***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 
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    ***EXAMPLES*** 
    Input: 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 BACKGROUND The antiepidermal growth factor receptor ( antiEGFR ) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10 % of patients with metastatic colorectal cancer that is resistant to chemotherapy . The molecular mechanisms underlying clinical response or resistance to these agents are unknown . METHODS Tumours from 31 patients with metastatic colorectal cancer who had either an objective response ( n=10 ) or stable disease or progressive disease ( n=21 ) after treatment with cetuximab or panitumumab  were screened for genetic changes in EGFR or its immediate intracellular effectors . Specifically , we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS , BRAF , and PIK3CA . RESULTS Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation ( FISH ) had an increased EGFR copy number . By contrast , one of 21 non-responders assessable by FISH had an increased EGFR copy number ( p<0.0001 for responders vs non-responders , Fisher 's exact test ) . The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA , KRAS , and BRAF did not correlate with disease response . In colorectal-cancer cell lines , the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR . INTERPRETATION We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number BACKGROUND Treatment with cetuximab , a monoclonal antibody directed against the epidermal growth factor receptor , improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy . The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value . METHODS We analyzed tumor sample s , obtained from 394 of 572 patients ( 68.9 % ) with colorectal cancer who were r and omly assigned to receive cetuximab plus best supportive care or best supportive care alone  , to look for activating mutations in exon 2 of the K-ras gene . We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups . RESULTS Of the tumors evaluated for K-ras mutations , 42.3 % had at least one mutation in exon 2 of the gene . The effectiveness of cetuximab was significantly associated with K-ras mutation status ( P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival , respectively ) . In patients with wild-type K-ras tumors , treatment with cetuximab as compared with supportive care alone significantly improved overall survival ( median , 9.5 vs. 4.8 months ; hazard ratio for death , 0.55 ; 95 % confidence interval [ CI ] , 0.41 to 0.74 ; P<0.001 ) and progression-free survival ( median , 3.7 months vs. 1.9 months ; hazard ratio for progression or death , 0.40 ; 95 % CI , 0.30 to 0.54 ; P<0.001 ) . Among patients with mutated K-ras tumors , there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival ( hazard ratio , 0.98 ; P=0.89 ) or progression-free survival ( hazard ratio , 0.99 ; P=0.96 ) . In the group of patients receiving best supportive care alone , the mutation status of the K-ras gene was not significantly associated with overall survival ( hazard ratio for death , 1.01 ; P=0.97 ) . CONCLUSIONS Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab , whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab . The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone . ( Clinical Trials.gov number , NCT00079066 . Purpose : Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations , and are important in colorectal carcinogenesis . KRAS mutation in metastatic colorectal cancer predicts resistance to anti – epidermal growth factor receptor (EGFR)-targeted therapy ( cetuximab or panitumumab ) . It remains uncertain , however , whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy . Methods : We conducted a study of 508 cases identified among 1,264 patients with stage III colon cancer who enrolled in a r and omized adjuvant chemotherapy trial ( 5-fluorouracil , leucovorin with or without irinotecan ) in 1999 - 2001 ( CALGB 89803 ) . KRAS mutations were detected in 178 tumors ( 35 % ) by pyrosequencing . Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age , sex , tumor location , tumor/node stage , performance status , adjuvant chemotherapy arm , and microsatellite instability status . Results : Compared with patients with KRAS-wild-type tumors , patients with KRAS-mutated tumors did not experience any difference in disease-free , recurrence-free , or overall survival . The 5-year disease-free , recurrence-free , and overall survival rates ( KRAS-mutated versus KRAS-wild-type patients ) were 62 % versus 63 % ( log-rank P = 0.89 ) , 64 % versus 66 % ( P = 0.84 ) , and 75 % versus 73 % ( P = 0.56 ) , respectively . The effect of KRAS mutation on patient survival did not significantly differ according to clinical features , chemotherapy arm , or microsatellite instability status , and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status . Conclusions : In this large trial of chemotherapy in stage III colon cancer patients , KRAS mutational status was not associated with any significant influence on disease-free