Epidermal Growth Factor Recetor mutation study for 5 years, in a population of patients with non-small cell lung cancer

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Rezende Gonçalves, M. Corso Pereira, E.M. Figueiras Pedreira De Cerqueira, D. Oliveira Magro, M. Mello Moreira, I.A. Paschoal" "autores" => array:6 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Rezende Gonçalves" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Corso Pereira" ] 2 => array:2 [ "nombre" => "E.M." "apellidos" => "Figueiras Pedreira De Cerqueira" ] 3 => array:2 [ "nombre" => "D." "apellidos" => "Oliveira Magro" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "Mello Moreira" ] 5 => array:2 [ "nombre" => "I.A." 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Penafortes, F.S. Guimarães, V.J.R. Moço, V.P. Almeida, R.F. Dias, A.J. Lopes" "autores" => array:6 [ 0 => array:2 [ "nombre" => "J.T.S." "apellidos" => "Penafortes" ] 1 => array:2 [ "nombre" => "F.S." "apellidos" => "Guimarães" ] 2 => array:2 [ "nombre" => "V.J.R." "apellidos" => "Moço" ] 3 => array:2 [ "nombre" => "V.P." "apellidos" => "Almeida" ] 4 => array:2 [ "nombre" => "R.F." "apellidos" => "Dias" ] 5 => array:2 [ "nombre" => "A.J." "apellidos" => "Lopes" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S217351151300002X?idApp=UINPBA00004E" "url" => "/21735115/0000001900000001/v1_201305151601/S217351151300002X/v1_201305151601/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Epidermal Growth Factor Recetor mutation study for 5 years, in a population of patients with non-small cell lung cancer" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "7" "paginaFinal" => "12" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "A.S. Castro, B. Parente, I. Gonçalves, A. Antunes, A. Barroso, S. Conde, S. Neves, J.C. Machado" "autores" => array:8 [ 0 => array:4 [ "nombre" => "A.S." "apellidos" => "Castro" "email" => array:1 [ 0 => "anasfcastro@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:4 [ "nombre" => "B." "apellidos" => "Parente" "email" => array:1 [ 0 => "barbaraparente@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "¿¿" "identificador" => "cor0010" ] ] ] 2 => array:3 [ "nombre" => "I." "apellidos" => "Gonçalves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 3 => array:3 [ "nombre" => "A." "apellidos" => "Antunes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 4 => array:3 [ "nombre" => "A." "apellidos" => "Barroso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 5 => array:3 [ "nombre" => "S." "apellidos" => "Conde" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 6 => array:3 [ "nombre" => "S." "apellidos" => "Neves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 7 => array:3 [ "nombre" => "J.C." "apellidos" => "Machado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidade de Pneumologia Oncológica, Serviço de Pneumologia, Centro Hospitalar Vila Nova de Gaia-Espinho, Vila Nova de Gaia, Portugal" "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Porto, Portugal" "etiqueta" => "b" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Estudo da mutação do recetor do fator de crescimento epidérmico, durante 5 anos, numa população de doentes com cancro do pulmão de não pequenas células" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 999 "Ancho" => 2944 "Tamanyo" => 144776 ] ] "descripcion" => array:1 [ "en" => "A. Mutated patients versus non mutated patients overal survival (47 vs 22 months; p=0,038). B. Median survival after erlotinib in EGFR mutated-positive vs negative patients (14 vs 6 months, p=0,003)." ] ] ] "textoCompleto" => "1IntroductionPrognostic and predictive factors in lung cancer are important for patient and doctor, because they provide a more accurate prognosis (in terms of recurrence of the disease, progression and survival), and help establish the best treatment.The classic prognostic factors include smoking history, general health status and co-morbidities. Nowadays there are also molecular markers that have become prognostic factors, and the most carefully studied are: epidermal growth factor receptor (EGFR) and KRAS mutation, which in association with histology are considered potential predictive factors.Early identification of the subpopulation of patients most likely to respond to a particular treatment is currently the main goal of lung cancer treatment; this not only increases the probability of response but also avoids unnecessary treatment for those patients who are unlikely to benefit from it.There is not a reliable lung cancer record in Portugal and so it is very difficult to define our national epidemiological profile or the actual NSCLC incidence rate and therefore difficult to make a clinical assessment of potential treatment.In 2000 and 2002, the Portuguese Pulmonology Society Ontological Commission<a class="elsevierStyleCrossRef" href="#bib0005">1</a>, carried out a study involving 22 Portuguese hospitals, in which 4396 new lung cancer cases were registered; the most frequent histological subtype was adenocarcinoma and 76.9% of the cases were patients with advanced or metastatic disease.Although it is our understanding that of these patients with advanced disease, only 10–12% might benefit from 1st line tyrosine kinase inhibitor (TKI), the appearance of EGFR-TKI was significant for advanced or metastatic NSCLC treatment, first line in patients with EGFR mutation and even in second and third line therapy.There are several clinical and molecular parameters that are useful for predicting which patients with NSCLC advanced disease are most likely to benefit from treatment with TK inhibitors, both for initial therapy or as second-line therapy. These indicators, from phase II<a class="elsevierStyleCrossRefs" href="#bib0010">2-5</a> and III<a class="elsevierStyleCrossRef" href="#bib0030">6</a> studies which identified a number of clinical parameters associated with better clinical response, are adenocarcinoma, female gender, non-smoking and Asian ethnicity.<a class="elsevierStyleCrossRefs" href="#bib0035">7-9</a>Specific EGFR TK domain activating mutations (exons 18-21) are usually associated with an increased response to TK inhibitors, erlotinib or gefitinib, which occur, according to the literature, in Europe in 10-15% of patients with NSCLC and have easily manageable side effects.The “gold standard” method for EGFR mutation analysis is direct DNA sequencing (exons 18-21). The percentage of mutations in each exon is still controversial; the majority of studies, including the Spanish group<a class="elsevierStyleCrossRef" href="#bib0050">10</a>, only studied exons 19 and 21 (and only the mutation Leu858Arg). There has also been mention of mutations also in exons 18 and 20 and some of which had predictive value of response.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Values such as 5% were found in exon 18, 49% in exon 19, 1% in exon 20 and 45% in exon 21. The positive predictive value of Gly719 mutation in exon 18, and the negative predictive value of exon 20 insertions<a class="elsevierStyleCrossRef" href="#bib0060">12</a> are well established. Penzel et al<a class="elsevierStyleCrossRef" href="#bib0065">13</a> in 1047 analyzed cases, found a 15,6% mutation rate (exon 18–10,4%, exon 19–49,7%, exon 20–5,5% exon 21–34,4%).There is also no also consensus as to which group of patients should be examined for EGFR mutation and studies have typically excluded patients with epidermoid tumors and heavy smokers.Neither is there a defined consensus about which is the best biopsy value (primary tumor vs metastases) for the mutation study; however, whenever possible, the first study of EGFR mutations is performed in primary tumor and not in the metastases. It is not common to perform a new puncture or biopsy in patients who are progressing when treated with ITK. In about 50% of progression cases Thr790Met (exon 20) mutation occurs. This mutation provides resistance to treatment with TKIs, but that is a secondary mutation which appears only after treatment and resistance acquisition and is only very rarely a primary mutation (although some authors argue that it may already have been present in sub-clones of residual tumor cells before treatment with TKIs)<a class="elsevierStyleCrossRef" href="#bib0070">14</a>.The best responses to treatment are obtained in patients with exon 19 deletions and in exon 21 Leu858Arg mutation, although results tend to be slightly lower than exon 19 deletion; exon 18 Gly719 mutations and exon 21 Leu 861 are associated with a good response. The evidence for this is clinical and experimental (in vitro)<a class="elsevierStyleCrossRef" href="#bib0070">14</a>.In 2006, Gaia-Espinho Hospital Center (CHGE) Pulmonology Service, Pulmonary Oncology Unit (POU), started performing EGFR gene mutation sequencing in collaboration with IPATIMUP (Oporto University Molecular Pathology and Immunology Institute) in selected patients and by this time erlotinib had been approved in Portugal for use in 2nd and 3rd line therapy. In 2010, with the approval of gefitinib for first line therapy, systematic sequencing was started in all NSCLC patients regardless of histology, stage, smoking habits or sex, and treatment with Gefitinib in 1st line all patients with positive EGFR mutation.