***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: 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 Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor ( EGFR ) therapy . Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy . METHODS In this prospect ive-retrospective analysis , we assessed the efficacy and safety of panitumumab plus oxaliplatin , fluorouracil , and leucovorin ( FOLFOX4 ) as compared with FOLFOX4 alone , according to RAS ( KRAS or NRAS ) or BRAF mutation status . A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following : KRAS exon 3 or 4 ; NRAS exon 2 , 3 , or 4 ; or BRAF exon 15 . The overall rate of ascertainment of RAS status was 90 % . RESULTS Among 512 patients without RAS mutations , progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone ( hazard ratio for progression or death with combination therapy , 0.72 ; 95 % confidence interval [ CI ] , 0.58 to 0.90 ; P=0.004 ) . Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group ( hazard ratio for death , 0.78 ; 95 % CI , 0.62 to 0.99 ; P=0.04 ) . A total of 108 patients ( 17 % ) with nonmutated KRAS exon 2 had other RAS mutations . These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment , which was consistent with the findings in patients with KRAS mutations in exon 2 .  BRAF mutations were a negative prognostic factor . No new safety signals were identified . CONCLUSIONS Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4 . In patients who had metastatic colorectal cancer without RAS mutations , improvements in overall survival were observed with panitumumab-FOLFOX4 therapy . ( Funded by Amgen and others ; PRIME Clinical Trials.gov number , NCT00364013 . ) Summary Background Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer , but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain . Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer . Methods In this open-label , r and omised trial , we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK . From December , 2006 until June , 2008 , molecularly unselected patients were recruited to a three-arm design including irinotecan ( control ) , irinotecan plus ciclosporin , and irinotecan plus panitumumab ( IrPan ) groups . From June 10 , 2008 , in response to new data , the trial was amended to a prospect ively stratified design , restricting panitumumab r and omisation to patients with KRAS wild-type tumours ; the results of the comparison between the irinotcan and IrPan groups are reported here . We used a computer-generated r and omisation sequence ( stratified by previous EGFR targeted therapy and then minimised by centre , WHO performance status , previous oxaliplatin , previous bevacizumab , previous dose modifications , and best previous response ) to r and omly allocate patients to either irinotecan or IrPan . Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks ( 300 mg/m2 if aged ≥70 years or a performance status of 2 ) ; patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks . The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy , analysed by intention to treat . Tumour DNA was pyrosequenced for KRASc.146 , BRAF , NRAS , and PIK3CA mutations , and predefined molecular subgroups were analysed for interaction with the effect of panitumumab . This study is registered , number IS RCT N93248876 . Results Between Dec 4 , 2006 , and Aug 31 , 2010 , 1198 patients were enrolled , of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy . 230 patients were r and omly allocated to irinotecan and 230 to IrPan . There was no difference in overall survival between groups ( HR 1·01 , 95 % CI 0·83–1·23 ; p=0·91 ) , but individuals in the IrPan group had longer progression-free survival ( 0·78 , 0·64–0·95 ; p=0·015 ) and a greater number of responses ( 79 [ 34 % ] patients vs 27 [ 12 % ] ; p<0·0001 ) than did individuals in the irinotecan group . Grade 3 or worse diarrhoea ( 64 [ 29 % ] of 219 patients vs 39 [ 18 % ] of 218 patients ) , skin toxicity ( 41 [ 19 % ] vs none ) , lethargy ( 45 [21]% vs 24 [ 11 % ] ) , infection ( 42 [ 19 % ] vs 22 [ 10 % ] ) and haematological toxicity ( 48 [ 22 % ] vs 27 [ 12 % ] ) were reported more commonly in the IrPan group than in the irinotecan group . We recorded five treatment-related deaths , two in the IrPan group and three in the irinotecan group . Interpretation Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours . Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents . Funding Cancer Research UK , Amgen One approach to delivering cost-effective healthcare requires the identification of patients as individuals or sub population s that are more likely to respond to an appropriate dose and /or schedule of a therapeutic agent , or as sub population s that are less likely to develop an adverse event ( i.e. , personalized or stratified medicine ) . Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development . In this article , the Industry Pharmacogenomics Working Group provides , for regulatory consideration , its perspective on the rationale for the conduct of what is commonly referred to as the prospect ive-retrospective analysis ( PRA ) of biomarkers . Reflecting on published proposals and material s presented by the US FDA , a decision tree for generating robust scientific data from sample s collected from an already conducted trial to allow PRA is presented . The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary , nor practical or ethical to conduct a new prospect i ve clinical study 
    Output:
    
Regarding PFS benefit with  anti-EGFR mAbs  , the hazard ratio was 0.86 ( 95 % CI ; 0.61–1.21 ) for RAS WT/BRAF MT tumours as compared with 0.62 ( 95 % CI ; 0.50–0.77 ) for RAS WT/BRAF WT tumours ( test of interaction , P=0.07).Interpretation : This meta- analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals .
As such , there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC