease-free survival for patients with tumors thathad low levels of RRM1 (gene-expression score, <40.5) was54.5 months (95% confidence interval [CI], 32.9 to 74.2). Forpatients with tumors that had high levels of RRM1 (gene-expressionscore, >40.5), the median disease-free survival was morethan 120.0 months. This difference was statistically significant(P=0.004; hazard ratio for low vs. high expression, 2.2) (Figure 3A).The median overall survival was 60.2 months (95% CI, 47.3 to88.2) for patients with tumors with low levels of RRM1 and morethan 120 months for those with high levels of RRM1. This differencewas significant (P=0.02; hazard ratio for death for patientswith RRM1 levels, 1.6) (Figure 3B). In a multivariate analysisthat included RRM1 expression, tumor stage, ECOG performancestatus, sex, and smoking status, RRM1 was the only variablethat was significantly associated with disease-free survival(P=0.03); the association with overall survival, however, wasnot statistically significant (P=0.11).
Figure 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 value for RRM1 protein expression (determined with R1AS-6 and AQUA scoring) was used to divide the patients into high-expression and low-expression groups.
There was no significant association between RRM1 expressionand tumor stage, histologic type, or age, sex, ECOG performancestatus, 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 patientswere available. The scores for RRM1 were not correlated withthose for PTEN (rho=–0.07, P>0.37), and PTEN expressionwas not significantly associated with survival (P=0.08 for disease-freesurvival, and P=0.11 for overall survival). However, the AQUAscores were significantly correlated with ERCC1 (rho=0.3, P<0.001)(Figure 4), 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 intofour categories. With the median scores for RRM1 and ERCC1 usedas cutoff values (Figure 4), 55 patients had tumors with highexpression of both proteins (high/high), 54 had low expressionof both (low/low), 38 had high RRM1 expression and low ERCC1expression (high/low), and 37 had low RRM1 and high ERCC1 (low/high).Kaplan–Meier survival curves were generated (Figure 5),and the log-rank test was used to test for significant differencesamong these groups. Patients in the high/high group had a mediandisease-free survival and a median overall survival of morethan 120 months, which were significantly longer than thosefor the patients in the other groups (P=0.01 for disease-freesurvival, and P=0.02 for overall survival). The outcomes forpatients in the high/low group (disease-free survival, 56.0months; overall survival, 80.0 months), the low/high group (disease-freesurvival, 51.0 months; overall survival, 56.8 months), and thelow/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).
Figure 4. Scatter Plot Comparing RRM1 and ERCC1 Protein Expression.
Data are based on AQUA scores in triplicate specimens from 184 patients with lung cancer. The horizontal line indicates the median score for ERCC1 (65.9), and the vertical line indicates the median score for RRM1 (40.5).
Figure 5. Disease-free Survival and Overall Survival among 184 Patients with AQUA Scores for RRM1 and ERCC1.
Discussion
RRM1 is involved in tumor invasiveness and metastasis.12,13PTEN, a bifunctional phosphatase that regulates cellular signaling,survival, and migration,25 is thought to mediate these effectsof RRM1. The increased expression of RRM1 decreases the formationof metastases, inhibits the development of carcinogen-inducedlung tumors, and prolongs survival in tumor-bearing mice.12,13,14An association between high expression of RRM1, as determinedby quantitative, real-time RT-PCR, and prolonged survival hasbeen reported in patients with non–small-cell lung cancer.11Similar data were reported for ERCC1.24 Results from small datasets have suggested coordinate expression of RRM1 and ERCC1in non–small-cell lung cancer.17,26 Recent data have providedevidence of a strong association between the expression of nuclearERCC1, as measured by visual immunohistochemical scoring, andclinical outcome.27
Analysis of the RRM1 protein in non–small-cell lung-cancerspecimens has not been possible to date because of technicallimitations. Our study showed that the RRM1 protein in non–small-celllung-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 andERCC1 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 associatedwith a good prognosis, coexpression of the two proteins characterizedthe group with an excellent outcome (Figure 5).
The apparent lack of an association between RRM1 and PTEN contrastswith the previously reported positive correlation between thesegenes at the RNA level.11 This discrepancy may be due to differential,post-translational processing or compartmentalization for PTENand RRM1 or to technical issues.28,29
Previously, the determination of RRM1 expression was technicallydifficult. However, with the development of an immunohistochemicaltechnique and the integration of a fully automated and quantitativesystem, the gene-expression analysis for RRM1 and ERCC1 is nowobjective, reliable, and reproducible.22
This technical development is important in the context of recentdata showing that high levels of expression of RRM1 and ERCC1are predictive of the resistance of non–small-cell lungcancer to gemcitabine and platinum.17 Moreover, there are encouragingpreliminary data from trials using RNA-based expression analysisof these genes for decision making about treatment.30,31 Giventhat high levels of expression of both genes are associatedwith long survival among patients with completely resected lungcancer and are also associated with a poor response to chemotherapycontaining gemcitabine and platinum, a trial comparing the currentstandard of care with adjuvant treatment selected on the basisof 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 Annand David Murphey and Amy and James Shimberg.