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> We therefore decided on a prospective epidemiological data collection.2Material and MethodsWe present the results of a continuous record, of research for EGFR mutations in patients with NSCLC, which was carried out in the CHGE Pulmonology Department between 2006 and 2010. We evaluated the results obtained after 2nd and 3rd line treatment with ITK in NSCLC patients with advanced disease who were studied for EGFR mutation. The 1st-line treatment results in mutated patients are not presented, as the number of cases is still small.Between 2006 and 2009, the inclusion criteria for the EGFR mutations study were adenocarcinoma histology, non-smokers or former smokers, regardless of gender. In 2010, the inclusion criteria were diagnosis of NSCLC (regardless of gender), disease stage or smoking habits. Patients were classified according to their smoking habits as: smokers, former smokers (patients that had given up for more than 12 months) and nonsmokers. The material available for analysis and the average delay of exam results, according to the material submitted were also taken into account.In patients with advanced stage treated in second and 3rd line with erlotinib between 2006 and 2010, the evaluated parameters included age, sex, smoking, histology, TNM stage at presentation, chemotherapy prior schemes, EGFR mutational state and overall survival according to mutational status, median overall survival after erlotinib.All statistical calculations were performed using SPSS (Statistical Package for the Social Sciences) software version 17.0.3ResultsIn the period between January 1st 2006 and December 31st 2010, EGFR sequencing was carried out in 374 patients with NSCLC (248 patients between 2006 and 2009 and 126 patients in 2010). Of the total number of analyzed patients, 266 (71.1%) were male and 108 (28.9%) female. The average age was 64.5±11.3 years. 35.8% were former smokers, 31.3% non-smokers and 32.9% smokers. The predominant histological type was adenocarcinoma,57.8%, followed by squamous cell carcinoma - 23.5% (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>10.1% of patients were in TNM stage I, 2.4% of cases in stage II, 5.8% in stage IIIA and in stage IIIB / IV 81.6% of cases.EGFR gene mutations were detected in 49 out of 374 patients, corresponding to a 13.1% mutation rate (the mutation rate was 9% in males and 23% in females). Of the total number of mutated patients, 46.9% were non-smokers and 59.2% were adenocarcinomas. (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)When considered separately, the mutation rate in selected patients (2006/2009) was 16.3% vs 10.4% in 2010, the year the mutation study began to be carried out on all patients with NSCLC.The exon distribution was: 10.2% in exon 18, 38.8% in exon 19 and 18.4% in exon 20 (6.2% were of resistance), 32, 7% in exon 21.In female patients with positive mutation (n=25), most were non-smokers (22/88,0%) and had an adenocarcinoma histology predominance (20/80,0%). In this subgroup, 44% of mutations occurred in exon 19, 28% in exon 21, 12% in exon 18:12% in exon 20. (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>)<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>In mutated men (n=24), 91.7% were smokers or ex-smokers and the predominant histological type was squamous cell carcinoma, in 45.8% of patients. Mutations occurred 37.5% in exon 21, 29.2% in exon 19, 25% in exon 20 and 8.3% in exon 18. (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>)Non-smoker mutated patients (23), were mostly female (21/91, 3%), 78.3% were adenocarcinomas, 17.4% NSCLC and 4.3% squamous cell carcinomas. In the majority of non-smokers, mutation occurred in exon 19 (43.5%) and exon 21 (34.8%), followed by exon 18 (13.0%) and exon 20 (4.3%).The average delay-time for obtaining a sequencing result<a class="elsevierStyleCrossRef" href="#bib0080">16</a>, varied according to the type of material available for study, using blades the average was 20 days, with paraffin block it took 8.32 days and with cellular debris (with fresh products EBUS BAT and other punctures in Pathology) the result was available within 6.5 days on average. (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Of the total patients sequenced, 71 with advanced or metastatic stage had 2nd and 3rd line treatment with erlotinib 150mg/day, up until death, disease progression or unacceptable toxicity levels. Within this subgroup of patients, there were females (43/60,6%), non-smokers (31/43,7%) and predominantly patients with adenocarcinoma histology (43/60,6%). EGFR mutation was positive in 20 patients (19.2%), 55% men and 45% women, mainly non-smokers (12/60, 0%) and with adenocarcinoma histology (14/70%). (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>) Regarding overall response to treatment with erlotinib in patients with negative EGFR mutation (n=51), 47.9% (24) had progressive disease, 45,1% (23) stable disease and 7.8% (4) were in partial remission.In the subgroup of patients with positive EGFR mutation treated with erlotinib (n=20), 35,0% (7) showed progressive disease, 50.0% (10) stable disease and 15.0% (3) partial remission, in other words as would be expected there was better disease control in patients with positive EGFR mutations when compared to patients with negative mutation (65.0% vs 52.9%). (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>)<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>For EGFR mutation positive patients treated with erlotinib the overall survival rate vs. non-mutated was 47 vs 22 months (p=0.038), respectively. (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) The average survival rate after treatment with erlotinib in the positive EGFR mutation group was also higher in this subgroup when compared with patients with negative mutation (14 vs 6 months, respectively, p=0.003). (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>4DiscussionOur group of patients showed a global (2006-2010) EGFR mutation rate of 13.1%. The fact that between 2006 and 2009 there was patient selection has to be taken into account, when the mutation rate was 16% vs 10.4% in 2010 when the mutation study was performed on all patients with NSCLC regardless of sex and stage. These figures add value to our knowledge about EGFR mutation rate in the Portuguese population. The European prevalence EGFR mutations in lung cancer studies, was 10% in unselected patients. In Spain, Rosell et al, found a mutation rate of 16.6%<a class="elsevierStyleCrossRef" href="#bib0050">10</a>, in a selected patients group with NSCLC in advanced stages. The follow-up of our work (which in 2011 and 2012 has also included an unselected population) will give a reliable definition of the EGFR mutation profile in the Portuguese population and confirm the data presented here, which includes data on the presence of the mutation in male patients, squamous cell carcinomas and some smokers. The difference in mutation rates however is very significant as regards the 2 sexes, adenocarcinoma being responsible for most cases.It was possible to perform the EGFR gene sequencing in various types of diagnostic samples. DNA sequencing from cellular debris (fresh or after cell block) was faster than paraffin block or blades. This difference was statistically significant and impacted on when treatment started; it was only possible when there was close collaboration between the various elements involved in lung cancer diagnosis (Oncology, Bronchology, Interventional Radiology and Pathology). In peripheral tumors or whenever it is possible to perform aspirative biopsies, it should a priority to send this fresh material so as to obtain faster results (6.5 days after sending samples).EGFR mutation study should be carried out routinely in all patients diagnosed with NSCLC, and its use should be facilitated in all hospitals treating lung cancer, to support proper treatment, and to consider the use of TKI 1st-line in mutated patients, which controls the disease better than conventional chemotherapy protocols. All these assumptions are based on treatment response and overall survival rates in the group of patients treated with TKI.