Background A clinical trial that compared erlotinib with a placebofor non–small-cell lung cancer demonstrated a survivalbenefit for erlotinib. We used tumor-biopsy samples from participantsin this trial to investigate whether responsiveness to erlotiniband its impact on survival were associated with expression bythe tumor of epidermal growth factor receptor (EGFR) and EGFRgene amplification and mutations.
Methods EGFR expression was evaluated immunohistochemicallyin non–small-cell lung cancer specimens from 325 of 731patients in the trial; 197 samples were analyzed for EGFR mutations;and 221 samples were analyzed for the number of EGFR genes.
Results In univariate analyses, survival was longer in the erlotinibgroup than in the placebo group when EGFR was expressed (hazardratio for death, 0.68; P=0.02) or there was a high number ofcopies of EGFR (hazard ratio, 0.44; P=0.008). In multivariateanalyses, adenocarcinoma (P=0.01), never having smoked (P<0.001),and expression of EGFR (P=0.03) were associated with an objectiveresponse. In multivariate analysis, survival after treatmentwith erlotinib was not influenced by the status of EGFR expression,the number of EGFR copies, or EGFR mutation.
Conclusions Among patients with non–small-cell lung cancerwho receive erlotinib, the presence of an EGFR mutation mayincrease responsiveness to the agent, but it is not indicativeof a survival benefit.
The epidermal growth factor receptor family of genes (EGFR)encodes widely expressed transmembrane molecules that have beenimplicated in the development and progression of cancer.1,2,3,4After ligand binding, the transmembrane receptor forms homodimersor heterodimers, internalizes, and autophosphorylates tyrosineresidues in its cytoplasmic domain, thereby triggering a cascadethat leads to cellular proliferation, angiogenesis, metastasis,and inhibition of apoptosis.2
The EGFR gene is frequently expressed in solid tumors, and insome tumors, expression of the gene correlates with a poor clinicaloutcome.5 Non–small-cell lung cancer frequently expressesEGFR,6,7,8,9,10,11,12,13,14 and for this reason, it is of considerableinterest for clinical trials of inhibitors of the tyrosine kinaseof EGFR.4,15 The kinase inhibitors erlotinib (Tarceva, OSI Pharmaceuticals)and gefitinib (Iressa, AstraZeneca) have been studied most extensivelyin clinical trials.15,16,17,18
Somatic mutations in the region of EGFR that encodes the tyrosinekinase domain of the receptor (exons 18 through 21) have beenidentified in lung cancer,19,20,21 and many studies suggestthat they can be used to predict responsiveness to gefitiniband erlotinib.19,20,21,22,23,24,25,26,27,28,29,30 Such mutationsoccur more frequently in patients with adenocarcinoma, women,Asians, and patients who have never smoked. Whether EGFR mutationsare more accurate predictors of responsiveness to inhibitorsof EGFR than are these clinical factors has not been established.The effect of an EGFR mutation on prognosis and survival aftertreatment with an EGFR inhibitor is unclear, since studies todate have not included an untreated control group. The presenceof mutations that affect extracellular domains of the receptor31does not predict outcome, and it is not known whether some ofthe newly identified mutations of the tyrosine kinase regionare superior to others in predicting responsiveness. Stephenset al.32 recently identified mutations in the kinase domainof the gene for the growth factor receptor HER2 in 4 percentof non–small-cell lung cancer tumors (10 percent of adenocarcinomas),but their clinical significance is unknown.
The National Cancer Institute of Canada Clinical Trials Group(NCIC CTG) BR.21 placebo-controlled study demonstrated a survivaladvantage for patients with non–small-cell lung cancerwho received erlotinib after other treatments had failed.33Women, Asians, patients with adenocarcinoma, and patients whohad never smoked were more likely than other patients to havea response to erlotinib; however, those who had never smokedhad a significant survival benefit from erlotinib. To clarifythe role of EGFR in the outcome of non–small-cell lungcancer, we evaluated the expression of EGFR protein, the numberof copies of EGFR, and mutation status of the gene in a subgroupof patients in the BR.21 study.
