***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: Between June 1990 and April 1991 , 62 colorectal tumors were assessed in a prospect i ve fashion on the basis of various tumor characteristics . Parameters included K-ras mutation , overexpression of the p53 protein , and proliferating cell nuclear cell antigen , as well as st and ard histopathologic examination . A multivariate analysis showed that K-ras mutation correlated with vascular invasion ( P < 0.01 ) and hematogenous metastasis ( P < 0.01 ) . With regard to survival time , multivariate analyses using the Cox proportional hazard model suggested that status of lymph node metastasis ( P < 0.01 , relative risk [ rr ] = 7.27 ) , TNM stage ( P < 0.05 , rr = 5.37 ) , lymphatic invasion ( P < 0.05 , rr = 4.48 ) , and K-ras mutation ( P < 0.06 , rr = 3.69 ) are the most independent prognostic factors . We compared the prognostic value of the molecular assays and st and ard TNM prognostic factors by multivariate analysis 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 . ) BACKGROUND The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil , folinic acid and oxaliplatin ( FOLFOX4 ) significantly improved objective response and progression-free survival ( PFS ) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer ( mCRC ) . In patients with KRAS exon 2 mutations , a detrimental effect was seen upon addition of cetuximab to FOLFOX4 . The current study reports outcomes in subgroups defined by extended RAS testing . PATIENTS AND METHODS Sample s from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons ( exons 3 - 4 ) and six NRAS codons ( exons 2 - 4 ) using BEAMing . A cutoff of ⩾5 % mutant/wild-type sequences was selected to define RAS status ; we also report an analysis using a cutoff based on the technical lower limit for mutation identification ( 0.1 % ) . RESULTS Other RAS mutations were detected in 31/118 ( 26 % ) evaluable patients . In the extended analysis of RAS wild-type tumours ( n=87 ) , objective response was significantly improved by addition of cetuximab to FOLFOX4 ( 58 % versus 29 % ; odds ratio 3.33 [ 95 % confidence interval 1.36 - 8.17 ] ; P=0.0084 ) ; although limited by population size , there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group . There was no evidence that patients with other RAS mutations benefited from cetuximab , but small numbers precluded precise estimations of treatment effects . In the combined population of patients with any RAS mutation ( KRAS exon 2 or other RAS ) , a clear detrimental effect was associated with addition of cetuximab to FOLFOX4 . CONCLUSION Patients with RAS-mutant mCRC , as defined by mutations in KRAS and NRAS exons 2 - 4 , derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4 . Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit PURPOSE The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil , leucovorin , and irinotecan ( FOLFIRI ) significantly improved overall survival , progression-free survival , and objective response in the first-line treatment of patients with KRAS codon 12/13 ( exon 2 ) wild-type metastatic colorectal cancer ( mCRC ) . Outcome was reassessed in subgroups defined by extended RAS mutation testing . PATIENTS AND METHODS Existing DNA sample s from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons ( exons 3 and 4 ) and six NRAS codons ( exons 2 , 3 , and 4 ) using beads , emulsion , amplification , and magnetics technology . No tissue microdissection was performed . A ≥ 5 % mutant allele cutoff was used to call mutations . RESULTS Mutation status was evaluable in 430 ( 64.6 % ) of 666 patients with KRAS exon 2 wild-type tumors . Other RAS mutations were detected in 63 ( 14.7 % ) of 430 patients . In those with RAS wild-type tumors , a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI . In patients with other RAS tumor mutations , no difference in efficacy outcomes between treatment groups was seen . The safety profile in RAS subgroups was similar and in line with expectations . CONCLUSION In the first-line treatment of mCRC , patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI ; patients with RAS tumor mutations did not . Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy , thereby allowing the further tailoring of cetuximab administration to maximize patient benefit 
    Output:
    
This meta- analysis suggests both KRAS and BRAF mutations as poor , prognostic biomarkers , associated with worse survival outcomes , in patients undergoing hepatic resection of CLM