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Imaging, Diagnosis, Prognosis |
Authors' Affiliations: 1 Catalan Institute of Oncology, 2 Pathology Department, Hospital Germans Trias i Pujol, Badalona, Spain; 3 National Kyushu Cancer Center, 4 Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 5 Prince of Wales Hospital, 6 St. Teresa Hospital Cancer Centre, Hong Kong, China; 7 Hospital General de Alicante, Alicante, Spain; 8 Heidelberg University Medical Center, Mannheim, Mannheim, Germany; 9 Comprehensive Cancer Center, University of California, San Francisco, California; and 10 Autonomous University of Madrid, Madrid, Spain
Requests for reprints: Rafael Rosell, Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n 08916 Barcelona, Spain. Phone: 34-93-497-8925; Fax: 34-93-497-8950; E-mail: rrosell{at}ns.hugtip.scs.es.
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Abstract |
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Experimental Design: We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non–small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non–small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers.
Results: Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant).
Conclusions: The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.
The value of EGFR inhibitors as an NSCLC treatment approach has been limited by the lack of reliable methods for predicting which patients are likely to respond. The logical supposition that tumors overexpressing EGFR would respond best to EGFR inhibitors has not been borne out either in preclinical models(6, 7) or in clinical trials (8, 9). However, recent discoveries of EGFR mutations in the tyrosine kinase domain have shed light on the relationship between EGFR and sensitivity to both gefitinib and the related kinase inhibitor erlotinib. Accumulated data from three studies (10–12) show that 25 of 31 (81%) tumors from NSCLC patients with partial response or marked clinical improvement contained mutations in the EGFR tyrosine kinase domain. In contrast, none of 29 specimens from patients refractory to EGFR inhibitors had such mutations (P < 0.0001). The mutations included small in-frame deletions (746-750) adjacent to K745 (ELREA amino acids) and missense mutations, mainly L858R adjacent to the DFG motif in the COOH-terminal lobe in the activation loop of the kinase (10–12). These EGFR mutations are bona fide somatic mutations in NSCLC and have not been identified in other primary tumor types (10, 13, 14), with the exception of colorectal tumors. One of 293 tumors contained a G719S point mutation (15) that had previously been reported in NSCLC (11), and recently, 4 of 33 tumors harbored point mutations in exons 19 and 20 (16). In vitro studies of lung cancer cell lines with endogenous EGFR mutations displayed elevated activation of downstream antiapoptotic targets like AKT and signal transducer and activation of transcription (STAT5 and STAT3), conferring enhanced gefitinib sensitivity and increased cisplatin resistance (17).
The transcription activity of the EGFR gene is closely related to the enhancer region in intron 1 that is located near a polymorphic CA single sequence repeat containing 14 to 21 CA dinucleotides. Decreased numbers (<19) of CA dinucleotides in this CA sequence correlate with increased EGFR transcription (18, 19), and in breast cancer, this CA sequence is a frequent target for EGFR gene alterations (20). Moreover, interethnic studies have found that Japanese breast cancer patients carry increased numbers (>19) of CA dinucleotides than Caucasian patients (20). It has been shown that the number of repeats itself affects the mutation rate of nucleotide repeats (21).
A variety of cell surface receptors, including EGFR, as well as intracellular signaling molecules, are concentrated in specialized plasma membrane domains known as caveolae (22). Caveolin-1 mRNA expression is elevated in multidrug-resistant cultured cancer cells (23), and up-regulation of caveolin-1 and caveolae organelles has been observed in drug-resistant human and ovarian cancer cell lines (24). In addition, high caveolin-1 mRNA expression has been observed in potentially chemoresistant NSCLC cell lines established from metastatic NSCLCs (25). We therefore hypothesized that tumors harboring EGFR mutations might be associated with higher levels of caveolin-1 mRNA.
In the present study, we examined EGFR mutations in tumor tissue from gefitinib-treated, chemorefractory, advanced NSCLC patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive NSCLC cell line (26) and correlated their presence with response and survival. In addition, in a subgroup of patients for whom remaining tumor tissue was available, we examined the relationship among EGFR mutations, number of CA repeats, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers.
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Materials and Methods |
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Patients were divided into smokers and nonsmokers (having smoked <100 cigarettes in their lifetimes; ref. 27). Tumor response was defined according to the Response Evaluation Criteria in Solid Tumors (28). Survival was calculated from the start of gefitinib treatment. Follow-up was calculated from the start of gefitinib treatment; median follow-up was 11.4 months (range, 1.7-40.3 months).