Methods
Clinical Study
The BR.21 study was a phase 3 trial of erlotinib involving patientswho had had progression after standard chemotherapy for non–small-celllung cancer.33 Patients were randomly assigned in a 2:1 ratioto receive 150 mg of erlotinib daily (OSI Pharmaceuticals) orplacebo. The primary end point was overall survival. Response34was a secondary end point. Separate written consent was obtainedfor optional tissue banking and correlative studies. All studieswere designed, executed, and analyzed by the NCIC CTG; the databasewas maintained by the NCIC CTG; and the manuscript was writtenby members of the NCIC CTG. OSI Pharmaceuticals reviewed thefinal manuscript.
Pathology, Analysis of Expression of EGFR, and Molecular Analyses
Interpretation of all EGFR analyses was blinded with respectto clinical response and demographic information. Paraffin blocksor 10 to 20 unstained slides were collected from diagnosticor resection specimens. The presence of adequate tumor tissuewas verified by the study pathologist. The expression of EGFRprotein was determined by means of immunohistochemistry withthe use of Dako EGFR PharmDx kits (DakoCytomation). When morethan 10 percent of tumor cells demonstrated membranous (partialor complete) staining of any intensity, the tumor was consideredpositive for EGFR.
The entire 5-µm tissue section of specimens with cellularityof more than 50 percent was scraped from the slide for DNA isolationand mutational analyses. For specimens with lesser degrees oftumor cellularity or uneven distribution of tumor cells, enrichedDNA was isolated from tumor cells that were microdissected fromsections stained with toluidine blue (Fisher Canada) with theuse of a dissecting microscope (model SZPT40, Olympus) at 40xmagnification. In some cases, we used laser capture microdissectionwith a PixCell II System (Arcturus Bioscience). After proteinaseK digestion, DNA was isolated according to the phenol–chloroformprotocol. Exons 18 through 21 of the EGFR gene were sequentiallyamplified by two rounds of polymerase-chain-reaction (PCR) assayswith the use of AmpliTaq Gold (Applied Biosystems) and externaland internal primer sets designed by Paez et al.20 PurifiedPCR products were sequenced in both directions with the useof the BigDye Terminator Cycle Sequencing Kit (version 3.1,Applied Biosystems) and an ABI Genetic Analyzer (model 3100,Applied Biosystems). Sequence data were analyzed by means ofSeqScape software (version 2.1.1, Applied Biosystems), followedby manual review. Only sequence variations that were presentin both directions in more than 15 percent of specimens wereincluded in the analysis. When sufficient material was available,a second PCR assay was performed.
Fluorescence in situ hybridization (FISH) studies were performedwith the use of dual-color DNA FISH probes containing the LSIEGFR (Vysis) probe specific for the EGFR locus (7p12) labeledwith Spectrum Orange (Vysis) and the CEP7 chromosome 7 centromere(7p11.1 through q11.1) probe labeled with Spectrum Green (Vysis).We analyzed 33 to 100 nonoverlapping tumor-cell nuclei to determinethe number of red (EGFR) and green (CEP7) signals observed aswell as the pattern of distribution of signals. We also determinedthe number of copies of EGFR and classified them according tothe six FISH categories defined by Cappuzzo et al.22 Sampleswith a high number of copies of EGFR (high degrees of polysomyor amplification) were considered to be FISH-positive.
Statistical Analysis
Exploratory analyses were performed to characterize the relationshipsbetween EGFR status and baseline clinical characteristics andoutcomes with the use of the chi-square or Fisher's exact test.Cox regression models were used to correlate outcomes accordingto the time to an event, and logistic-regression models wereused to correlate response to EGFR status and other baselinefactors. All 731 randomized patients were included in survivalanalyses, and all 427 patients with measurable disease who weretreated with erlotinib were included in analyses of the response.All reported P values are two-sided.
Results
Patients
Between August 2001 and January 2003, 731 patients were enrolled:488 were assigned to receive erlotinib, and 243 to receive placebo.Biopsy tissue was available from 532 patients, but only 472patients (313 in the erlotinib group and 159 in the placebogroup) consented to tissue banking. A tissue sample adequatefor at least one analysis was available from 328 patients (212in the erlotinib group and 116 in the placebo group). The characteristicsof samples that, after pathological review, contained sufficienttumor cells to attempt mutational and FISH analyses are describedin Table 1 of the Supplementary Appendix (available with thefull text of this article at www.nejm.org).
