***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 Biomarkers can add substantial value to current medical practice by providing an integrated approach to prediction using the genetic makeup of the tumor and the genotype of the patient to guide patient-specific treatment selection . We discuss and evaluate various clinical trial design s for the validation of biomarker-guided therapy . METHODS Design s for predictive marker validation are broadly classified as retrospective ( ie , using data from previously well-conducted r and omized controlled trials [ RCTs ] ) versus prospect i ve ( enrichment , unselected , hybrid , or adaptive analysis ) . We discuss the salient features of each design in the context of real trials . RESULTS Well- design ed retrospective analysis from well-conducted prospect i ve RCTs can bring forward effective treatments to marker-defined subgroups of patients in a timely manner ( eg , KRAS and colorectal cancer ) . Enrichment design s are appropriate when preliminary evidence suggest that patients with or without that marker profile do not benefit from the treatments in question ; however , this may sometimes leave questions unanswered ( eg , trastuzumab and breast cancer ) . An unselected design is optimal where preliminary evidence regarding treatment benefit and assay reproducibility is uncertain ( eg , epidermal growth factor receptor and lung cancer ) . Hybrid design s are appropriate when preliminary evidence demonstrate the efficacy of certain treatments for a marker-defined subgroup , making it unethical to r and omly assign patients with that marker status to other treatments ( eg , multigene assay and breast cancer ) . Adaptive analysis design s allow for prespecified marker-defined subgroup analyses of data from an RCT . CONCLUSION The implementation of these design strategies will lead to a more rapid clinical validation of biomarker-guided therapy 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 The development of tumor biomarkers ready for clinical use is complex . We propose a refined system for biomarker study design , conduct , analysis , and evaluation that incorporates a hierarchal level of evidence scale for tumor marker studies , including those using archived specimens . Although fully prospect i ve r and omized clinical trials to evaluate the medical utility of a prognostic or predictive biomarker are the gold st and ard , such trials are costly , so we discuss more efficient indirect " prospect ive-retrospective " design s using archived specimens . In particular , we propose new guidelines that stipulate that 1 ) adequate amounts of archived tissue must be available from enough patients from a prospect i ve trial ( which for predictive factors should generally be a r and omized design ) for analyses to have adequate statistical power and for the patients included in the evaluation to be clearly representative of the patients in the trial ; 2 ) the test should be analytically and preanalytically vali date d for use with archived tissue ; 3 ) the plan for biomarker evaluation should be completely specified in writing before the performance of biomarker assays on archived tissue and should be focused on evaluation of a single completely defined classifier ; and 4 ) the results from archived specimens should be vali date d using specimens from one or more similar , but separate , studies 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 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 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 PURPOSE This phase III study ( V-15 - 32 ) compared gefitinib ( 250 mg/d ) with docetaxel ( 60 mg/m(2 ) ) in patients ( N = 489 ) with advanced/metastatic non-small-cell lung cancer ( NSCLC ) who had failed one or two chemotherapy regimens . METHODS The primary objective was to compare overall survival to demonstrate noninferiority for gefitinib relative to docetaxel . An unadjusted Cox regression model was used for the primary analysis . RESULTS Noninferiority in overall survival was not achieved ( hazard ratio [ HR ] , 1.12 ; 95.24 % CI , 0.89 to 1.40 ) according to the predefined criterion ( upper CI limit for HR < or= 1.25 ) ; however , no significant difference in overall survival ( P = .330 ) was apparent between treatments . Post study , 36 % of gefitinib-treated patients received subsequent docetaxel , and 53 % of docetaxel-treated patients received subsequent gefitinib . Gefitinib significantly improved objective response rate and quality of life versus docetaxel ;  progression-free survival , disease control rates , and symptom improvement were similar for the two treatments . Grade s 3 to 4 adverse events occurred in 40.6 % ( gefitinib ) and 81.6 % ( docetaxel ) of patients . Incidence of interstitial lung disease was 5.7 % ( gefitinib ) and 2.9 % ( docetaxel ) . Four deaths occurred due to adverse events in the gefitinib arm ( three deaths as a result of interstitial lung disease , judged to be treatment related ; one as a result of pneumonia , not treatment related ) , and none occurred in the docetaxel arm . CONCLUSION Noninferiority in overall survival between gefitinib and docetaxel was not demonstrated according to predefined criteria ; however , there was no statistically significant difference in overall survival . Secondary end points showed similar or superior efficacy for gefitinib compared with docetaxel . Gefitinib remains an effective treatment option for previously treated Japanese patients with NSCLC 
    Output:
    
Among TKI-treated patients , increased EGFR gene copy number appears to be associated with improved survival outcomes .
The effect on OS appears to be limited to patients of non-Asian descent