***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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    Input: Background The prognostic value of BRAF and KRAS mutations within microsatellite-unstable ( MSI ) and microsatellite-stable ( MSS ) subgroups of resected colon carcinoma patients remains controversial . We examined this question in prospect ively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX + /- cetuximab in two adjuvant therapy trials . Methods Three groups were defined : BRAF Mutant , KRAS Mutant , and double wild-type . The analytic strategy involved estimation of study -specific effects , assessment of homogeneity of results , and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials . Associations of mutations with patient outcome were analyzed , and multivariable models were adjusted for treatment and relevant factors . Results Four thous and four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status ; 3934 were MSS and 477 were MSI . In MSS patients , all BRAF V600E mutations ( hazard ratio [ HR ] = 1.54 , 95 % confidence interval [ CI ] = 1.23 to 1.92 , P < .001 ) , KRAS codon 12 alterations , and p . G13D mutations ( HR = 1.60 , 95 % CI = 1.40 to 1.83 , P < .001 ) were associated with shorter time to recurrence ( TTR ) and shorter survival after relapse ( SAR ; HR = 3.02 , 95 % CI = 2.32 to 3.93 , P < .001 , and HR = 1.20 , 95 % CI = 1.01 to 1.44 , P = .04 , respectively ) . Overall survival ( OS ) in MSS patients was poorer for BRAF-mutant patients ( HR = 2.01 , 95 % CI = 1.56 to 2.57 , P < .001 ) and KRAS-mutant patients ( HR = 1.62 , 95 % CI = 1.38 to 1.91 , P < .001 ) vs wild-type . No prognostic role of KRAS or BRAF mutations was seen in MSI patients . Furthermore , no interaction was found between treatment arm ( with or without cetuximab ) and KRAS and BRAF mutations for TTR or OS in MSS patients . Conclusions In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX , BRAF or KRAS mutations are independently associated with shorter TTR , SAR , and OS in patients with MSS , but not MSI , tumors . Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors PURPOSE Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer . We took advantage of PETACC-3 , an adjuvant trial with 3,278 patients with stage II to III colon cancer , to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting . PATIENTS AND METHODS  Formalin-fixed paraffin-embedded tissue blocks ( n = 1,564 ) were prospect ively collected and DNA was extracted from tissue sections from 1,404 cases . Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction .  Survival analyses were based on univariate and multivariate proportional hazard regression models . RESULTS KRAS and BRAF tumor mutation rates were 37.0 % and 7.9 % , respectively , and were not significantly different according to tumor stage . In a multivariate analysis containing stage , tumor site , nodal status , sex , age , grade , and microsatellite instability ( MSI ) status , KRAS mutation was associated with grade ( P = .0016 ) , while BRAF mutation was significantly associated with female sex ( P = .017 ) , and highly significantly associated with right-sided tumors , older age , high grade , and MSI-high tumors ( all P < 10(-4 ) ) . In univariate and multivariate analysis , KRAS mutations did not have a major prognostic value regarding relapse-free survival ( RFS ) or overall survival ( OS ) . BRAF mutation was not prognostic for RFS , but was for OS , particularly in patients with MSI-low ( MSI-L ) and stable ( MSI-S ) tumors ( hazard ratio , 2.2 ; 95 % CI , 1.4 to 3.4 ; P = .0003 ) . CONCLUSION In stage II-III colon cancer , the KRAS mutation status does not have major prognostic value . BRAF is prognostic for OS in MS-L/S tumors Background The aim of our study was to evaluate whether a panel of biomarkers , prospect ively analysed might be able to predict patients ’ clinical outcome more accurately than RAS status alone . Methods K-RAS ( exons 2 , 3 , 4 ) wild type colorectal cancer patients , c and i date s to second/third-line cetuximab with chemotherapy  were prospect ively allocated into 2 groups on the basis of their profile : favourable ( BRAF and PIK3CA exon 20 wild type , EGFR GCN ≥ 2.6 , HER-3 Rajkumar score ≤ 8 , IGF-1 immunostaining < 2 ) or unfavourable ( any of the previous markers altered or mutated ) . After the