Table 1 shows the baseline characteristics of all patients andthose who underwent EGFR testing. Although there were significantdifferences in some characteristics between patients who underwentvarious EGFR tests and the study population as a whole, thebenefit of erlotinib, as compared with placebo, was similarin both the entire study group (hazard ratio for death, 0.70;P<0.001) (Figure 1A) and the subgroup that underwent at leastone EGFR analysis (hazard ratio, 0.76; P=0.03) (Figure 1B).
Table 1. Baseline Demographic Characteristics of All Patients and the Patients Who Underwent Immunohistochemical (IHC) Analysis, Fluorescence in Situ Hybridization, and Mutational Analysis.
Panel A shows the results for all 731 study patients. Panel B shows the results for the 328 patients who had at least one EGFR analysis. Panel C shows the results for patients who did not have expression of EGFR on immunohistochemical analysis (less than 10 percent of tumor cells had membranous staining). Panel D shows the results for patients who had expression of EGFR on immunohistochemical analysis (10 percent or more of tumor cells had membranous staining). Panel E shows the results for patients who did not have EGFR amplification or high polysomy (four or more copies of EGFR in at least 40 percent of cells). Panel F shows the results for patients who had EGFR amplification or high polysomy. Panel G shows the results for patients who had wild-type EGFR. Panel H shows the results for patients who had EGFR mutations. P values were calculated with the use of a stratified log-rank test in Panel A and the log-rank test in Panels B through H.
Expression of EGFR, Number of Copies of EGFR, and EGFR Mutations
Among 325 tumors subjected to immunohistochemical analysis (Figure 2and Table 2), 184 (57 percent) were EGFR-positive (50 percentof adenocarcinoma samples and 63 percent of samples of othertypes of tumors). FISH was attempted in 221 tumors and was successfulin 125 (57 percent) (Figure 2 and Table 2). Of these, 45 percenthad high polysomy or amplification (48 percent of adenocarcinomasamples and 41 percent of samples of other types of tumors).
Figure 2. Expression of EGFR Protein on Immunohistochemical Analysis (Panels A and B) and Fluorescence in Situ Hybridization Analysis of the Number of Gene Copies (Panels C and D).
Incomplete (Panel A) and complete (Panel B) membranous immunohistochemical staining are scored as positive. FISH of diploid tumor cells shows one or two red (EGFR) and one or two green (CEP7) signals in most cells (Panel C), whereas cells with amplification show an excess of red signals (Panel D).
Table 2. Summary of the Results of EGFR Analyses and Characteristics of the Patients with EGFR Mutations in Tumor Specimens.
Mutational analyses were attempted in 197 samples, 110 of whichyielded sufficient DNA to amplify and sequence exons 18 through21 (59 required microdissection). Among these 110 samples, theanalysis was unsuccessful in 3 samples and exons 19 and 21 weresuccessfully analyzed in 107 samples, 24 of which (22 percent)contained one or more mutations. The 83 samples without mutationsin exons 19 and 21 were classified as wild type, although someanalyses of exons 18 (6 samples) and 20 (7 samples) had failed.The remaining 87 biopsy specimens of the original 197 containedsmall amounts of tissue (1 to 3 mm in diameter); microdissectionwas required for 45, since only 20 to 30 percent of cells weremalignant. These 87 samples yielded DNA that was adequate foranalysis of exons 19 and 21 alone. Analysis of 17 of the specimenswas considered unsuccessful because one of these exons had nomutations and the other failed to yield a definitive result.Analysis of the remaining 70 specimens revealed 17 mutationsin 16 samples (23 percent). Thus, mutational analysis was successfulin 177 of the 197 tumor specimens that were evaluated (90 percent).
In total, 45 mutations were found in 40 patients: 3 mutationsin exon 18, 13 deletions and 8 mutations in exon 19, 5 mutationsin exon 20, and 16 mutations in exon 21 (Figure 3 and Table2 in the Supplementary Appendix). Mutations were found in 28percent of adenocarcinoma samples examined, 16 percent of tumorspecimens of other histologic types (P=0.05), 24 percent ofspecimens from women, 22 percent of specimens from men, 31 percentof specimens from patients who had never smoked, 21 percentof specimens from patients who were current or former smokers,50 percent of specimens from Asian patients, and 21 percentof specimens from patients in other racial or ethnic groups(P=0.03). The presence of a mutation was not correlated withthe expression of EGFR or the number of copies of EGFR.
Panel A shows the distribution of 45 mutations in exons 18 through 21 of the EGFR gene. Panel B shows representative sequencing results of typical mutations (delE746_A750 and 2573T>G) and novel variant mutations. For the specimen with the V851A mutation, the minor peak represents the wild-type T nucleotide. All mutations were confirmed bidirectionally with forward and reverse sequencing.
Responsiveness to Erlotinib
Univariate analysis of data from 427 patients who could be evaluatedand who had received erlotinib (Table 3) showed that the followingclinical features were significantly associated with responsivenessto erlotinib: female sex (P=0.007), Asian origin (P=0.02), neverhaving smoked (P<0.001), adenocarcinoma (P<0.001), andpolysomy or amplification of EGFR (P=0.03). Mutational statushad no significant association with responsiveness: 7 percentof those with wild-type EGFR had a response, as compared with16 percent of those with an EGFR mutation (P=0.37). Multiplelogistic-regression analyses revealed that only never havingsmoked (P<0.001), adenocarcinoma (P=0.01), and expressionof EGFR (P=0.03) were associated with responsiveness in patientswith samples that underwent immunohistochemical analysis andthat never having smoked (P<0.001), adenocarcinoma (P=0.02),and polysomy or amplification of EGFR (P=0.04) were associatedwith responsiveness in patients with samples subjected to FISH.
Among the patients in both the placebo and erlotinib groupswho had at least one EGFR test, the status of EGFR protein expression,the number of copies of EGFR, and EGFR mutational status werenot significantly associated with survival in multivariate analysis,nor were there significant interactions between treatment groupswith respect to the status of protein expression (P=0.25), thenumber of copies of EGFR (P=0.10), or mutational status (P=0.97).Survival among patients with expression of EGFR was longer inthe erlotinib group than in the placebo group (hazard ratiofor death, 0.68; 95 percent confidence interval, 0.49 to 0.95;P=0.02) (Table 3 and Figure 1D), but there was no survival advantageamong patients with EGFR-negative tumors (hazard ratio, 0.93;95 percent confidence interval, 0.63 to 1.36; P=0.70) (Table 3and Figure 1C).
Among patients with polysomy or amplification of EGFR, survivalwas significantly longer among those who received erlotinibthan among those who received placebo (hazard ratio for death,0.44; 95 percent confidence interval, 0.23 to 0.82; P=0.008)(Table 3 and Figure 1F), but there was no significant differencein the length of survival between groups among patients withFISH-negative tumors (hazard ratio, 0.85; 95 percent confidenceinterval, 0.48 to 1.51; P=0.59) (Table 3 and Figure 1E). Mutationalstatus had no significant effect on survival. The risk of deathdid not differ significantly among patients with EGFR mutations(even Asian patients) who received erlotinib, as compared withsuch patients who received placebo (hazard ratio for death,0.77; 95 percent confidence interval, 0.40 to 1.50; P=0.54)(Figure 1H), or among patients with wild-type EGFR who receivederlotinib, as compared with such patients who received placebo(hazard ratio for death, 0.73; 95 percent confidence interval,0.49 to 1.10; P=0.13) (Figure 1G).
Twenty-one mutations (in 20 patients) were previously describeddeletions in exon 19 or the L858R mutation in exon 21. Therewas no significant difference in survival associated with erlotinibtherapy, as compared with placebo, among patients with the classicexon 19 deletions or the exon 21 L858R mutation (hazard ratiofor death, 0.65; 95 percent confidence interval, 0.24 to 1.75;P=0.39) and those with only novel mutations (hazard ratio, 0.67;95 percent confidence interval, 0.26 to 1.75; P=0.41) (Figure1 of the Supplementary Appendix).
