***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: Importance RAS wild-type ( wt ) status is necessary but not sufficient for response to anti-epidermal growth factor receptor ( EGFR ) agents in advanced colorectal cancer ( aCRC ) . RNA expression of EGFR lig and s epiregulin ( EREG ) and amphiregulin ( AREG ) may correlate with EGFR-targeted therapy efficacy in aCRC , so may represent a much-needed additional predictive marker for these drugs . Objective To examine a novel lig and model in a r and omized clinical trial of panitumumab , irinotecan , and ciclosporin in colorectal cancer ( PICCOLO ) with with the a priori hypothesis that high tumor expression of either AREG or EREG would predict panitumumab therapy benefit in RAS-wt patients ; and low expression , lack of efficacy . Design , Setting , and Participants Prospect ively planned retrospective biomarker study from the PICCOLO trial , which tested the addition of panitumumab to irinotecan therapy in patients with KRAS wt aCRC who experienced failure with prior fluoropyrimidine treatment . The analysis was conducted between 2012 and 2014 . A predefined dichotomous model classified tumors as " high expressor " ( either EREG or AREG in top tertile for messenger RNA level ) or " low expressor " ( neither EREG nor AREG in top tertile ) . Lig and expression was assessed as a prognostic and predictive biomarker . Expression of AREG/EREG and RAS and BRAF mutations were assessed in archival tumor tissue . Main Outcomes and Measures Primary end point was progression-free survival ( PFS ) ; secondary end points were response rate and overall survival ( OS ) . Results Of the 696 PICCOLO trial patients in the irinotecan-vs-irinotecan  with panitumumab r and omization , 331 had sufficient tumor tissue available and measurement of lig and expression was successful in 323 . High lig and expression was not prognostic for OS ( hazard ratio [ HR ] , 0.79 [ 95 % CI , 0.58 - 1.09 ] ; P = .15 ) or PFS ( HR , 0.93 [ 95 % CI , 0.68 - 1.27 ] ; P = .64 ) . The primary population had RAS wt aCRC ( n = 220 ) ; for RAS wt patients with high lig and expression , median ( interquartile range [ IQR ] ) PFS was 8.3 [ 4.0 - 11.0 ] months ( irinotecan with panitumumab ) vs 4.4 [ 2.8 - 6.7 ] months ( irinotecan alone ) ; HR , 0.38 [ 95 % CI , 0.24 - 0.61 ] ; P < .001 ) . In RAS wt patients with low lig and expression , median ( IQR ) PFS was 3.2 [ 2.7 - 8.1 ] months ( irinotecan with panitumumab ) vs 4.0 [ 2.7 - 7.5 ] months ( irinotecan ) ; HR , 0.93 [ 95 % CI , 0.64 - 1.37 ] ; P = .73 ; interaction test results were significant [ P = .01 ] ) . Less marked effects were seen for response rate ( interaction P = .17 ) and OS ( interaction P = .11 ) . Conclusions and Relevance High lig and expression is a predictive marker for panitumumab therapy benefit on PFS in RAS wt patients ; conversely , patients with low lig and expression gained no benefit . The current " opt-in " strategy for anti-EGFR therapy in all patients with RAS wt aCRC should be question ed . Expression of EREG/AREG is a useful biomarker for anti-EGFR therapy ; optimization for clinical use is indicated . Trial Registration is rct n Identifier : IS RCT N93248876 The epidermal growth factor receptor ( EGFR ) , which participates in signalling pathways that are deregulated in cancer cells , is frequently mutated in colorectal-cancer cells . Cetuximab is a monoclonal antibody that specifically blocks the EGFR . We evaluated the efficacy of cetuximab in weekly combination with irinotecan in metastatic colorectal cancer patients refractory to previous treatments based on oxaliplatin or irinotecan . We included 55 heavily pretreated patients ( colon/rectum : 34/11 , M/F : 16/29 , median age 63 years , range : 27–79 ) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy and a irinotecan-based second-line regimen . Patients were followed for tumour response and were also evaluated for the time to tumour progression , and safety of treatment . Cetuximab was given at an initial dose of 400 mg m−2 , followed by weekly infusions of 250 mg m−2 . Irinotecan was administered weekly at the dose of 90 mg m−2 . All patients were assessable for treatment efficacy and safety response rate was 25.4 % ( 95 % CI : 21.7–39.6 % ) ; 38.2 % ( 95 CI : 18.6–39.8 % ) of patients showed a disease stability as the best response . As a consequence , the overall tumour control rate was 63.6 % ( 95 % CI : 46.4–70.6 % ) . The median time to progression was 4.7 months ( 95 % CI : 2.5–7.1 months ) and the median survival time was 9.8 months ( 95 % CI : 3.9–10.1 months ) . The most common G3 - 4 noncutaneous side toxicities were : diarrhoea ( 16.4 % ) , fatigue ( 12.7 % ) and stomatitis ( 7.3 % ) . 89.1 % of patients developed skin toxicity and 32.6 % of cases was of grade 3–4 . No allergic reactions were identified at any courses in any patients . Fever was documented in 27.3 % of patients and was most commonly recorded after the first administration . Cetuximab has clinical ly significant activity even in heavily pretreated colorectal cancer patients progressed after both oxaliplatin and irinotecan-based chemotherapy regimens 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 ] . ) The authors explored the association of skin toxicity ( ST ) severity as measured by patient‐reported ST and Common Terminology Criteria for Adverse Events ( CTCAE ) grading with efficacy of panitumumab , a fully human antiepidermal growth factor receptor antibody , from a phase 3 metastatic colorectal cancer ( CRC ) trial 
    Output:
    
Results Pooled data revealed that the occurrence of ST and ETS ≥20 % ( v < 20 % ) during anti-EGFR MoAb treatment were both associated with better OS , PFS and ORR .
This association could not be disturbed by KRAS status .
Mean changes in safety follow-up life health state from baseline appeared unaffected by ST .
Only mCRC patients with wild-type KRAS tumor who suffered grade 2 + ST could benefit from additional anti-EGFR treatment to chemotherapy or best supportive care ( BSC ) alone .
ETS was also a predictor for absolute survival benefit acquired from additional anti-EGFR treatment for patients with wild-type KRAS tumors , and the more early shrinkage the tumor was , the much benefit was observed .
ConclusionS T and ETS are predictive of absolute benefit acquired from anti-EGFR treatment in mCRC patients with wild-type KRAS tumors .