Epidermal growth factor receptor sequencing. Pure tumor genomic DNA was derived from paraffin-embedded tissue obtained by laser capture microdissection (Palm, Oberlensheim, Germany). For isolation of DNA from deparaffinated, microdissected tissue, the material was incubated with proteinase K and DNA was extracted with phenol-chloroform and ethanol precipitation. Primers for PCR amplification in nested reactions for exons 18, 19, and 21 of EGFR (Genbank accession no. X00558) were as follows: exon 18 (first PCR, forward 5'-CAAATGAGCTGGCAAGTGCCGTGTC-3' and reverse 5'-GAGTTTCCCAAACACTCAGTGAAAC-3'; nested PCR, forward 5'-CAAGTGCCGTGTCCTGGCACCCAAGC-3' and reverse 5'-CCAAACACTCAGTGAAACAAAGAG-3'); exon 19 (first PCR, forward 5'-GCAATATCAGCCTTAGGTGCGGCTC-3' and reverse 5'-CATAGAAAGTGAACATTTAGGATGTG-3'; nested PCR, forward 5'-GTGCATCGCTGGTAACATCC-3' and reverse 5'-TGTGGAGATGAGCAGGGTCT-3'); exon 21 (first PCR, forward 5'-CTAACGTTCGCCAGCCATAAGTCC-3' and reverse 5'-GCTGCGAGCTCACCCAGAATGTCTGG-3'; nested PCR, forward 5'-GCTCAGAGCCTGGCATGAA-3' and reverse 5'-CATCCTCCCCTGCATGTGT-3'). Sequencing was done using forward and reverse nested primers with the ABI Prism 3100 DNA Analyzer (Applied Biosystems, Foster City, CA). Electropherograms were analyzed for the presence of mutations using Seqscape v2.1.1 software in combination with Factura to mark heterozygous positions. The human NSCLC cell line (PC9) derived from an adenocarcinoma (Kyushu Cancer Center, Fukuoka, Japan) was also examined using the same methods.
CA repeats in intron 1. In the subgroup of 28 patients, genomic DNA from peripheral blood or adjacent normal lung tissue was used to determine the number of CA repeats in intron 1. PCR amplification was done with 50 ng of genomic DNA; the primer sequences specific for this microsatellite marker were as follows: forward 5'-FAMGGGCTCACAGCAAACTTCTC-3' and reverse 5'-AAGCCAGACTCGCTCATGTT-3'. One microliter of each PCR product was mixed with 0.5 µL of size standard (GenScan-350 Rox Standard, Applied Biosystems) and denatured in 18 µL of formamide at 95°C for 5 minutes. Separation was done with a four-color laser-induced fluorescence capillary electrophoresis system (ABI Prism 3100 DNA Analyzer, Applied Biosystems). The collected data was evaluated with the GeneScan Analysis Software (Applera, Norwalk, CT). DNA from the tumor cell line Hep-2 was used as a control for PCR amplified microsatellite fragment length.
Quantitative PCR. In the subgroup of 28 patients, total RNA was derived from paraffin-embedded tissue obtained by laser capture microdissection. After standard tissue sample deparaffinization using xylene and alcohols, samples were lysed in a Tris-chloride, EDTA, SDS, and proteinase K containing buffer. RNA was then extracted with phenol-chloroform-isoamyl alcohol followed by precipitation with isopropanol in the presence of glycogen and sodium acetate. RNA was resuspended in RNA storage solution (Ambion, Inc., Austin, TX) and treated with DNase I to avoid DNA contamination. cDNA was synthesized using Moloney murine leukemia virus retrotranscriptase enzyme. Template cDNA was added to Taqman Universal Master Mix (Applied Biosystems) in a 12.5-µL reaction with specific primers and probe for each gene. The primer and probe sets were designed using Primer Express 2.0 Software (Applied Biosystems). Quantification of gene expression was done using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems). Primers and probe for EGFR and caveolin-1 mRNA expression analysis were designed according to the Ref Seq NM_005228 and NM_001753, respectively (http://www.ncbi.nlm.nih.gov/LocusLink). The primers and labeled fluorescent reporter dye probe were as follows: ß-actin, forward 5'-TGAGCGCGGCTACAGCTT-3', reverse 5'-TCCTTAATGTCACGCACGATTT-3', probe 5'-FAMACCACCACGGCCGAGCGG-3'TAMRA; EGFR, forward 5'-GGAAATTACCTATGTGCAGAGGAATT-3', reverse 5'-TAACCAGCCACCCCCTGGAT-3', MGB probe 5'-FAMTGATCTTTCCTTCTTAAAGAC-3'; Caveolin-1, forward 5'-CGACCCTAAACACCTCAACGA-3', reverse 5'-GGTTCTGCAATCACATCTTCAAAG-3', MGB probe 5'-FAMCGTGGTCAAGATTG-3'. Relative gene expression quantification was calculated according to the comparative Ct method using ß-actin as an endogenous control and commercial RNA controls (Stratagene, La Jolla, CA) as calibrators. Final results were determined as follows: 2–(
Ct sample – Ct calibrator), where Ct values of the calibrator and sample are determined by subtracting the Ct value of the target gene from the value of the ß-actin gene. In all experiments, only triplicates with a SD of the Ct < 0.20 were accepted. In addition, for each sample analyzed, a retrotranscriptase minus control was run in the same plate to assure lack of genomic DNA contamination.