In multivariate Cox regression analysis, treatment with erlotinib,as compared with placebo, remained significantly associatedwith longer survival (P=0.001). In the entire group, Asian patients(P=0.01), patients who had never smoked (P<0.001), patientswho lost less than 5 percent of their body weight (P=0.03),patients with a performance status of 0 or 1 (P<0.001), patientswho had not previously received cisplatin (P=0.04), and patientswho enrolled in the study more than 12 months after receivinga diagnosis of non–small-cell lung cancer (P<0.001)survived longest.
Discussion
Phase 2 studies have shown that female sex, adenocarcinoma,Asian origin, and never having smoked are associated with responsivenessof non–small-cell lung cancer to erlotinib or gefitinib.16,17,18,35,36,37We confirmed these associations.
The expression of EGFR protein on immunohistochemistry has notbeen a reliable predictor of responsiveness in most studiesof EGFR inhibitors.18,37,38 In our trial, 57 percent of thepatients who were tested had tumors that expressed EGFR, andon multivariate analysis, their response rate was higher thanthat of patients with EGFR-negative tumors (11 percent vs. 4percent). The expression of EGFR is often associated with polysomyor amplification of EGFR.12 We found that the response ratewas significantly higher among patients with tumors with highpolysomy or amplification of EGFR than among those without thischaracteristic (20 percent vs. 2 percent). Cappuzzo et al.22found that an increased number of copies of EGFR was a strongerpredictor of response than was the expression of EGFR.
Several groups have found mutations in the EGFR tyrosine kinasedomain (exons 18 through 21) that sensitize tumor cells to theeffects of erlotinib or gefitinib and appear to be associatedwith responsiveness to these drugs.19,20,21,22,23,24,25,26,27,28,29,30The reported mutations are in-frame deletions, with or withoutinsertions in exon 19, and missense point mutations, mainlyin exon 21. The prevalence of mutations varies, ranging from20 to 40 percent in Asian countries (Taiwan, Korea, and Japan)23,24,26,27,28and from 5 to 19 percent in Italy.22,25 We identified 45 mutations(13 deletions and 32 point mutations) in 40 patients. The 23percent prevalence of mutations in our population (40 of 177patients) is similar to that reported by Shigematsu et al.,who analyzed 617 tumors from patients from various regions ofthe world and found the highest rates among Asian patients.27The most common mutations in their study were short deletionsin exon 19, corresponding to the region between amino acids746 and 753 in EGFR, and the exon 21 L858R mutation. They alsoidentified point mutations that had not previously been reported.Huang et al.24 reported 10 new mutations among 117 tumors; 5were found in 16 tumors that had been embedded in paraffin.Among the approximately 2400 reported analyses for EGFR mutations,19,20,21,22,23,24,25,26,27,28only about 10 percent were performed in formalin-fixed paraffin-embeddedspecimens, and few routinely used microdissection to increasethe number of tumor cells in a given sample.22,24 The routineapplication of microdissection to enrich tumor-cell DNA mayincrease the rate of detection of new mutations. Multiple (twoor three) mutations have been identified in individual tumors.21,23,24,27,29
In our study, 21 mutations were either deletions in exon 19or the exon 21 L858R mutation and 24 were novel mutations. Inkeeping with our results, increasing numbers of novel mutationsare being reported in lung cancers and other types of tumors.23,24,39,40Among the 24 novel mutations we identified, 1 involves a previouslyreported codon (V851) but a change in a different amino acid(V851A rather than V851I),22 and several have also been identifiedrecently by other groups39 (and unpublished data). In 21 ofour patients with such mutations, sufficient DNA was availablefor reanalysis, and thus, we used independent PCR to confirmthe novel sequence in one specimen (D761N). No information onthe functional significance of these mutations is available,and none of these mutations have been reported as polymorphisms.A more important point is that no significant difference insurvival was associated with erlotinib therapy, as comparedwith placebo, among patients with the classic exon 19 deletionsor the exon 21 L858R mutation (hazard ratio for death, 0.65;95 percent confidence interval, 0.24 to 1.75; P=0.39) and thosewith only novel mutations (hazard ratio, 0.67; 95 percent confidenceinterval, 0.26 to 1.75; P=0.41) (Figure 1 of the Supplementary Appendix).
