***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: Purpose : Mutations in PIK3CA [ the gene encoding the p110α catalytic subunit of phosphatidylinositide-3-kinase ( PI3 K ) ] play an important role in colorectal carcinogenesis . Experimental evidence suggests that PIK3CA exon 9 and exon 20 mutations trigger different biologic effects , and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects . Thus , we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer , and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior . Experimental Design : We sequenced PIK3CA by pyrosequencing in 1,170 rectal and colon cancers in two prospect i ve cohort studies , and found 189 ( 16 % ) PIK3CA mutated tumors . Mortality HR according to PIK3CA status was computed using Cox proportional hazards model , adjusting for clinical and molecular features , including microsatellite instability , CpG isl and methylator phenotype , LINE-1 methylation , and BRAF and KRAS mutations . Results : Compared with PIK3CA wild-type cases , patients with concomitant PIK3CA mutations in exons 9 and 20 experienced significantly worse cancer-specific survival [ log-rank P = 0.031 ; multivariate HR = 3.51 ; 95 % confidence interval ( CI ) : 1.28–9.62 ] and overall survival ( log-rank P = 0.0008 ; multivariate HR = 2.68 ; 95 % CI : 1.24–5.77 ) . PIK3CA mutation in either exon 9 or 20 alone was not significantly associated with patient survival . No significant interaction of PIK3CA mutation with BRAF or KRAS mutation was observed in survival analysis . Conclusion : Coexistence of PIK3CA ( the PI3 K p110α subunit ) exon 9 and 20 mutations , but not PIK3CA mutation in either exon 9 or 20 alone , is associated with poor prognosis of colorectal cancer patients . Clin Cancer Res ; 18(8 ) ; 2257–68 . © 2012 AACR CONTEXT The fraction of malignant cells in tumor tissue su bmi tted for tests of genetic alterations is a critical variable in testing accuracy . That fraction is currently determined by pathologist visual estimation of the percentage of malignant cells . Inaccuracy could lead to a false-negative test result . OBJECTIVE To describe a prospect i ve , multi-institutional study to determine pathologist estimation accuracy . DESIGN Ten ×20 magnification images of hematoxylin-eosin-stained colon tissue specimens were sent as an educational component of the College of American Pathologists KRAS-B 2011  Survey . Data from 194 labs were analyzed and compared to a criterion st and ard with comprehensive manual nuclear counts . RESULTS Survey responses indicated low interlaboratory precision of pathologist estimation , but mean estimates were fairly accurate . A total of 5 of the 10 cases assessed showed more than 10 % of respondents overestimating in a manner that could lead to false-negative test results . CONCLUSIONS The significance of estimation errors result ing in molecular testing failures with implication s for patient care is unknown , but the current study suggests false-negative test results may occur Lynch syndrome ( LS ) is characterised by the development of colorectal cancer , endometrial cancer and various other cancers , and is caused by a mutation in one of the mismatch repair genes : MLH1 , MSH2 , MSH6 or PMS2 . In 2007 , a group of European experts ( the Mallorca group ) published guidelines for the clinical management of LS . Since then substantial new information has become available necessitating an up date of the guidelines . In 2011 and 2012 workshops were organised in Palma de Mallorca . A total of 35 specialists from 13 countries participated in the meetings . The first step was to formulate important clinical questions . Then a systematic literature search was performed using the Pubmed data base and manual search es of relevant articles . During the workshops the outcome of the literature search was discussed in detail . The guidelines described in this paper may be helpful for the appropriate management of families with LS . Prospect i ve controlled studies should be undertaken to improve further the care of these families Purpose : Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer . We examined the predictive and prognostic significance of additional biomarkers in this setting , in particular BRAF , PIK3CA , and PTEN . Experimental Design : Available colorectal tumor sample s were analyzed from the CO.17 study . BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing . PTEN expression by immunohistochemistry ( IHC ) was performed on tissue microarrays . For each biomarker , prognostic and predictive effects were examined using a Cox model with tests for treatment – biomarker interaction . Results : A total of 572 patients with pretreated colorectal cancer were r and omly assigned to receive cetuximab or best supportive care ( BSC ) . Of 401 patients assessed for BRAF status , 13 ( 3.2 % ) had mutations . Of 407 patients assessed for PIK3CA status , 61 ( 15 % ) had mutations . Of 205 patients assessed for PTEN , 148 ( 72 % ) were negative for IHC expression . None of BRAF , PIK3CA , or PTEN was prognostic for overall or progression-free survival in the BSC arm . None was predictive of benefit from cetuximab , either in the whole study population or the K-ras wild-type subset . In the K-ras wild-type subgroup , the overall survival adjusted HR according to BRAF mutation status was 1.39 ( interaction P = 0.69 ) , PIK3CA mutation status HR = 0.79 ( interaction P = 0.63 ) , and PTEN expression HR = 0.75 ( interaction P = 0.61 ) . Conclusions : In chemotherapy-refractory colorectal cancer , neither PIK3CA mutation status nor PTEN expression were prognostic , nor were they predictive of benefit from cetuximab . Evaluation of predictive significance of BRAF mutations requires a larger sample size . Clin Cancer Res ; 20(3 ) ; 744–53 . © 2013 AACR 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 : To test the prognostic value of tumour protein and genetic markers in colorectal cancer ( CRC ) and examine whether deficient mismatch repair ( dMMR ) tumours had a distinct profile relative to proficient mismatch repair ( pMMR ) tumours . Methods : This prospect i ve multicentric study involved 251 stage I – III CRC patients . Analysed biomarkers were EGFR ( binding assay ) , VEGFA , thymidylate synthase ( TS ) , thymidine phosphorylase ( TP ) and dihydropyrimidine dehydrogenase ( DPD ) expressions , MMR status , mutations of KRAS ( codons 12–13 ) , BRAF ( V600E ) , PIK3CA ( exons 9 and 20 ) , APC ( exon 15 ) and P53 ( exons 4–9 ) , CpG isl and methylation phenotype status , ploidy , S-phase , LOH . Results : The only significant predictor of relapse-free survival ( RFS ) was tumour staging . Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated ( P=0.005 ) , BRAF wt ( P=0.009 ) and pMMR tumours ( P=0.036 ) . Deficient mismatch repair tumours significantly demonstrated higher TS ( median 3.1 vs 1.4 ) and TP ( median 5.8 vs 3.5 ) expression relative to pMMR ( P<0.001 ) and show higher DPD expression ( median 14.9 vs 7.9 , P=0.027 ) and EGFR content ( median 69 vs 38 , P=0.037 ) relative to pMMR . Conclusions : Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy 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 
    Output:
    
Evidence supports mutational testing for EGFR signaling pathway genes , since they provide clinical ly actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC .
Mutations in several of the biomarkers have clear prognostic value .