<a class="elsevierStyleCrossRefs" href="#bib0080">16–18</a>The results of our sample in 2nd and 3rd line treatment showed statistical significance in the group of patients with positive EGFR mutation, compared to patients with negative mutation, despite the fact that the presence of EGFR mutation is not a mandatory condition for starting treatment. We still do not have enough patients to present the results of the mutated patients with 1st line treatment with TKIs.5Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres175782" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Methods" 3 => "Results" 4 => "Conclusion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec164115" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres175781" "titulo" => array:5 [ 0 => "Resumo" 1 => "Introdução" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusão" ] ] 3 => array:2 [ "identificador" => "xpalclavsec164116" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-01-12" "fechaAceptado" => "2012-08-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec164115" "palabras" => array:4 [ 0 => "Non Small Cell Lung Cancer" 1 => "Epidermal Growth Factor Receptor" 2 => "Tyrosine kinase inhibitor" 3 => "Survival" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec164116" "palabras" => array:4 [ 0 => "Carcinoma pulmonar não pequenas células" 1 => "Recetor do fator de crescimento epidérmico" 2 => "Inibidores da tirosina quinase" 3 => "Sobrevida" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "IntroductionIn 2006, the Vila Nova de Gaia/Espinho Hospital Centre Pulmonary Oncology Unit started performing EGFR (Epidermal Growth Factor Receptor) mutation sequencing in selected patients with NSCLC and systematically in all patients since 2010, regardless of histology, smoking habits, age or sex. The aim of this study was to characterize the group of patients that carried out the sequencing between 2006-2010, to determine EGFR mutation frequency, to evaluate the overall survival and the survival after the use of tyrosine kinase inhibitors (TKI), in patients who performed this therapy in second and third line, knowing the EGFR mutation status. MethodsDescriptive statistical analysis of patients who did EGFR sequencing in 2006-2010 and of overall survival in patients treated with TKI as 2nd and 3rd line therapy. Record of the material available for analysis and average delay of exam results, according to the material submitted. ResultsThe sequencing was performed in 374 patients, 71,1% males, 67,1% non/ex-smokers, 32,9% smokers, 57,8% adenocarcinoma and 23,5% squamous cell carcinoma (SCC). The mutation was detected in 49 patients (13,1%). In all studied patients, the mutation rate was 9% in males and 23% in females. Median overall survival after erlotinib use of was 14 months for patients with positive EGFR mutation versus 6 months in not mutated patients (p = 0.003). ConclusionOur group had an overall mutation rate of 13.1% with female, non-smokers, adenocarcinoma histology predominance. In selected patients (2006/2009), the mutation rate was 16%, in not selected patients (2010) the mutation rate was 10.4%. This study has permitted a better understanding of the EGFR mutation rate in the Portuguese population as welll as an evaluation of the patients survival after the use of of tyrosine kinase inhibitors, in second and third line therapy with previous knowledge of the EGFR mutational status. Statistical significant differences in survival were found in the two patient groups (EGFR mutated and non mutated).The EGFR mutation research should be performed in all patients with NSCLC, giving the possibility to a considerable number of patients to perform a first line treatment with TKI (EGFR mutated patients) and the advantage of performing other chemotherapy schemes, when progression occurs." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "IntroduçãoEm 2006, a Unidade de Pneumologia Oncológica do Serviço de Pneumologia do Centro Hospitalar de Vila Nova de Gaia/Espinho iniciou a sequenciação da mutação do recetor do fator de crescimento epidérmico (EGFR) em doentes com CPNPC selecionados e desde 2010 realiza a sequenciação sistematicamente em todos os doentes, independentemente da histologia, hábitos tabágicos, idade ou sexo. O objetivo deste trabalho foi caracterizar o grupo de doentes que efetuou a sequenciação entre 2006-2010, determinar a frequência da mutação EGFR, avaliar as sobrevidas globais e após uso de inibidores da tirosina quinase (ITK), nos doentes que efetuaram esta terapêutica em 2.a e 3.a linha com conhecimento do estado da mutação do EGFR. MétodosAnálise estatística descritiva dos doentes que efetuaram sequenciação EGFR em 2006-2010 e sobrevida mediana global nos doentes que efetuaefetuaram ITK em 2.a e 3.a linha. Registo do material disponível para análise e demora média de resultado do exame, de acordo com o material enviado. ResultadosA sequenciação foi efetuada em 374 doentes, 71,1% sexo masculino, 67,1% não/ex-fumadores, 32,9% fumadores; 57,8% adenocarcinoma e 23,5% carcinoma epidermoide (CE). A mutação foi detetada em 49 doentes (13,1%). No total dos doentes estudados, a taxa de mutação foi de 9% no sexo masculino e 23% no sexo feminino. A sobrevida mediana global após o uso de erlotinib foi de 14 meses para os doentes com mutação positiva do EGFR versus 6 meses nos doentes não mutados (p = 0,003). ConclusãoO nosso grupo teve uma taxa de mutação global de 13,1%, com predomínio no sexo feminino, não fumadores, histologia adenocarcinoma. Em doentes selecionados (2006/2009), a taxa de mutação foi de 16%; nos doentes não selecionados (2010) foi de 10,4%. Este estudo tem vindo a permitir um melhor conhecimento da taxa de mutação do EGFR na população portuguesa, bem como avaliar os resultados das sobrevidas dos doentes após uso de inibidores da tirosina quinase (ITK), efetuada em 2.a e 3.a linha com conhecimento prévio do estado da mutação do EGFR, tendo sido encontradas diferenças nas sobrevidas nos 2 grupos de doentes (mutados e não mutados) com significado estatístico.A pesquisa mutação do EGFR deve ser efetuada em todos os doentes com CPNPC, dando possibilidade a um número considerável de doentes de poder efetuar um tratamento de 1.a linha com ITK (doentes mutados), bem como de poder usufruir de outros esquemas de quimioterapia, quando progredirem." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Castro, AS Estudo da mutação do recetor do fator de crescimento epidérmico, durante 5 anos, numa população de doentes com cancro do pulmão de não pequenas células. Rev Port Pneumol 2012. http://dx.doi.org/10.1016/j.rppneu.2012.08.002" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 999 "Ancho" => 2944 "Tamanyo" => 144776 ] ] "descripcion" => array:1 [ "en" => "A. Mutated patients versus non mutated patients overal survival (47 vs 22 months; p=0,038). B. Median survival after erlotinib in EGFR mutated-positive vs negative patients (14 vs 6 months, p=0,003)." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Positive mutation patients (N=49)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Variables \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">All patients (N=374)n/% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mutated patients (N=49)n/% \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">266/71,1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24/9,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">108/28,9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25/23,1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">medium±sd \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64,52±11,3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">69±9,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">minimum/maximum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20/87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56/77 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking habits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ex-smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">134/35,8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15/30,6% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123/32,9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11/22,4% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">non-smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">117/31,3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23/46,9% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">adenocarcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">216/57,8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29/59,2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Squamous cell ca \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">88/23,5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12/24,5% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Large cells ca \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/0,5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bronquioloalveolar ca \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/1,9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CPNPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61/16,3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/14,3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exon \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/10,2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19/38,8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9/18,4%* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16/32,6% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab268157.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Characterization of the total group of patients and EGFR mutation frequency (* 6,2% were resistance mutations)." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Variables \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">females (n/%) (N=25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">males (n/%) (N=24) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking habits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">non-smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22/88% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/8,3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ex-smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/29,2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/12% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15/62,5% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">adenocarcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20/80% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9/37,5% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Squamous cell ca \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/ 4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11/45,8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CPNPC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4/6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4/16,7% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mutated exon \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/12% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/ 8,3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11/44% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/29,2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/12% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/25% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/28% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9/37,5% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab268154.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Characterization of male/female EGFR mutated patients." ] ] 3 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Type of material \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Average time delay (days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Time difference (days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">paraffin block \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8,32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Citology blades \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,6721 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0,0255 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histology blades \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20,42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12,0888 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,1108 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">cellular debris \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,5556 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-1,7723 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0,1789 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab268155.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Average time-delay in obtaining a sequencing result according with the type of material available for study." ] ] 4 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Patients total (N=71)n/% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Positive mutated patients (N=20)n/% \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EGFR mutation study and treatment with Erlotinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28/39,4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11/55,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43/60,6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9/45,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68±8,46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking habbits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ex-smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24/33,8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/35% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16/22,5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/15,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">non-smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31/43,7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12/60,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">adenocarcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43/60,6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14/70,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other histology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28/39,4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/30,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Response to Erlotinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EGFR -=51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EGFR +=20 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Parcial Remission \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4/7,8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/15,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stable disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23/45,1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10/50,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progressive disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24/47,1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7/35,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median overal survival \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Survival after Erlotinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 months \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab268156.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic data concerning the group of patients treated with erlotinib and treatment response." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estudo epidemiológico do cancro do pulmão em Portugal 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Gabriel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.1099314" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "2004" "volumen" => "304" "paginaInicial" => "1497" "paginaFinal" => "1500" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15118125" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations of the epidermal growth factor receptor gene predict prolonged survival after gef itinib treatment in patients with non-small-cell lung cancer with postoperative recurrence" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Mitsudomi" 1 => "T. Kosaka" 2 => "H. Endoh" 3 => "Y. Yatabe" 4 => "H. Kuwano" 5 => "T. Takahashi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2005.00.992" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2005" "volumen" => "23" "paginaInicial" => "2513" "paginaFinal" => "2520" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15738541" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1542356508006216" "estado" => "S300" "issn" => "15423565" ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gef itinib and erlotinib" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W. Pao" 1 => "V. Miller" 2 => "M. Zakowski" 3 => "J. Doherty" 4 => "K. Politi" 5 => "I. 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Original article