Dr. Bepler reports having a patent application pending on theuse of RRM1 with or without ERCC1 as a prognostic marker ofoutcome in cancer and for the prediction of response to therapy.No other potential conflict of interest relevant to this articlewas 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{at}moffitt.usf.edu.
References
Ruckdeschel JC, Schwartz AG, Bepler G, et al. Cancer of the lung: NSCLC and SCLC. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. Philadelphia: Elsevier, 2004:1649-743.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139. [Free Full Text]
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500. [Free Full Text]
Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer -- molecular and clinical predictors of outcome. N Engl J Med 2005;353:133-144. [Erratum, N Engl J Med 2006;355:1746.] [Free Full Text]
Rodenhuis S, van de Wetering ML, Mooi WJ, Evers SG, van Zandwijk N, Bos JL. Mutational activation of the K-ras oncogene: a possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med 1987;317:929-935. [Abstract]
Pezzella F, Turley H, Kuzu I, et al. bcl-2 Protein in non-small-cell lung carcinoma. N Engl J Med 1993;329:690-694. [Free Full Text]
Carbone DP, Mitsudomi T, Chiba I, et al. p53 Immunostaining positivity is associated with reduced survival and is imperfectly correlated with gene mutations in resected non-small cell lung cancer: a preliminary report of LCSG 871. Chest 1994;106:Suppl:377S-381S. [Medline]
Bepler G, Gautam A, McIntyre LM, et al. Prognostic significance of molecular genetic aberrations on chromosome segment 11p15.5 in non-small-cell lung cancer. J Clin Oncol 2002;20:1353-1360. [Free Full Text]
Bepler G, Garcia-Blanco MA. Three tumor-suppressor regions on chromosome 11p identified by high-resolution deletion mapping in human non-small-cell lung cancer. Proc Natl Acad Sci U S A 1994;91:5513-5517. [Free Full Text]
Pitterle DM, Kim YC, Jolicoeur EMC, Cao Y, O'Briant KC, Bepler G. Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1). Mamm Genome 1999;10:916-922. [CrossRef][Web of Science][Medline]
Bepler G, Sharma S, Cantor A, et al. RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol 2004;22:1878-1885. [Free Full Text]
Gautam A, Li ZR, Bepler G. RRM1-induced metastasis suppression through PTEN-regulated pathways. Oncogene 2003;22:2135-2142. [CrossRef][Web of Science][Medline]
Fan H, Huang A, Villegas C, Wright JA. The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments. Proc Natl Acad Sci U S A 1997;94:13181-13186. [Free Full Text]
Gautam A, Bepler G. Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. Cancer Res 2006;66:6497-6502. [Free Full Text]
Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res 2004;64:3761-3766. [Free Full Text]
Bergman AM, Eijk PP, van Haperen VW, et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as a major determinant. Cancer Res 2005;65:9510-9516. [Free Full Text]
Bepler G, Kusmartseva I, Sharma S, et al. RRM1-modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 2006;24:4731-4737. [Free Full Text]
Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2000;18:122-130. [Free Full Text]
Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98. [Free Full Text]
Gridelli C, Gallo C, Shepherd FA, et al. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:3025-3034. [Free Full Text]
Treat J, Belani C, Edelman M, et al. A randomized phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in advanced non-small cell lung cancer: update of the Alpha Oncology trial (A1-99002L). Proc Am Soc Clin Oncol 2005;23:627s.
Camp RL, Chung GG, Rimm DL. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med 2002;8:1323-1327. [CrossRef][Web of Science][Medline]
Shi SR, Cote RJ, Taylor CR. Antigen retrieval immunohistochemistry: past, present, and future. J Histochem Cytochem 1997;45:327-343. [Free Full Text]
Simon GR, Sharma S, Cantor A, Smith P, Bepler G. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest 2005;127:978-983. [CrossRef][Web of Science][Medline]
Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943-1947. [Free Full Text]
Ceppi P, Volante M, Novello S, et al. ERCC1 and RRM1 gene expression but not EGFR are predictive of shorter survival in advanced non-small cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 2006;17:1818-1825. [Free Full Text]
Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983-991. [Free Full Text]
Bertheau P, Cazals-Hatem D, Meignin V, et al. Variability of immunohistochemical reactivity on stored paraffin slides. J Clin Pathol 1998;51:370-374. [Abstract]
McCabe A, Dolled-Filhart M, Camp RL, Rimm DL. Automated quantitative analysis (AQUA) of in situ protein expression, antibody concentration, and prognosis. J Natl Cancer Inst 2005;97:1808-1815. [Free Full Text]
Rosell R, Cobo M, Isla D, et al. ERCC1 mRNA-based randomized phase III trial of docetaxel doublets with cisplatin or gemcitabine in stage IV non-small-cell lung cancer patients. Proc Am Soc Clin Oncol 2005;23:621s.