or overall survival . ( Clin Cancer Res 2009;15(23):7322–9 Background : We hypothesized that a serum proteomic profile predictive of survival benefit in non – small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKI )  reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent . Methods : Pretreatment serum or plasma from 230 patients treated with cetuximab , EGFR-TKIs , or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma ( HNSCC ) or colorectal cancer ( CRC ) were analyzed by mass spectrometry . Each sample was classified into “ good ” or “ poor ” groups using VeriStrat , and survival analyses of each cohort were done based on this classification . For the CRC cohort , this classification was correlated with the tumor EGFR lig and levels and KRAS mutation status . Results : In the EGFR inhibitor – treated cohorts , the classification predicted survival ( HNSCC : gefitinib , P = 0.007 and erlotinib/bevacizumab , P = 0.02 ; CRC : cetuximab , P = 0.0065 ) whereas the chemotherapy cohort showed no survival difference . For CRC patients , tumor EGFR lig and RNA levels were significantly associated with the proteomic classification , and combined KRAS and proteomic classification provided improved survival classification . Conclusions : Serum proteomic profiling can detect clinical ly significant tumor dependence on the EGFR pathway in non – small cell lung cancer , HNSCC , and CRC patients treated with either EGFR-TKIs or cetuximab . This classification is correlated with tumor EGFR lig and levels and provides a clinical ly practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors . Prospect i ve studies are necessary to confirm these findings . Cancer Epidemiol Biomarkers Prev ; 19(2 ) ; BACKGROUND Cetuximab , an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor ( EGFR ) , has activity against colorectal cancers that express EGFR . METHODS From December 2003 to August 2005 , 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine , irinotecan , and oxaliplatin or had contraindications to treatment with these drugs underwent r and omization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care  ( 287 patients ) or best supportive care alone  ( 285 patients ) . The primary end point was overall survival . RESULTS In comparison with best supportive care alone , cetuximab treatment was associated with a significant improvement in overall survival ( hazard ratio for death , 0.77 ; 95 % confidence interval [ CI ] , 0.64 to 0.92 ; P=0.005 ) and in progression-free survival ( hazard ratio for disease progression or death , 0.68 ; 95 % CI , 0.57 to 0.80 ; P<0.001 ) . These benefits were robust after adjustment in a multivariable Cox proportional-hazards model . The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone . Partial responses occurred in 23 patients ( 8.0 % ) in the cetuximab group but in none in the group assigned to supportive care alone ( P<0.001 ) ; the disease was stable in an additional 31.4 % of patients assigned to cetuximab and in 10.9 % of patients assigned to supportive care alone ( P<0.001 ) . Quality of life was better preserved in the cetuximab group , with less deterioration in physical function and global health status scores ( both P<0.05 ) . Cetuximab treatment was associated with a characteristic rash ; a rash of grade 2 or higher was strongly associated with improved survival ( hazard ratio for death , 0.33 ; 95 % CI , 0.22 to 0.50 ; P<0.001 ) . The incidence of any adverse event of grade 3 or higher was 78.5 % in the cetuximab group and 59.1 % in the group assigned to supportive care alone ( P<0.001 ) . CONCLUSIONS Cetuximab improves overall survival and progression-free survival and preserves quality -of-life measures in patients with colorectal cancer in whom other treatments have failed . ( Clinical Trials.gov number , NCT00079066 [ Clinical Trials.gov ] . ) Background Developments in biotechnology and genomics have increased the focus of biostatisticians on prediction problems . This has led to many exciting developments for predictive modeling where the number of variables is larger than the number of cases . Heterogeneity of human diseases and new technology for characterizing them presents new opportunities and challenges for the design and analysis of clinical trials . Purpose In oncology , treatment of broad population s with regimens that do not benefit most patients is less economically sustainable with expensive molecularly targeted therapeutics . The established molecular heterogeneity of human diseases requires the development of new paradigms for the design and analysis of r and omized clinical trials as a reliable basis for predictive medicine [ Simon R. An agenda for clinical trials : clinical trials in the genomic era . Clin Trials 2004 ; 1:468—70 , Simon R. New challenges for 21st century clinical trials . Clin Tri 
    Output:
    
KRAS mutations are consistently associated with reduced overall and progression-free survival and increased treatment failure rates among patients with advanced colorectal cancer treated with anti-EGFR antibodies .