***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 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 To evaluate the efficacy and tolerability of two doses of gefitinib ( Iressa [ ZD1839 ] ; AstraZeneca , Wilmington , DE ) , a novel epidermal growth factor receptor tyrosine kinase inhibitor , in patients with pretreated advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS This was a r and omized , double-blind , parallel-group , multicenter phase II trial . Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens ( at least one containing platinum )  were r and omly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily . RESULTS Efficacy was similar for the 250- and 500-mg/d groups . Objective tumor response rates were 18.4 % ( 95 % confidence interval [ CI ] , 11.5 to 27.3 ) and 19.0 % ( 95 % CI , 12.1 to 27.9 ) ; among evaluable patients , symptom improvement rates were 40.3 % ( 95 % CI , 28.5 to 53.0 ) and 37.0 % ( 95 % CI , 26.0 to 49.1 ) ; median progression-free survival times were 2.7 and 2.8 months ; and median overall survival times were 7.6 and 8.0 months , respectively . Symptom improvements were recorded for 69.2 % ( 250 mg/d ) and 85.7 % ( 500 mg/d ) of patients with a tumor response . Adverse events ( AEs ) at both dose levels were generally mild ( grade 1 or 2 ) and consisted mainly of skin reactions and diarrhea . Drug-related toxicities were more frequent in the higher-dose group . Withdrawal due to drug-related AEs was 1.9 % and 9.4 % for patients receiving gefitinib 250 and 500 mg/d , respectively . CONCLUSION Gefitinib showed clinical ly meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients . At 250 mg/d , gefitinib had a favorable AE profile . Gefitinib 250 mg/d is an important , novel treatment option for patients with pretreated advanced NSCLC [ corrected 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 Introduction : Relationships between clinical outcomes and epidermal growth factor receptor (EGFR)-related tumor markers were investigated in patients with advanced non-small cell lung cancer . Methods : Patients with stage IIIB/IV non-small cell lung cancer ( 0–2 prior regimens ) received erlotinib ( 150 mg PO per day ) .  Response and survival were evaluated , and tumor sample s were assessed by immunohistochemistry ( EGFR , phosphorylated mitogen-activated protein kinase , and phosphorylated AKT protein expression ) , fluorescence in situ hybridization ( FISH ; EGFR gene copy number ) , and DNA sequencing ( EGFR , KRAS gene mutations ) . Results : Among 311 patients , 8 % had a complete/partial response ; the disease control rate was 66 % . Median Overall survival ( OS ) was 6.1 months ; 1-year survival rate was 27.2 % . Two of 4 patients with EGFR mutations had tumor responses , versus 2/68 with wild-type EGFR ( p = 0.014 ) . Progression-free survival ( PFS ) ( HR = 0.31 ) and OS ( HR = 0.33 ) were significantly prolonged in patients with EGFR mutations . Response rate was significantly higher in patients with EGFR FISH-positive ( 17 % ) than FISH-negative tumors ( 6 % ) , and both PFS ( HR = 0.58 ) and OS ( HR = 0.63 ) significantly favored patients with EGFR FISH-positive tumors ; median OS was 8.6 months in the EGFR FISH-positive group . None of 17 patients with a KRAS mutation had a tumor response , but the impact of KRAS mutation status on survival outcomes was of borderline statistical significance . Neither phosphorylated mitogen-activated protein kinase nor phosphorylated AKT immunohistochemistry status had a significant effect on PFS and OS with erlotinib . Conclusions : The presence of EGFR mutations and EGFR FISH-positive tumors may predispose patients to achieving better outcomes on erlotinib , but may have a beneficial impact on prognosis ( irrespective of treatment ) . Prospect i ve , placebo-controlled studies are needed to determine the predictive value of the putative biomarkers Purpose : To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor ( EGFR ) signaling pathway in advanced non – small cell lung cancer patients refractory to platinum-based chemotherapy . Experimental Design : Patients were given erlotinib ( 150 mg/d ) . Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks ' treatment . Results : Of 73 evaluable patients , 7 ( 10 % ) had partial response and 28 ( 38 % ) had stable disease . In 53 patients with baseline tumor sample s , no relationship was observed between pretreatment levels of EGFR , phosphorylated (p)-EGFR , p-AKT , p-mitogen-activated protein kinase ( MAPK ) , or p27 and clinical benefit ( i.e. , response , or stable disease ≥12 weeks ) . Tumors from 15 of 57 patients had high EGFR gene copy number , assessed using fluorescence in situ hybridization ( FISH positive ) , 10 of whom had clinical benefit , compared with 5 of 42 FISH-negative patients . FISH-positive patients had longer median progression-free [ 137 versus 43 days , P = 0.002 ; hazard ratio ( HR ) , 0.37 ] and overall ( 226 versus 106 days , P = 0.267 ; HR , 0.70 ) survival than FISH-negative patients . In paired biopsy sample s from 14 patients , p-EGFR ( P = 0.002 ) , p-MAPK ( P = 0.001 ) , and Ki-67 ( P = 0.025 ) levels were significantly reduced after 6 weeks ' treatment . Apoptosis was significantly increased in patients with clinical benefit ( P = 0.029 ) , and may be a marker of clinical benefit . Conclusion : In this study , EGFR FISH-positive status was associated with improved  outcome after erlotinib therapy . Erlotinib led to reduced levels of p-EGFR , p-MAPK , and Ki-67 , and stimulated apoptosis in tumor sample s from patients with clinical benefit A number of different clinical characteristics and molecular markers related to epidermal growth factor receptor ( EGFR ) activation have been reported to singly correlate with therapeutic activity of EGFR tyrosine kinase inhibitors ( TKIs ) in advanced non-small cell lung cancer ( NSCLC ) . This study was design ed to evaluate the predictive value on gefitinib outcomes of a comprehensive panel of molecular parameters in advanced NSCLC patients . EGFR and K-ras mutations were detected by direct sequencing on tumor DNA from paraffin embedded sample s. EGFR and HER2 gene copy number was assessed by FISH . EGFR protein expression was quantified by immunohistochemistry . EGFR gene intron 1 polymorphism was assessed on genomic DNA isolated from venous whole blood sample s. Ninety-one patients were prospect ively enrolled and the overall gefitinib  response rate was 18.7 % ( 2 complete and 15 partial responses ) . Sex ( p=0.005 ) , non-smoking status ( p=0.010 ) , skin toxicity ( p=0.020 ) , EGFR gene mutations ( p<0.001 ) and EGFR FISH positivity ( p=0.016 ) were found to be associated with gefitinib response . K-ras mutation was detected in only seven non-responder patients . The median overall survival was of 10 months . Only non-smoking status and EGFR intron 1 polymorphism showed a statistically significant correlation with survival ( p=0.031 and 0.044 , respectively ) . In conclusion , we have confirmed the role of EGFR gene mutation as predictor of response to EGFR TKIs . Moreover , EGFR gene copy number and , potentially , also EGFR intron 1 polymorphism could aid in better prediction of EGFR TKI responsiveness in advanced NSCLC PURPOSE Erlotinib is a highly specific epidermal growth factor receptor ( HER1/EGFR ) tyrosine kinase inhibitor . This phase II study of erlotinib in patients with HER1/EGFR-expressing non-small-cell lung cancer previously treated with platinum-based chemotherapy evaluated tumor response , survival , and symptom improvement . PATIENTS AND METHODS Fifty-seven patients received an oral , continuous daily dose of 150 mg of erlotinib . Assessment s of objective response used WHO and Response Evaluation Criteria in Solid Tumors criteria . The European Organization for Research and Treatment of Cancer Quality of Life Question naire C30 , supplemented with a lung cancer module ,  Quality of Life Question naire LC13 , was used to measure health-related quality of life .  Additional analyses were performed to identify predictors of response and survival . RESULTS The objective response 
    Output:
    
The result of the analysis found that EGFR gene copy number was associated with increased OS and PFS , supporting the idea that EGFR gene copy number is a biomarker for response to EGFR-TKI therapy in patients with advanced NSCLC