To distinguish between high and low gene expression levels, median levels obtained were used as cutoffs: 3.28 for EGFR and 0.52 for caveolin-1 mRNA expression.
Fluorescence in situ hybridization assay. For each patient in the subgroup of 28 patients, two sections of 3- to 5-µm paraffin-embedded tumor tissue were placed over silenized treated slides. Another section was stained with H&E and confirmed to contain tumor tissue components. The silenized slides were left overnight at 60°C; deparaffinized in two changes of xylene for 10 minutes; rehydrated in 100% ethanol, 90% ethanol, and 70% ethanol for 1 minute each; and left in deionized water for 5 minutes. After tissue hydration, sections were placed in citrate buffer and heated in a microwave twice for 5 minutes at 800 W each. Slices were then digested by proteinase K treatment for 15 minutes at 37°C, fixed with formalin solution (pH 7.5), and washed in 2x SSC buffer. The hybridization was done using Vysis probes (LSI EGFR/CEP 7 Dual Color, Downers Grove, IL) following the manufacturer's instructions. Briefly, 5 µL of the probe solution were added to each slide and covered by a coverslip. Slides and probes were denatured for 3 minutes at 85°C in a slide warmer plaque (Hybrite, Vysis) and left at 37°C overnight. The coverslips were removed and the slides washed in 2x SSC/0.3%NP40 solution for 2 minutes at 72°C followed by an additional wash in 2x SSC/0.3%NP40 solution for 10 seconds at room temperature. Finally, slides were counterstained using a 4'-6'-diamidine-2-phenylindole-containing medium that specifically binds to DNA. For each patient, 100 nuclei from the selected tumor region were analyzed in a fluorescence microscope. The ratio of the average number of EGFR spots/nucleus by the average number of CEP 7 (centromeric chromosome 7) spots/nucleus was used for the scoring criteria. EGFR status in tumors was scored as follows: (a) single copy, up to four specific signals of both EGFR and CEP 7 probes with a ratio equal to 1; (b) polysomy, more than four specific signals of both probes per nucleus and a ratio <2; (c) amplification, more than four specific signals of EGFR probe per nucleus compared with CEP 7 with a ratio >2. Tumors scored as polysomy and/or amplification were labeled as having increased EGFR copy numbers.
Statistical methods. The primary objective of this study was to compare clinical characteristics, response rates, and survival in gefitinib-treated patients with and without mutations in the EGFR tyrosine kinase domain. In the subgroup of 28 patients, further analyses were done to examine the correlation among EGFR mutations, the number of CA repeats in intron 1 of EGFR in normal tissue, EGFR and caveolin-1 mRNA expression levels in tumor tissue, and EGFR gene copy numbers.
The nonparametric Mann-Whitney U test and one-way ANOVA test were used to analyze differences in EGFR mutation status, number of CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA expression, and EGFR gene copy numbers. Normality of the distribution of continuous variables was assessed with the Kolmogorov-Smirnov test. The 
2 and Fisher's exact tests were used to compare differences in response according to EGFR mutation status, number of CA repeats in intron 1, EGFR and caveolin-1 mRNA expression, and gene copy numbers. Univariate Cox regression models were used to measure hazard ratios. To identify relevant variables of influence, a multivariable logistic regression model was used, and the fit of the models was evaluated with the Hosmer-Lemeshow likelihood ratio test. The Wald test was used to test the statistical significance of each variable in the model. Survival curves were drawn with the Kaplan-Meier product limit method and P values assessed with the Tarone-Ware test. All reported P values are two sided; P < 0.05 was considered statistically significant. SPSS software version 11.5 (SPSS, Inc., Chicago, IL) was used for all analyses.