Bepler G, Li X, Sharma A, et al. Clinical value of tumoral RRM1 and ERCC1 expression for treatment response and therapeutic decisions in NSCLC. In: Perry MC, ed. ASCO 2006 educational book. Alexandria, VA: American Society of Clinical Oncology, 2006:431-3.
ERCC1 and Non–Small-Cell Lung Cancer
Niedernhofer L. J., Bhagwat N., Wood R. D., Zhou S.-F., Panasci L., Cohen V., Bepler G., Zheng Z., Chen T.
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(2008). Proteomic Contributions to Personalized Cancer Care. Mol. Cell. Proteomics
7: 1780-1794
[Abstract][Full Text]
Herbst, R. S., Heymach, J. V., Lippman, S. M.
(2008). Lung Cancer. NEJM
359: 1367-1380
[Full Text]
Yeatman, T. J., Mule, J., Dalton, W. S., Sullivan, D.
(2008). On the Eve of Personalized Medicine in Oncology. Cancer Res.
68: 7250-7252
[Full Text]
Einhorn, L. H.
(2008). First-Line Chemotherapy for Non-Small-Cell Lung Cancer: Is There a Superior Regimen Based on Histology?. JCO
26: 3485-3486
[Full Text]
Kim, M. K., Cho, K.-J., Kwon, G. Y., Park, S.-I., Kim, Y. H., Kim, J. H., Song, H.-Y., Shin, J. H., Jung, H. Y., Lee, G. H., Choi, K. D., Kim, S.-B.
(2008). Patients with ERCC1-Negative Locally Advanced Esophageal Cancers May Benefit from Preoperative Chemoradiotherapy. Clin. Cancer Res.
14: 4225-4231
[Abstract][Full Text]
Khuri, F. R., Roman, J.
(2008). From Nihilism to Individualism: The Evolution of Lung Cancer Therapy. Am. J. Respir. Crit. Care Med.
177: 1299-1300
[Full Text]
Kim, S.-O., Jeong, J.-Y., Kim, M.-R., Cho, H.-J., Ju, J.-Y., Kwon, Y.-S., Oh, I.-J., Kim, K.-S., Kim, Y.-I., Lim, S.-C., Kim, Y.-C.
(2008). Efficacy of Gemcitabine in Patients with Non-Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene. Clin. Cancer Res.
14: 3083-3088
[Abstract][Full Text]
Breen, D., Barlesi, F.
(2008). The place of excision repair cross complementation 1 (ERCC1) in surgically treated non-small cell lung cancer. Eur. J. Cardiothorac. Surg.
33: 805-811
[Abstract][Full Text]
Yu, D., Zhang, X., Liu, J., Yuan, P., Tan, W., Guo, Y., Sun, T., Zhao, D., Yang, M., Liu, J., Xu, B., Lin, D.
(2008). Characterization of Functional Excision Repair Cross-Complementation Group 1 Variants and Their Association with Lung Cancer Risk and Prognosis. Clin. Cancer Res.
14: 2878-2886
[Abstract][Full Text]
Xu, X., Page, J. L., Surtees, J. A., Liu, H., Lagedrost, S., Lu, Y., Bronson, R., Alani, E., Nikitin, A. Yu., Weiss, R. S.
(2008). Broad Overexpression of Ribonucleotide Reductase Genes in Mice Specifically Induces Lung Neoplasms. Cancer Res.
68: 2652-2660
[Abstract][Full Text]
Sun, Z., Wigle, D. A., Yang, P.
(2008). Non-Overlapping and Non-Cell-Type-Specific Gene Expression Signatures Predict Lung Cancer Survival. JCO
26: 877-883
[Abstract][Full Text]
Olaussen, K. A., Fouret, P., Kroemer, G.
(2007). ERCC1-Specific Immunostaining in Non-Small-Cell Lung Cancer. NEJM
357: 1559-1561
[Full Text]
Soria, J.-C.
(2007). ERCC1-Tailored Chemotherapy in Lung Cancer: The First Prospective Randomized Trial. JCO
25: 2648-2649
[Full Text]
Simon, G., Sharma, A., Li, X., Hazelton, T., Walsh, F., Williams, C., Chiappori, A., Haura, E., Tanvetyanon, T., Antonia, S., Cantor, A., Bepler, G.
(2007). Feasibility and Efficacy of Molecular Analysis-Directed Individualized Therapy in Advanced Non-Small-Cell Lung Cancer. JCO
25: 2741-2746
[Abstract][Full Text]
Niedernhofer, L. J., Bhagwat, N., Wood, R. D., Zhou, S.-F., Panasci, L., Cohen, V., Bepler, G., Zheng, Z., Chen, T.
(2007). ERCC1 and Non-Small-Cell Lung Cancer. NEJM
356: 2538-2541
[Full Text]
Cosgrove, J.
(2007). Using molecular markers as a means of predicting prognosis and outcomes in the treatment of lung cancer. Thorax
62: 535-535
[Full Text]
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