The clinical characteristics of our patients with mutationswere similar to those of patients in published studies, witha preponderance of female patients, patients with adenocarcinoma,nonsmoking patients, and Asian patients,19,20,21,22,23,24,25,26,27,28but we also identified mutations in other subgroups of patients.As in other reports, in our study, the response rate among patientswith mutations was more than twice that among patients withwild-type EGFR, although the difference was not significant,perhaps because the number of responses was small. The presenceof a mutation was not more likely to be associated with responsivenessthan were other clinical characteristics.
A meta-analysis14 has suggested that in patients with non–small-celllung cancer who are not receiving EGFR-inhibitor therapy, expressionof EGFR is not a strong prognostic factor for survival. Ourfindings were similar, but whether the expression of EGFR isassociated with responsiveness to erlotinib or to a differentialeffect of erlotinib on survival requires further exploration.
Cappuzzo et al.22 reported that only the number of copies ofEGFR was significantly related to survival in a multivariateanalysis of patients who were treated with gefitinib. In ourstudy, however, the number of copies of EGFR was not a significantprognostic factor in multivariate analysis.
The view that patients with wild-type tumors would not benefitfrom treatment with EGFR inhibitors and thus should not receivethese agents was reinforced by reports that patients with EGFRmutations in their tumor cells survived longer than patientswithout such mutations.26,28,30 However, none of these studiesincluded an untreated control group, and thus, they were unableto determine whether this finding was due to a differentialeffect of treatment on tumors with mutations or to the indolentbehavior of tumors with mutations. Although there was a higherrate of response among the small number of patients with mutationsthan among those with wild-type EGFR in our study, the presenceof a mutation was not associated with the survival benefit oferlotinib therapy. The benefit from erlotinib, as compared withplacebo, among patients with wild-type EGFR (hazard ratio fordeath, 0.73) was similar to that observed in the populationas a whole (hazard ratio, 0.70).
In summary, multivariate analysis revealed that expression ofEGFR and an increased number of copies of EGFR, but not mutationsin EGFR, were associated with responsiveness to erlotinib butnot with increased survival. Our results suggest that mutationalanalysis is not necessary to identify patients in whom treatmentwith EGFR inhibitors is appropriate.
Supported by grants (NCIC-00448 and NCIC-015469) from the NCIC,grants from OSI Pharmaceuticals, a research grant (OCRN-03-APR-0324)from the Ontario Cancer Research Network, a Canadian Institutesof Health Research (CIHR) grant (MOP-62797), and a researchaward from the Jacqueline Seroussi Memorial Foundation for CancerResearch. Dr. Cutz is supported by a CIHR Strategic TrainingProgram Grant for Clinician Scientists in Molecular OncologicPathology (STP-53912). Dr. da Cunha Santos is supported by agrant from the Ministry of Education of Brazil.
We are indebted to Dr. Lois Shepherd, Shakeel Virk, and thestaff members of the Correlative Sciences and Tumour Bank WorkingGroup of the NCIC CTG for the collection and preparation oftumor samples.
Source Information
From the University Health Network, Princess Margaret Hospital Site, and the Ontario Cancer Institute, University of Toronto, Toronto (M.-S.T., A.S., J.-C.C., C.-Q.Z., S.K.-R., J.S., T.Z., N.L., P.M., G.C.S., F.A.S.); the Ottawa Health Research Institute, University of Ottawa, Ottawa (I.L., M.D., A.L.); OSI Pharmaceuticals, Boulder, Colo. (F.R.); and the National Cancer Institute of Canada Clinical Trials Group and Queen's University, Kingston, Ont., Canada (L.S., M.W., K.D., J.P.). Drs. Sakurada, Cutz, and Zhu contributed equally to this article.
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Assessing EGFR Mutations
Marchetti A., Felicioni L., Buttitta F., Tsao M.-S., Kamel-Reid S., Shepherd F. A.
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N Engl J Med 2006;
354:526-528, Feb 2, 2006.
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Black, P. C., Brown, G. A., Inamoto, T., Shrader, M., Arora, A., Siefker-Radtke, A. O., Adam, L., Theodorescu, D., Wu, X., Munsell, M. F., Bar-Eli, M., McConkey, D. J., Dinney, C. P.N.
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