***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: BACKGROUND We conducted a r and omized , placebo-controlled , double-blind trial to determine whether the epidermal growth factor receptor inhibitor erlotinib prolongs survival in non-small-cell lung cancer after the failure of first-line or second-line chemotherapy . METHODS Patients with stage IIIB or IV non-small-cell lung cancer , with performance status from 0 to 3 , were eligible if they had received one or two prior chemotherapy regimens .  The patients were stratified according to center , performance status , response to prior chemotherapy , number of prior regimens , and prior platinum-based therapy and were r and omly assigned in a 2:1 ratio to receive oral erlotinib , at a dose of 150 mg daily , or placebo . RESULTS The median age of the 731 patients who underwent r and omization was 61.4 years ; 49 percent had received two prior chemotherapy regimens , and 93 percent had received platinum-based chemotherapy .  The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group ( P<0.001 ) ; the median duration of the response was 7.9 months and 3.7 months , respectively . Progression-free survival was 2.2 months and 1.8 months , respectively ( hazard ratio , 0.61 , adjusted for stratification categories ; P<0.001 ) . Overall survival was 6.7 months and 4.7 months , respectively ( hazard ratio , 0.70 ; P<0.001 ) , in favor of erlotinib . Five percent of patients discontinued erlotinib because of toxic effects . CONCLUSIONS Erlotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy PURPOSE In non-small-cell lung cancer ( NSCLC ) , clinical and biologic predictors for epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor sensitivity have been identified in retrospective studies , and there is urgent need to vali date these results in prospect i ve trials . The ONCOBELL trial is a prospect i ve phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or have increased EGFR gene copy number or activation of the antiapoptotic protein Akt . PATIENTS AND METHODS EGFR gene copy number was evaluated using fluorescence in situ hybridization ( FISH ) , and presence of phospho-Akt was evaluated using immunohistochemistry . Additional tests included immunohistochemistry analysis of EGFR , FISH analysis of HER2 , and mutation analysis of EGFR , HER2 , and K-ras . RESULTS From November 2004 to February 2006 , 183 patients were screened , and 42 patients were enrolled onto the trial . We observed one complete and 19 partial responses , for an overall response rate ( RR ) of 47.6 % ( 95 % CI , 32.5 % to 62.7 % ) . Median duration of response was 6.1 months , median time to progression ( TTP ) was 6.4 months , 1-year survival rate was 64.3 % , and median survival time was not reached . EGFR FISH-positive patients , compared with negative patients , had higher RR ( 68.0 % v 9.1 % , respectively ; P < .001 ) , longer TTP ( 7.6 v 2.7 months , respectively ; P = .02 ) , and a trend for longer survival ( median survival not reached v 7.4 months , respectively ; P = .3 ) . Therapy was well tolerated , and there were no drug-related deaths . Median follow-up time was too short for significance tests of differences in survival outcomes . CONCLUSION Gefitinib is active and well tolerated in patients with trial characteristics , and EGFR FISH analysis is an accurate predictor for such therapy 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 PURPOSE Epidermal growth factor receptor ( EGFR ) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer ( NSCLC ) . The implication s of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown . KRAS is frequently activated in NSCLC . The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described . PATIENTS AND METHODS Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were r and omly assigned to carboplatin and paclitaxel with erlotinib or placebo  were assessed for survival , response , and time to progression ( TTP ) . EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients . Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses . RESULTS EGFR mutations were detected in 13 % of tumors and were associated with longer survival , irrespective of treatment ( P < .001 ) . Among erlotinib-treated patients , EGFR mutations were associated with improved response rate ( P < .05 ) and there was a trend toward an erlotinib benefit on TTP ( P = .092 ) , but not improved survival ( P = .96 ) . KRAS mutations ( 21 % of tumors ) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients . CONCLUSION EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib , and may predict greater likelihood of response . Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy . Further studies are needed to confirm the findings of this retrospective subset analysis PURPOSE To evaluate the relationship between mutations of the epidermal growth factor receptor ( EGFR ) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection . PATIENTS AND METHODS We sequenced exons 18 - 21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer .  Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen ( CEA ) levels . RESULTS EGFR mutations were found in 33 patients ( 56 % ) . Of these mutations , 17 were deletions around codons 746 - 750 and 15 were point mutations ( 12 at codon 858 , three at other codons ) , and one was an insertion . EGFR mutations  were significantly more prevalent in females , adenocarcinoma , and never-smokers .  Gefitinib treatment result ed in tumor shrinkage and /or CEA decrease to less than half of the baseline level in 26 patients , tumor growth and /or CEA elevation in 24 patients , and  gefitinib effect was not assessable in nine patients . Female , never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment . Gefitinib was effective in 24 of 29 patients with EGFR mutations , compared with two of 21 patients without mutations ( P < .0001 ) . Of note , del746 - 750 might be superior to L858R mutations for prediction of gefitinib response . Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment ( P = .0053 ) . CONCLUSION EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting Purpose : Erlotinib has proven activity in pretreated patients with advanced non – small cell lung cancer ( NSCLC ) . We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome . Experimental Design : In this phase II study , chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib ( 150 mg/d ) until disease progression or unacceptable toxicity occurred . Tumor response was assessed every 6 weeks , and sample s were analyzed for potential molecular markers of treatment response and survival . The primary end point was the proportion of patients without disease progression after 6 weeks of treatment . Results : Fifty-three patients were eligible . The overall rate of nonprogression at 6 weeks was 52.8 % ( 28 of 53 patients ) . Tumor response rate was 22.7 % , with 1 complete response , 11 partial responses , and 16 cases of stable disease . Responses were seen across most patient clinical characteristics . The median duration of tumor response was 333 days ; median overall survival was 391 days ; and median time to disease progression was 84 days . Erlotinib was well tolerated , the main treatment-related adverse events being mild-to-moderate rash and diarrhea . Histologic material for biological studies was available in 29 cases . Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation . Two progressing patients exhibited epidermal growth factor receptor point mutations ( one with T790 M mutation ) , and K-ras mutations were detected in 10 nonresponders . Conclusions : Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy . Patient selection can not easily be based on clinical or biological variables PURPOSE The phase III Iressa Survival Evaluation in Lung Cancer ( ISEL ) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer . We analyzed ISEL tumor biopsy sample s to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting . METHODS Biomarkers included epidermal growth factor receptor ( EGFR ) gene copy number by fluorescence in situ hybridization ( n = 370 ) ; EGFR ( n = 379 ) and phosphorylated Akt ( p-Akt ) protein expression ( n = 382 ) by immunohistochemistry ; and mutations in EGFR ( n = 215 ) , KRAS ( n = 152 ) , and BRAF ( n = 118 ) . RESULTS High EGFR gene copy number was a predictor of a gefitinib-related effect on survival ( hazard ratio [ HR ] , 0.61 for high copy number and HR , 1.16 for low copy number ; comparison of high v low copy number HR , P = .045 ) . EGFR protein expression was also related to clinical outcome ( HR for positive , 0.77 ; HR for negative , 1.57 ; comparison of high v low protein expression HR , P = .049 ) . Patients with EGFR mutations had higher response rates than patients without EGFR mutations ( 37.5 % v 2.6 % ) ; there were insufficient data for survival analysis . No relationship was observed between p-Akt protein expression and survival outcome , and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations . CONCLUSION EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL . Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment 
    Output:
    
Conclusion In conclusion , EGFR mutation and protein expression status may provide useful clinical information in terms of the likelihood of tumor response and disease prognosis .