Epidermal Growth Factor Recetor mutation study for 5 years, in a population of patients with non-small cell lung cancer

Estudo da mutação do recetor do fator de crescimento epidérmico, durante 5 anos, numa população de doentes com cancro do pulmão de não pequenas células

A.S. Castroa,

, B. Parentea,¿¿, I. Gonçalvesa, A. Antunesa, A. Barrosoa, S. Condea, S. Nevesa, J.C. Machadob

a Unidade de Pneumologia Oncológica, Serviço de Pneumologia, Centro Hospitalar Vila Nova de Gaia-Espinho, Vila Nova de Gaia, Portugal

b Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Porto, Portugal

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    "titulo" => "Epidermal Growth Factor Recetor mutation study for 5 years&#44; in a population of patients with non-small cell lung cancer"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">A&#46; Mutated patients versus non mutated patients overal survival &#40;47 vs 22 months&#59; p&#61;0&#44;038&#41;&#46; B&#46; Median survival after erlotinib in EGFR mutated-positive vs negative patients &#40;14 vs 6 months&#44; p&#61;0&#44;003&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Prognostic and predictive factors in lung cancer are important for patient and doctor&#44; because they provide a more accurate prognosis &#40;in terms of recurrence of the disease&#44; progression and survival&#41;&#44; and help establish the best treatment&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The classic prognostic factors include smoking history&#44; general health status and co-morbidities&#46; Nowadays there are also molecular markers that have become prognostic factors&#44; and the most carefully studied are&#58; <span class="elsevierStyleItalic">epidermal growth factor receptor &#40;EGFR&#41;</span> and <span class="elsevierStyleItalic">KRAS</span> mutation&#44; which in association with histology are considered potential predictive factors&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Early identification of the subpopulation of patients most likely to respond to a particular treatment is currently the main goal of lung cancer treatment&#59; this not only increases the probability of response but also avoids unnecessary treatment for those patients who are unlikely to benefit from it&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">There is not a reliable lung cancer record in Portugal and so it is very difficult to define our national epidemiological profile or the actual NSCLC incidence rate and therefore difficult to make a clinical assessment of potential treatment&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In 2000 and 2002&#44; the Portuguese Pulmonology Society Ontological Commission<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#44; carried out a study involving 22 Portuguese hospitals&#44; in which 4396 new lung cancer cases were registered&#59; the most frequent histological subtype was adenocarcinoma and 76&#46;9&#37; of the cases were patients with advanced or metastatic disease&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Although it is our understanding that of these patients with advanced disease&#44; only 10&#8211;12&#37; might benefit from 1st line tyrosine kinase inhibitor &#40;TKI&#41;&#44; the appearance of <span class="elsevierStyleItalic">EGFR-</span>TKI was significant for advanced or metastatic NSCLC treatment&#44; first line in patients with <span class="elsevierStyleItalic">EGFR</span> mutation and even in second and third line therapy&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">There are several clinical and molecular parameters that are useful for predicting which patients with NSCLC advanced disease are most likely to benefit from treatment with TK inhibitors&#44; both for initial therapy or as second-line therapy&#46; These indicators&#44; from phase II<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2-5</span></a> and III<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> studies which identified a number of clinical parameters associated with better clinical response&#44; are adenocarcinoma&#44; female gender&#44; non-smoking and Asian ethnicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7-9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Specific <span class="elsevierStyleItalic">EGFR TK</span> domain activating mutations &#40;exons 18-21&#41; are usually associated with an increased response to TK inhibitors&#44; erlotinib or gefitinib&#44; which occur&#44; according to the literature&#44; in Europe in 10-15&#37; of patients with NSCLC and have easily manageable side effects&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The &#8220;gold standard&#8221; method for <span class="elsevierStyleItalic">EGFR</span> mutation analysis is direct DNA sequencing &#40;exons 18-21&#41;&#46; The percentage of mutations in each exon is still controversial&#59; the majority of studies&#44; including the Spanish group<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#44; only studied exons 19 and 21 &#40;and only the mutation <span class="elsevierStyleItalic">Leu858Arg</span>&#41;&#46; There has also been mention of mutations also in exons 18 and 20 and some of which had predictive value of response&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Values such as 5&#37; were found in exon 18&#44; 49&#37; in exon 19&#44; 1&#37; in exon 20 and 45&#37; in exon 21&#46; The positive predictive value of <span class="elsevierStyleItalic">Gly719</span> mutation in exon 18&#44; and the negative predictive value of exon 20 insertions<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> are well established&#46; Penzel <span class="elsevierStyleItalic">et al</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> in 1047 analyzed cases&#44; found a 15&#44;6&#37; mutation rate &#40;exon 18&#8211;10&#44;4&#37;&#44; exon 19&#8211;49&#44;7&#37;&#44; exon 20&#8211;5&#44;5&#37; exon 21&#8211;34&#44;4&#37;&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">There is also no also consensus as to which group of patients should be examined for <span class="elsevierStyleItalic">EGFR</span> mutation and studies have typically excluded patients with epidermoid tumors and heavy smokers&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Neither is there a defined consensus about which is the best biopsy value &#40;primary tumor <span class="elsevierStyleItalic">vs</span> metastases&#41; for the mutation study&#59; however&#44; whenever possible&#44; the first study of <span class="elsevierStyleItalic">EGFR</span> mutations is performed in primary tumor and not in the metastases&#46; It is not common to perform a new puncture or biopsy in patients who are progressing when treated with ITK&#46; In about 50&#37; of progression cases <span class="elsevierStyleItalic">Thr790Met</span> &#40;exon 20&#41; mutation occurs&#46; This mutation provides resistance to treatment with TKIs&#44; but that is a secondary mutation which appears only after treatment and resistance acquisition and is only very rarely a primary mutation &#40;although some authors argue that it may already have been present in sub-clones of residual tumor cells before treatment with TKIs&#41;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The best responses to treatment are obtained in patients with exon 19 deletions and in exon 21 <span class="elsevierStyleItalic">Leu858Arg</span> mutation&#44; although results tend to be slightly lower than exon 19 deletion&#59; exon 18 <span class="elsevierStyleItalic">Gly719</span> mutations and exon 21 <span class="elsevierStyleItalic">Leu 861</span> are associated with a good response&#46; The evidence for this is clinical and experimental &#40;in vitro&#41;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In 2006&#44; Gaia-Espinho Hospital Center &#40;CHGE&#41; Pulmonology Service&#44; Pulmonary Oncology Unit &#40;POU&#41;&#44; started performing <span class="elsevierStyleItalic">EGFR</span> gene mutation sequencing in collaboration with IPATIMUP &#40;Oporto University Molecular Pathology and Immunology Institute&#41; in selected patients and by this time erlotinib had been approved in Portugal for use in 2nd and 3rd