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Results |
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19). The highly gefitinib-sensitive PC9 lung adenocarcinoma cell line, which harbored the deletion delE746-A750, also displayed increased numbers of CA repeats (20 of 20). There were no differences in median mRNA levels of EGFR or caveolin-1 according to EGFR mutation status. Increased EGFR gene copy numbers were observed more frequently in patients with EGFR mutations. Gene amplification ranged widely from low to high levels, and in some patients, amplification was seen in only 25% of the tumor cells examined. In this subset of 28 patients, the response rate for patients with increased gene copy numbers was 45%, in contrast with 89% for patients with EGFR mutations (P = 0.02). The response rate was 100% in patients with both EGFR mutations and gene amplification. Table 5 illustrates the levels of EGFR and caveolin-1 mRNA according to EGFR mutation status and further broken down by gene copy numbers and number of CA repeats. The highest levels of EGFR mRNA were observed in the group of patients with both EGFR mutations and increased EGFR copy numbers. Patients with both EGFR mutations and low levels of EGFR or caveolin-1 mRNA had a median survival of 13 months, whereas median survival has not been reached for those patients with EGFR mutations and high levels of EGFR or caveolin-1 mRNA (data not shown).
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Discussion |
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In the original studies (10, 11), only one mutation per tumor was detected. However, Pao et al. (12) found a tumor sample with two mutations, from a female never smoker with adenocarcinoma, treated with erlotinib for 13 months, and surviving 22 months. Furthermore, in the study by Huang et al. (13), two patients had two mutations in their tumors; one responded and one did not. In our study, one patient had two mutations: a 67-year-old Hong Kong Chinese female never smoker with adenocarcinoma. She attained a partial response and is still alive at 22 months (January 2005). It is not possible to draw definite conclusions from only four patients, and more data regarding the potential predictive value of two mutations in the same tumor is needed.
In the present study, 6 of 51 patients with wild-type EGFR attained partial response to gefitinib. There were no differences in baseline clinical characteristics between responders with EGFR mutations and responders with wild-type EGFR (Table 2). However, only 16% of responders with wild-type EGFR remain alive at the time of submitting this article, in contrast with 81% of responders harboring EGFR mutations. In the series reported by Lynch et al. (10), one of nine gefitinib-sensitive patients did not have EGFR mutations. Along the same lines, Pao et al. (12) reported that 5 of 17 patients with partial response or clinical improvement to gefitinib or erlotinib had wild-type EGFR in exons 18 to 24. Mutations in these responders may not have been detected because they were below the detection rate of sequencing assays (30), or increased EGFR gene copy numbers in these responders may have conferred enhanced gefitinib sensitivity (12) in the absence of EGFR mutations. NSCLC cell lines with wild-type EGFR but with high levels of EGFR, ErbB2, or ERbB3 mRNA have shown intermediate sensitivity to gefitinib and erlotinib (31).
The small number of patients examined in the present study limits the conclusions that can be drawn as to the role of CA repeats, EGFR and caveolin-1 mRNA expression, and EGFR gene copy numbers. However, interethnic differences in the number of CA repeats warrant further investigation in Asian lung cancer patients, in whom increased numbers of CA repeats may be more frequently associated with the presence of EGFR mutations (19, 20). Amador et al. (32) found that head and neck cell lines with decreased numbers of CA repeats had higher expression of EGFR mRNA and were more sensitive to the inhibitory effects of erlotinib. In addition, in 19 gefitinib-treated colorectal cancer patients (32), 84% of those with decreased numbers of CA repeats developed skin toxicity, a feature related to the antitumor activity of EGFR inhibitors (33), compared with only 33% of those with increased numbers of CA repeats (P = 0.04; ref. 32).
In surgically resected NSCLC patients (13, 34), EGFR mutations were associated with well and moderately differentiated adenocarcinomas and smoking status but not with female gender. Dramatic clinical response to gefitinib is observed in only 10% to 19% of chemorefractory advanced NSCLC. Kris et al. (5) showed that female gender predicted response to gefitinib, whereas the number of prior chemotherapy regimens did not influence response. In our study, the number of prior chemotherapy regimens increased the probability of response in tumors containing EGFR mutations.
The strong correlation we observed between EGFR mutations and improved response and survival leads us to recommend the assessment of EGFR mutations in lung adenocarcinoma patients to customize treatment. NSCLC cell lines containing EGFR mutations are chemoresistant but highly sensitive to gefitinib (17, 35). In the present study, we detected an unprecedented median survival in patients with EGFR mutations. The Spanish Lung Cancer Group is currently screening for EGFR mutations in metastatic lung adenocarcinomas to identify patients who could benefit from treatment with tyrosine kinase inhibitors.
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Footnotes |
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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.
Note: The sponsors of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Received 12/20/04; revised 3/15/05; accepted 3/21/05.
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