introduction of N-RAS status ( exons 2 , 3 , 4 ) only RAS wild type patients were considered eligible . Primary aim was response rate ( RR ) . To detect a difference in terms of RR among patients with an unfavourable profile ( estimated around 25 % ) and patients with a favourable profile ( estimated around 60 % ) , with a probability alpha of 0.05 and beta of 0.05 , required sample size was 46 patients . Secondary endpoints were progression free survival ( PFS ) and overall survival ( OS ) . Results Forty-six patients were enrolled . Seventeen patients ( 37 % ) were allocated to the favourable and 29 patients ( 63 % ) to the unfavourable profile . RR in the favourable and unfavourable group was 11/17 ( 65 % ) and 2/29 ( 7 % ) ( p = 0.007 ) respectively . The favourable group also showed an improved PFS ( 8 months vs. 3 months , p < 0.0001 ) and OS ( 15 months vs. 6 months , p < 0.0001 ) . Conclusions Our results suggest that prospect i ve selection of optimal c and i date s for cetuximab treatment is feasible and may be able to improve clinical outcome 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 . BACKGROUND & AIMS Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes . METHODS We used a polymerase chain reaction-based assay to detect mutations in BRAF ( V600E ) and in KRAS in 2720 stage III cancer sample s , collected prospect ively from patients participating in an adjuvant chemotherapy trial ( NCCTG N0147 ) . Tumors deficient or proficient in DNA mismatch repair ( MMR ) were identified based on detection of MLH1 , MSH2 , and MSH6 proteins and methylation of the MLH1 promoter . Findings were vali date d using tumor sample s from a separate set of patients with stage III cancer ( n = 783 ) . Association with 5-year disease-free survival was evaluated using Cox proportional hazards models . RESULTS Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive . Three subtypes were MMR proficient : those with mutations in BRAF ( 6.9 % of sample s ) , mutations in KRAS ( 35 % ) , or tumors lacking either BRAF or KRAS mutations ( 49 % ) . Two subtypes were MMR deficient : the sporadic type ( 6.8 % ) with BRAF mutation and /or or hypermethylation of MLH1 and the familial type ( 2.6 % ) , which lacked BRAF(V600E ) or hypermethylation of MLH1 . A higher percentage of MMR-proficient tumors with BRAF(V600E ) were proximal ( 76 % ) , high- grade ( 44 % ) , N2 stage ( 59 % ) , and detected in women ( 59 % ) , compared with MMR-proficient tumors without BRAF(V600E ) or KRAS mutations ( 33 % , 19 % , 41 % , and 42 % , respectively ; all P < .0001 ) . A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF ( hazard ratio = 1.43 ; 95 % confidence interval : 1.11 - 1.85 ; Padjusted = .0065 ) or mutant KRAS ( hazard ratio = 1.48 ; 95 % confidence interval : 1.27 - 1.74 ; Padjusted < .0001 ) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene . Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations . The observed differences in survival rates of patients with different tumor subtypes were vali date d in an independent cohort . CONCLUSIONS We identified subtypes of stage III colon cancer , based on detection of mutations in BRAF ( V600E ) or KRAS , and MMR status that show differences in clinical and pathologic features and disease-free survival .  Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations . The tumor subtype found in nearly half of the study cohort ( MMR-proficient without BRAF(V600E ) or KRAS mutations ) had similar outcomes to those of patients with MMR-deficient cancers Importance The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin , fluorouracil , and oxaliplatin (FOLFOX)-based adjuvant chemotherapy is controversial , possibly owing to a lack of stratification on mismatch repair status . Objective To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab . Design , Setting , and Participants This study 
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Tumors with microsatellite stability and mutations in KRAS or BRAF were associated with decreased survival times , compared with tumors with microsatellite stability and no mutations .
Conclusions In a systematic review of studies of molecular classifications of CRC and patient survival , we found that most subtypes were not significantly or not differentially associated with survival .
None of the systems integrated TNM staging .