line therapy&#46; In 2010&#44; with the approval of gefitinib for first line therapy&#44; systematic sequencing was started in all NSCLC patients regardless of histology&#44; stage&#44; smoking habits or sex&#44; and treatment with Gefitinib in 1st line all patients with positive <span class="elsevierStyleItalic">EGFR</span> mutation&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> We therefore decided on a prospective epidemiological data collection&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle">Material and Methods</span><p id="par0070" class="elsevierStylePara elsevierViewall">We present the results of a continuous record&#44; of research for <span class="elsevierStyleItalic">EGFR</span> mutations in patients with NSCLC&#44; which was carried out in the CHGE Pulmonology Department between 2006 and 2010&#46; We evaluated the results obtained after 2nd and 3rd line treatment with ITK in NSCLC patients with advanced disease who were studied for <span class="elsevierStyleItalic">EGFR</span> mutation&#46; The 1st-line treatment results in mutated patients are not presented&#44; as the number of cases is still small&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Between 2006 and 2009&#44; the inclusion criteria for the <span class="elsevierStyleItalic">EGFR</span> mutations study were adenocarcinoma histology&#44; non-smokers or former smokers&#44; regardless of gender&#46; In 2010&#44; the inclusion criteria were diagnosis of NSCLC &#40;regardless of gender&#41;&#44; disease stage or smoking habits&#46; Patients were classified according to their smoking habits as&#58; smokers&#44; former smokers &#40;patients that had given up for more than 12 months&#41; and nonsmokers&#46; The material available for analysis and the average delay of exam results&#44; according to the material submitted were also taken into account&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In patients with advanced stage treated in second and 3rd line with erlotinib between 2006 and 2010&#44; the evaluated parameters included age&#44; sex&#44; smoking&#44; histology&#44; TNM stage at presentation&#44; chemotherapy prior schemes&#44; <span class="elsevierStyleItalic">EGFR</span> mutational state and overall survival according to mutational status&#44; median overall survival after erlotinib&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">All statistical calculations were performed using <span class="elsevierStyleItalic">SPSS</span> &#40;<span class="elsevierStyleItalic">Statistical Package for the Social Sciences</span>&#41; software version 17&#46;0&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle">Results</span><p id="par0090" class="elsevierStylePara elsevierViewall">In the period between January 1st 2006 and December 31st 2010&#44; <span class="elsevierStyleItalic">EGFR</span> sequencing was carried out in 374 patients with NSCLC &#40;248 patients between 2006 and 2009 and 126 patients in 2010&#41;&#46; Of the total number of analyzed patients&#44; 266 &#40;71&#46;1&#37;&#41; were male and 108 &#40;28&#46;9&#37;&#41; female&#46; The average age was 64&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;3 years&#46; 35&#46;8&#37; were former smokers&#44; 31&#46;3&#37; non-smokers and 32&#46;9&#37; smokers&#46; The predominant histological type was adenocarcinoma&#44;57&#46;8&#37;&#44; followed by squamous cell carcinoma - 23&#46;5&#37; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">10&#46;1&#37; of patients were in TNM stage I&#44; 2&#46;4&#37; of cases in stage II&#44; 5&#46;8&#37; in stage IIIA and in stage IIIB &#47; IV 81&#46;6&#37; of cases&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">EGFR</span> gene mutations were detected in 49 out of 374 patients&#44; corresponding to a 13&#46;1&#37; mutation rate &#40;the mutation rate was 9&#37; in males and 23&#37; in females&#41;&#46; Of the total number of mutated patients&#44; 46&#46;9&#37; were non-smokers and 59&#46;2&#37; were adenocarcinomas&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;</p><p id="par0105" class="elsevierStylePara elsevierViewall">When considered separately&#44; the mutation rate in selected patients &#40;2006&#47;2009&#41; was 16&#46;3&#37; <span class="elsevierStyleItalic">vs</span> 10&#46;4&#37; in 2010&#44; the year the mutation study began to be carried out on all patients with NSCLC&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The exon distribution was&#58; 10&#46;2&#37; in exon 18&#44; 38&#46;8&#37; in exon 19 and 18&#46;4&#37; in exon 20 &#40;6&#46;2&#37; were of resistance&#41;&#44; 32&#44; 7&#37; in exon 21&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In female patients with positive mutation &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41;&#44; most were non-smokers &#40;22&#47;88&#44;0&#37;&#41; and had an adenocarcinoma histology predominance &#40;20&#47;80&#44;0&#37;&#41;&#46; In this subgroup&#44; 44&#37; of mutations occurred in exon 19&#44; 28&#37; in exon 21&#44; 12&#37; in exon 18&#58;12&#37; in exon 20&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In mutated men &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41;&#44; 91&#46;7&#37; were smokers or ex-smokers and the predominant histological type was squamous cell carcinoma&#44; in 45&#46;8&#37; of patients&#46; Mutations occurred 37&#46;5&#37; in exon 21&#44; 29&#46;2&#37; in exon 19&#44; 25&#37; in exon 20 and 8&#46;3&#37; in exon 18&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Non-smoker mutated patients &#40;23&#41;&#44; were mostly female &#40;21&#47;91&#44; 3&#37;&#41;&#44; 78&#46;3&#37; were adenocarcinomas&#44; 17&#46;4&#37; NSCLC and 4&#46;3&#37; squamous cell carcinomas&#46; In the majority of non-smokers&#44; mutation occurred in exon 19 &#40;43&#46;5&#37;&#41; and exon 21 &#40;34&#46;8&#37;&#41;&#44; followed by exon 18 &#40;13&#46;0&#37;&#41; and exon 20 &#40;4&#46;3&#37;&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The average delay-time for obtaining a sequencing result<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#44; varied according to the type of material available for study&#44; using blades the average was 20 days&#44; with paraffin block it took 8&#46;32 days and with cellular debris &#40;with fresh products EBUS BAT and other punctures in Pathology&#41; the result was available within 6&#46;5 days on average&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Of the total patients sequenced&#44; 71 with advanced or metastatic stage had 2nd and 3rd line treatment with erlotinib 150<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; up until death&#44; disease progression or unacceptable toxicity levels&#46; Within this subgroup of patients&#44; there were females &#40;43&#47;60&#44;6&#37;&#41;&#44; non-smokers &#40;31&#47;43&#44;7&#37;&#41; and predominantly patients with adenocarcinoma histology &#40;43&#47;60&#44;6&#37;&#41;&#46; <span class="elsevierStyleItalic">EGFR</span> mutation was positive in 20 patients &#40;19&#46;2&#37;&#41;&#44; 55&#37; men and 45&#37; women&#44; mainly non-smokers &#40;12&#47;60&#44; 0&#37;&#41; and with adenocarcinoma histology &#40;14&#47;70&#37;&#41;&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; Regarding overall response to treatment with erlotinib in patients with negative <span class="elsevierStyleItalic">EGFR</span> mutation &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>51&#41;&#44; 47&#46;9&#37; &#40;24&#41; had progressive disease&#44; 45&#44;1&#37; &#40;23&#41; stable disease and 7&#46;8&#37; &#40;4&#41; were in partial remission&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In the subgroup of patients with positive <span class="elsevierStyleItalic">EGFR</span> mutation treated with erlotinib &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41;&#44; 35&#44;0&#37; &#40;7&#41; showed progressive disease&#44; 50&#46;0&#37; &#40;10&#41; stable disease and 15&#46;0&#37; &#40;3&#41; partial remission&#44; in other words as would be expected there was better disease control in patients with positive <span class="elsevierStyleItalic">EGFR</span> mutations when compared to patients with negative mutation &#40;65&#46;0&#37; <span class="elsevierStyleItalic">vs</span> 52&#46;9&#37;&#41;&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">For <span class="elsevierStyleItalic">EGFR</span> mutation positive patients treated with erlotinib the overall survival rate vs&#46; non-mutated was 47 <span class="elsevierStyleItalic">vs</span> 22 months &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;038&#41;&#44; respectively&#46; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; The average survival rate after treatment with erlotinib in the positive <span class="elsevierStyleItalic">EGFR</span> mutation group was also higher in this subgroup when compared with patients with negative mutation &#40;14 <span class="elsevierStyleItalic">vs</span> 6 months&#44; respectively&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0150" class="elsevierStylePara elsevierViewall">Our group of patients showed a global &#40;2006-2010&#41; <span class="elsevierStyleItalic">EGFR</span> mutation rate of 13&#46;1&#37;&#46; The fact that between 2006 and 2009 there was patient selection has to be taken into account&#44; when the mutation rate was 16&#37; vs 10&#46;4&#37; in 2010 when the mutation study was performed on all patients with NSCLC regardless of sex and stage&#46; These figures add value to our knowledge about <span class="elsevierStyleItalic">EGFR</span> mutation rate in the Portuguese population&#46; The European prevalence <span class="elsevierStyleItalic">EGFR</span> mutations in lung cancer studies&#44; was 10&#37; in unselected patients&#46; In Spain&#44; <span class="elsevierStyleItalic">Rosell et al</span>&#44; found a mutation rate of 16&#46;6&#37;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#44; in a selected patients group with NSCLC in advanced stages&#46; The follow-up of our work &#40;which in 2011 and 2012 has also included an unselected population&#41; will give a reliable definition of the <span class="elsevierStyleItalic">EGFR</span> mutation profile in the Portuguese population and confirm the data presented here&#44; which includes data on the presence of the mutation in male patients&#44; squamous cell carcinomas and some smokers&#46; The difference in mutation rates however is very significant as regards the 2 sexes&#44; adenocarcinoma being responsible for most cases&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">It was possible to perform the <span class="elsevierStyleItalic">EGFR</span> gene sequencing in various types of diagnostic samples&#46; DNA sequencing from cellular debris &#40;fresh or after cell block&#41; was faster than paraffin block or blades&#46; This difference was statistically significant and impacted on when treatment started&#59; it was only possible when there was close collaboration between the various elements involved in lung cancer diagnosis &#40;Oncology&#44; Bronchology&#44; Interventional Radiology and Pathology&#41;&#46; In peripheral tumors or whenever it is possible to perform aspirative biopsies&#44; it should a priority to send this fresh material so as to obtain faster results &#40;6&#46;5 days after sending samples&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">EGFR</span> mutation study should be carried out routinely in all patients diagnosed with NSCLC&#44; and its use should be facilitated in all hospitals treating lung cancer&#44; to support proper treatment&#44; and to consider the use of TKI 1st-line in mutated patients&#44; which controls the disease better than conventional chemotherapy protocols&#46; All these assumptions are based on treatment response and overall survival rates in the group of patients treated with TKI&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#8211;18</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">The results of our sample in 2nd and 3rd line treatment showed statistical significance in the group of patients with positive <span class="elsevierStyleItalic">EGFR</span> mutation&#44; compared to patients with negative mutation&#44; despite the fact that the presence of EGFR mutation is not a mandatory condition for starting treatment&#46; We still do not have enough patients to present the results of the mutated patients with 1st line treatment with TKIs&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">5</span><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Palavras-chave"
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    "fechaRecibido" => "2012-01-12"
    "fechaAceptado" => "2012-08-30"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Non Small Cell Lung Cancer"
            1 => "Epidermal Growth Factor Receptor"
            2 => "Tyrosine kinase inhibitor"
            3 => "Survival"
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            0 => "Carcinoma pulmonar n&#227;o pequenas c&#233;lulas"
            1 => "Recetor do fator de crescimento epid&#233;rmico"
            2 => "Inibidores da tirosina quinase"
            3 => "Sobrevida"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">In 2006&#44; the Vila Nova de Gaia&#47;Espinho Hospital Centre Pulmonary Oncology Unit started performing EGFR &#40;Epidermal Growth Factor Receptor&#41; mutation sequencing in selected patients with NSCLC and systematically in all patients since 2010&#44; regardless of histology&#44; smoking habits&#44; age or sex&#46; The aim of this study was to characterize the group of patients that carried out the sequencing between 2006-2010&#44; to determine EGFR mutation frequency&#44; to evaluate the overall survival and the survival after the use of tyrosine kinase inhibitors &#40;TKI&#41;&#44; in patients who performed this therapy in second and third line&#44; knowing the EGFR mutation status&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Descriptive statistical analysis of patients who did EGFR sequencing in 2006-2010 and of overall survival in patients treated with TKI as 2nd and 3rd line therapy&#46; Record of the material available for analysis and average delay of exam results&#44; according to the material submitted&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The sequencing was performed in 374 patients&#44; 71&#44;1&#37; males&#44; 67&#44;1&#37; non&#47;ex-smokers&#44; 32&#44;9&#37; smokers&#44; 57&#44;8&#37; adenocarcinoma and 23&#44;5&#37; squamous cell carcinoma &#40;SCC&#41;&#46; The mutation was detected in 49 patients &#40;13&#44;1&#37;&#41;&#46; In all studied patients&#44; the mutation rate was 9&#37; in males and 23&#37; in females&#46; Median overall survival after erlotinib use of was 14 months for patients with positive EGFR mutation versus 6 months in not mutated patients &#40;p &#61; 0&#46;003&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusion</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Our group had an overall mutation rate of 13&#46;1&#37; with female&#44; non-smokers&#44; adenocarcinoma histology predominance&#46; In selected patients &#40;2006&#47;2009&#41;&#44; the mutation rate was 16&#37;&#44; in not selected patients &#40;2010&#41; the mutation rate was 10&#46;4&#37;&#46; This study has permitted a better understanding of the EGFR mutation rate in the Portuguese population as welll as an evaluation of the patients survival after the use of of tyrosine kinase inhibitors&#44; in second and third line therapy with previous knowledge of the EGFR mutational status&#46; Statistical significant differences in survival were found in the two patient groups &#40;EGFR mutated and non mutated&#41;&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The EGFR mutation research should be performed in all patients with NSCLC&#44; giving the possibility to a considerable number of patients to perform a first line treatment with TKI &#40;EGFR mutated patients&#41; and the advantage of performing other chemotherapy schemes&#44; when progression occurs&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introdu&#231;&#227;o</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Em 2006&#44; a Unidade de Pneumologia Oncol&#243;gica do Servi&#231;o de Pneumologia do Centro Hospitalar de Vila Nova de Gaia&#47;Espinho iniciou a sequencia&#231;&#227;o da muta&#231;&#227;o do <span class="elsevierStyleItalic">recetor do fator de crescimento epid&#233;rmico &#40;EGFR&#41;</span> em doentes com CPNPC selecionados e desde 2010 realiza a sequencia&#231;&#227;o sistematicamente em todos os doentes&#44; independentemente da histologia&#44; h&#225;bitos tab&#225;gicos&#44; idade ou sexo&#46; O objetivo deste trabalho foi caracterizar o grupo de doentes que efetuou a sequencia&#231;&#227;o entre 2006-2010&#44; determinar a frequ&#234;ncia da muta&#231;&#227;o <span class="elsevierStyleItalic">EGFR</span>&#44; avaliar as sobrevidas globais e ap&#243;s uso de inibidores da tirosina quinase &#40;ITK&#41;&#44; nos doentes que efetuaram esta terap&#234;utica em 2&#46;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">a</span></span> e 