***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose : All patients with EGF receptor (EGFR)–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors ( TKI ) . Smaller series have identified various mechanisms of resistance , but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted . Experimental Design : Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib  enrolled onto a prospect i ve biopsy protocol and underwent a rebiopsy after the development of acquired resistance . Histology was review ed . Sample s underwent genotyping for mutations in EGFR , AKT1 , BRAF , ERBB2 , KRAS , MEK1 , NRAS and PIK3CA , and FISH for MET and HER2 . Results : Adequate tumor sample s for molecular analysis were obtained in 155 patients . Ninety-eight had second-site EGFR T790 M mutations [ 63 % ; 95 % confidence interval ( CI ) , 55%–70 % ] and four had small cell transformation ( 3 % , 95 % CI , 0%–6 % ) . MET amplification was seen in 4 of 75 ( 5 % ; 95 % CI , 1%–13 % ) . HER2 amplification was seen in 3 of 24 ( 13 % ; 95 % CI , 3%–32 % ) . We did not detect any acquired mutations in PIK3CA , AKT1 , BRAF , ERBB2 , KRAS , MEK1 , or NRAS ( 0 of 88 , 0 % ; 95 % CI , 0%–4 % ) . Overlap among mechanisms of acquired resistance was seen in 4 % . Conclusions : This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy . We identified EGFR T790 M as the most common mechanism of acquired resistance , whereas MET amplification , HER2 amplification , and small cell histologic transformation occur less frequently . More comprehensive methods to characterize molecular alterations in this setting are needed to improve our underst and ing of acquired resistance to EGFR-TKIs . Clin Cancer Res ; 19(8 ) ; 2240–7 . © 2013 AACR Purpose : Somatic mutations in the epidermal growth factor receptor ( EGFR ) have been detected in patients with non – small cell lung cancer ( NSCLC ) and are associated with sensitivity to treatment with gefitinib or erlotinib . Our study explored the relationship between the two most common types of somatic EGFR mutations , exon 19 deletions and the L858R point mutation , and outcomes of patients following treatment with gefitinib or erlotinib .  Experimental Design : Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations . Patients with exon 19 deletion or L858R mutations were identified . The response rate , time to progression , and overall survival were determined for the two groups . Results : We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib .  Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation ( 38 versus 17 months ; P = 0.04 ) . There were also trends toward higher response rate ( 73 % versus 50 % ) and improved time to progression ( 24 versus 10 months ) for the patients with an exon 19 deletion , although these were not independently significant in a multivariate analysis . A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [ 18 of 23 ( 78 % ) versus 3 of 9 ( 33 % ) ; P = 0.04 ] . No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients . Conclusions : Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation . Pooling of greater numbers of patients and completion of prospect i ve trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib , erlotinib , and other EGFR inhibitors This study was design ed to prospect ively evaluate the efficacy and safety of first-line gefitinib treatment in patients with advanced pulmonary adenocarcinoma harboring epidermal growth factor receptor ( EGFR ) mutations and to explore the molecular factors affecting the efficacy of gefitinib . Tumor tissue , derived from either the original tumor or the metastatic or recurrent site was taken from chemo-naïve pts with advanced ( stage IIIB , IV , and recurrent ) pulmonary adenocarcinoma . Tumor genomic DNA underwent direct sequencing for EGFR exons 18 , 19 , 20 , and 21 . Patients with EGFR mutations received 250 mg of gefitinib daily until disease progression or unacceptable toxicity . The primary endpoint was objective response rate ( ORR ) . Secondary endpoints were progression free survival ( PFS ) , overall survival ( OS ) and tolerability .  Out of 147 screened patients , 45 pts ( 31 % ) had EGFR mutations and received  gefitinib . The most common EGFR mutations were in-frame exon 19 deletions ( 29 pts , 64 % ) and L858R point mutation in exon 21 ( 15 pts , 33 % ) . One patient had atypical mutation of L861Q in exon 21 . The ORR was 53.3 % ( 95 % CI , 38.6 - 67.9 ) and disease control rate ( DCR ) including stable disease was 86.7 % . The median progression free survival ( PFS ) was 398 days and the median overall survival ( OS ) was 819 days . Treatment was well tolerated . Grade 3/4 adverse events ( AEs ) were reported by 6 patients and treatment-related Grade 3 AEs by 3 patients . There were no treatment-related Grade 4 AEs . Exploratory subgroup analysis according to the EGFR mutation subtypes was carried out . The ORR and DCR were higher in patients with exon 19 deletions than those with L858R ( 62.1 % vs 33.3 % ; P=0.0705 and 96.6 % vs 66.7 % ; P=0.0062 , respectively ) . All 4 patients with progressive disease had a L858R mutation . No secondary resistant mutations such as T790 M mutation or insertions in exon 20 were found in those patients . In addition , OS was significantly better in patients with exon 19 deletions than those with L858R ( 24-month OS rate was 72.1 % vs 32.0 % , P=0.0148 ) . Gefitinib as the first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations was effective and well tolerated . Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in patients with the exon 19 deletion mutations ( Clinical Trials.gov number , NCT00344773 ) Purpose : Patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors ( TKI ) after a median of 10 to 16 months . In half of these cases , a second EGFR mutation , T790 M , underlies acquired resistance . We undertook this study to examine the clinical course of patients harboring the T790 M mutation following progression on TKI .  Experimental Design : EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs  were identified as part of a prospect i ve rebiopsy protocol in which postprogression tumor specimens were collected for molecular analysis . Postprogression survival and characteristics of disease progression were compared in patients with and without T790 M . Results : We identified T790 M in the initial rebiopsy specimens from 58 of 93 patients ( 62 % , 95 % CI : 52–72 ) . T790 M was more common in biopsies of lung/pleura tissue and lymph nodes than in more distant sites ( P = 0.014 ) . Median postprogression survival was 16 months ( interquartile range = 9–29 months ) ; patients with T790 M had a significantly longer postprogression survival ( P = 0.036 ) . Patients without T790 M more often progressed in a previously uninvolved organ system ( P = 0.014 ) and exhibited a poorer performance status at time of progression ( P = 0.007 ) . Conclusions : Among patients with acquired resistance to EGFR TKIs , the presence of T790 M defines a clinical subset with a relatively favorable prognosis and more indolent progression . Knowledge of T790 M status is therefore important both for the clinical care of these patients and for the optimal design and interpretation of clinical trials in this setting . Clin Cancer Res ; 17(6 ) ; 1616–22 . © 2010 AACR Purpose : In patients with non – small cell lung cancer ( NSCLC ) , mutations in the epidermal growth factor receptor ( EGFR ) tyrosine kinase domain have been associated with sensitivity to erlotinib and gefitinib . We undertook this study to explore the relationship between EGFR mutation type and clinical variables , including treatment with gefitinib and erlotinib . Experimental Design : In patients with NSCLC , EGFR exon 19 deletion mutations and EGFR L858R point mutations were analyzed by nonsequencing PCR-based methods from paraffin blocks of tissue obtained before treatment . The results were correlated with clinical information ( sex , pathologic subtype , race/ethnicity , treatment , and overall survival ) . Results : The two most common EGFR mutations were identified in 24 % ( 70 of 291 ; 95 % confidence interval , 26%-38 % ) of tumors from patients with NSCLC .  EGFR mutation was associated with Asian ethnicity ( P = 0.0023 ) and being a “ never smoker ” ( P = 0.0001 ) . Among patients with EGFR mutations , 39 % ( 27 of 70 ) had EGFR L858R , whereas 61 % ( 43 of 70 ) had an EGFR exon 19 deletion . After treatment with erlotinib ( n = 12 ) or gefitinib ( n = 22 ) , patients with EGFR mutations had a median overall survival of 20 months . After treatment with erlotinib or gefitinib , patients with EGFR exon 19 deletions had significantly longer median survival than patients with EGFR L858R ( 34 versus 8 months ; log-rank P = 0.01 ) . Conclusions : EGFR mutations in exons 19 or 21 are correlated with clinical factors predictive of response to gefitinib and erlotinib . Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation . These observations warrant confirmation in a prospect i ve study and exploration of the biological mechanisms of the differences between the two major EGFR mutations BACKGROUND Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor ( TKI ) therapy in non-small-cell lung cancer ( NSCLC ) . The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus st and ard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC . METHODS We undertook an open-label , r and omised , phase 3 trial at 22 centres in China . Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received either oral erlotinib ( 150 mg/day ) until disease progression or unacceptable toxic effects , or up to four cycles of gemcitabine plus carboplatin . Patients were r and omly assigned ( 1:1 ) with a minimisation procedure and were stratified according to EGFR mutation type , histological subtype ( adenocarcinoma vs non-adenocarcinoma ) , and smoking status . The primary outcome was progression-free survival , analysed in patients with confirmed disease who received at least one dose of study treatment . The trial is registered at Clinical Trials.gov , number NCT00874419 , and has completed enrolment ; patients are still in follow-up . FINDINGS 83 patients were r and omly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin ; 82 in the erlotinib  group and 72 in the  chemotherapy group were included in analysis of the primary endpoint . Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy ( 13.1 [ 95 % CI 10.58 - 16.53 ] vs 4.6 [ 4.21 - 5.42 ] months ; hazard ratio 0.16 , 95 % CI 0.10 - 0.26 ; p<0.0001 ) . Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlot 
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Conclusions T790 M occurred more frequently in patients with the exon 19 deletion than in those with exon 21 L858R , which gave the survival benefit of the T790 M mutation and may explain why patients with the exon 19 deletion had an improved overall survival