***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: Summary Background In the Medical Research Council ( MRC ) COIN trial , the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to st and ard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival . Methods In this r and omised controlled trial , patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were r and omly assigned to oxaliplatin and fluoropyrimidine chemotherapy ( arm A ) , the same combination plus cetuximab ( arm B ) , or intermittent chemotherapy ( arm C ) . The choice of fluoropyrimidine therapy ( capecitabine or infused fluouroracil plus leucovorin ) was decided before r and omisation . R and omisation was done central ly ( via telephone ) by the MRC Clinical Trials Unit using minimisation . Treatment allocation was not masked . The comparison of arms A and C is described in a companion paper . Here , we present the comparison of arm A and B , for which the primary outcome was overall survival in patients with KRAS wild-type tumours . Analysis was by intention to treat . Further analyses with respect to NRAS , BRAF , and EGFR status were done . The trial is registered , IS RCT N27286448 . Findings 1630 patients were r and omly assigned to treatment groups ( 815 to st and ard therapy and 815 to addition of cetuximab ) . Tumour sample s from 1316 ( 81 % ) patients were used for somatic molecular analyses ; 565 ( 43 % ) had KRAS mutations . In patients with KRAS wild-type tumours ( arm A , n=367 ; arm B , n=362 ) , overall survival did not differ between treatment groups ( median survival 17·9 months [ IQR 10·3–29·2 ] in the control group vs 17·0 months [ 9·4–30·1 ] in the cetuximab group ; HR 1·04 , 95 % CI 0·87–1·23 , p=0·67 ) . Similarly , there was no effect on progression-free survival ( 8·6 months [ IQR 5·0–12·5 ] in the control group vs 8·6 months [ 5·1–13·8 ] in the cetuximab group ; HR 0·96 , 0·82–1·12 , p=0·60 ) . Overall response rate increased from 57 % ( n=209 ) with chemotherapy alone to 64 % ( n=232 ) with addition of cetuximab ( p=0·049 ) . Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab ( 14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours , respectively ) . Overall survival differs by somatic mutation status irrespective of treatment received : BRAF mutant , 8·8 months ( IQR 4·5–27·4 ) ; KRAS mutant , 14·4 months ( 8·5–24·0 ) ; all wild-type , 20·1 months ( 11·5–31·7 ) . Interpretation This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer .  Cetuximab  increases response rate , with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours . The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases can not be recommended . Funding Cancer Research UK , Cancer Research Wales , UK Medical Research Council , Merck PURPOSE Microsatellite instability ( MSI ) , TP53 mutation , and KRAS mutation status have been reported as prognostic factors in colon cancer . Most studies , however , have included heterogeneous groups of patients with respect to cancer stage . We determined the prognostic relevance of high-frequency MSI ( MSI-H ) , TP53 mutations , and KRAS mutations in a well-defined group of patients with stage III colon cancer ( N = 391 ) , r and omly assigned for adjuvant treatment with fluorouracil-based chemotherapy .  METHODS Three hundred ninety-one tumor specimens were available .  MSI  was determined in 273 specimens , and mutation analyses of TP53 and KRAS were performed in 220 and 205 specimens , respectively . RESULTS In a univariate analysis , MSI-H ( 44 of 273 ; 16 % ) was associated with a longer disease-free survival ( DFS ; P = .038 ) , but in a multivariate model adjusting for nodal involvement , histology , invasion , and grade of tumor , the association of MSI status with DFS did no longer reach statistical significance , though the risk estimate for microsatellite stability versus MSI-H tumors did not change much . Mutant TP53 , found in 116 ( 53 % ) of 220 tumors , was associated with a shorter DFS , both in univariate ( P = .009 ) and multivariate analyses ( P = .018 ) , whereas KRAS mutations ( 58 of 205 ; 28 % ) did not show any prognostic significance . CONCLUSION Both mutant TP53 and MSI-H seem to be prognostic indicators for disease-free survival , but only TP53 retains statistical significance after adjusting for clinical heterogeneity . Thus , in adjuvantly treated patients with stage III colon cancer , presence or absence of a TP53 mutation should be considered as a better predictor for DFS than MSI status 
    Output:
    
Interpretation Metastatic CRC demonstrates high concordance across multiple biomarkers , suggesting that molecular testing of either the primary or liver and lung metastasis is adequate .