3&#46;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">a</span></span> linha com conhecimento do estado da muta&#231;&#227;o do <span class="elsevierStyleItalic">EGFR</span>&#46;</p> <span class="elsevierStyleSectionTitle">M&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">An&#225;lise estat&#237;stica descritiva dos doentes que efetuaram sequencia&#231;&#227;o <span class="elsevierStyleItalic">EGFR</span> em 2006-2010 e sobrevida mediana global nos doentes que efetuaefetuaram ITK em 2&#46;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">a</span></span> e 3&#46;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">a</span></span> linha&#46; Registo do material dispon&#237;vel para an&#225;lise e demora m&#233;dia de resultado do exame&#44; de acordo com o material enviado&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A sequencia&#231;&#227;o foi efetuada em 374 doentes&#44; 71&#44;1&#37; sexo masculino&#44; 67&#44;1&#37; n&#227;o&#47;ex-fumadores&#44; 32&#44;9&#37; fumadores&#59; 57&#44;8&#37; adenocarcinoma e 23&#44;5&#37; carcinoma epidermoide &#40;CE&#41;&#46; A muta&#231;&#227;o foi detetada em 49 doentes &#40;13&#44;1&#37;&#41;&#46; No total dos doentes estudados&#44; a taxa de muta&#231;&#227;o foi de 9&#37; no sexo masculino e 23&#37; no sexo feminino&#46; A sobrevida mediana global ap&#243;s o uso de erlotinib foi de 14 meses para os doentes com muta&#231;&#227;o positiva do <span class="elsevierStyleItalic">EGFR versus</span> 6 meses nos doentes n&#227;o mutados &#40;p&#160;&#61;&#160;0&#44;003&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclus&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O nosso grupo teve uma taxa de muta&#231;&#227;o global de 13&#44;1&#37;&#44; com predom&#237;nio no sexo feminino&#44; n&#227;o fumadores&#44; histologia adenocarcinoma&#46; Em doentes selecionados &#40;2006&#47;2009&#41;&#44; a taxa de muta&#231;&#227;o foi de 16&#37;&#59; nos doentes n&#227;o selecionados &#40;2010&#41; foi de 10&#44;4&#37;&#46; Este estudo tem vindo a permitir um melhor conhecimento da taxa de muta&#231;&#227;o do <span class="elsevierStyleItalic">EGFR</span> na popula&#231;&#227;o portuguesa&#44; bem como avaliar os resultados das sobrevidas dos doentes ap&#243;s uso de inibidores da tirosina quinase &#40;ITK&#41;&#44; efetuada em 2&#46;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">a</span></span> e 3&#46;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">a</span></span> linha com conhecimento pr&#233;vio do estado da muta&#231;&#227;o do <span class="elsevierStyleItalic">EGFR</span>&#44; tendo sido encontradas diferen&#231;as nas sobrevidas nos 2 grupos de doentes &#40;mutados e n&#227;o mutados&#41; com significado estat&#237;stico&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A pesquisa muta&#231;&#227;o do <span class="elsevierStyleItalic">EGFR</span> deve ser efetuada em todos os doentes com CPNPC&#44; dando possibilidade a um n&#250;mero consider&#225;vel de doentes de poder efetuar um tratamento de 1&#46;<span class="elsevierStyleSup"><span class="elsevierStyleItalic">a</span></span> linha com ITK &#40;doentes mutados&#41;&#44; bem como de poder usufruir de outros esquemas de quimioterapia&#44; quando progredirem&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Castro&#44; AS Estudo da muta&#231;&#227;o do <span class="elsevierStyleItalic">recetor do fator de crescimento epid&#233;rmico</span>&#44; durante 5 anos&#44; numa popula&#231;&#227;o de doentes com cancro do pulm&#227;o de n&#227;o pequenas c&#233;lulas&#46; Rev Port Pneumol 2012&#46; <span class="elsevierStyleInterRef" href="http://dx.doi.org/10.1016/j.rppneu.2012.08.002">http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;1016&#47;j&#46;rppneu&#46;2012&#46;08&#46;002</span></p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">A&#46; Mutated patients versus non mutated patients overal survival &#40;47 vs 22 months&#59; p&#61;0&#44;038&#41;&#46; B&#46; Median survival after erlotinib in EGFR mutated-positive vs negative patients &#40;14 vs 6 months&#44; p&#61;0&#44;003&#41;&#46;</p>"
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                  """
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>18&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;12&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47; 8&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#47;44&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#47;29&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;12&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#47;28&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#47;37&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Type of material&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Average time delay &#40;days&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Time difference &#40;days&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">paraffin block&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Citology blades&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44;6721&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;0255&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Histology blades&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#44;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#44;0888&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44;1108&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">cellular debris&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#44;5556&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-1&#44;7723&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;1789&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>male&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">28&#47;39&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#47;55&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>female&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#47;60&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#47;45&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#44;46&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">24&#47;33&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">7&#47;35&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>smoker&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#47;22&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;15&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>non-smoker&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#47;43&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#47;60&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Histology</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#47;60&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#47;70&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Other histology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#47;39&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;30&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Response to Erlotinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EGFR -<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">EGFR &#43;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Parcial Remission</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#47;7&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;15&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Stable disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#47;45&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#47;50&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Progressive disease</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#47;47&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#47;35&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Median overal survival</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">22 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">47 months&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Survival after Erlotinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 months&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 months&nbsp;\t\t\t\t\t\t\n
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                  """
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Demographic data concerning the group of patients treated with erlotinib and treatment response&#46;</p>"
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Article information

ISSN: 21735115
Original language: English

DOI:10.1016/j.rppnen.2013.01.002

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