***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: Background : The impact of thymidylate synthase ( TYMS ) and UDP-glucoronosyltransferase 1A ( UGT1A ) germline polymorphisms on the outcome of colorectal cancer ( CRC ) patients treated with irinotecan plus 5-fluorouracil ( irinotecan/5FU )  is still controversial . Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU . Methods : Genotyping of TYMS ( 5′TRP and 3′UTR ) , UGT1A1 * 28 , UGT1A9 * 22 and UGT1A7 * 3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a r and omised phase 3 study . Their association with response , toxicity and survival was investigated by univariate and multivariate statistical analysis . Results : TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response ( OR=5.87 , 95 % confidence interval (CI)=1.68–20.45 ; P=0.005 ) . UGT1A1 * 28/*28 was predictive for haematologic toxicity ( OR=6.27 , 95 % CI=1.09–36.12 ; P=0.04 ) , specifically for neutropenia alone ( OR=6.40 , 95 % CI=1.11–37.03 ; P=0.038 ) or together with diarrhoea ( OR=18.87 , 95 % CI=2.14–166.67 ; P=0.008 ) . UGT1A9 * 1/*1 was associated with non-haematologic toxicity ( OR=2.70 , 95 % CI=1.07–6.82 ; P=0.035 ) . Haplotype VII ( all non-favourable alleles ) was associated with non-haematologic toxicity ( OR=2.11 , 95 % CI=1.12–3.98 ; P=0.02 ) . Conclusion : TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients . A genetic-based algorithm to optimise treatment individualisation is proposed PURPOSE The aim of this study was to examine the clinical significance of the methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphism C677 T in colorectal cancer ( CRC ) . The hypothesis was that the genotype could affect the risk of cancer development and the results of cancer treatment . PATIENTS AND METHODS Genotyping was made for a r and om 30 % ( n = 544 ) of all patients treated for CRC at our unit from 1999 to 2006 ( n = 1812 ) . Basic clinical and pathologic factors were analyzed by genotype group and also compared with those of the entire cohort . Tolerability of chemotherapy and possible side effects were analyzed by genotype . Survival was analyzed by genotype for all stages for patients treated between 1999 and 2003 . The genotype prevalence was also compared with a control material of healthy blood donors . RESULTS No genotype was associated with an increased risk of CRC or higher cancer stage . The patients with CT/TT genotype had significantly greater risk of suffering side effects from fluoropyrimidine ( 5-fluorouracil ) treatment ( P < .05 ) . In stage III colon cancer , the patients with CT/TT genotype had a poorer prognosis than those with the CC genotype . The difference was significant in univariate ( P < .003 ) and multivariate ( P < .040 ) analysis . Though the genotype-associated side effect risks remained in stage IV , the effect on survival was not significant ( P < .1 ) . CONCLUSION The MTHFR polymorphism C677 T does , in our material , not affect the risk of CRC ; however , it can affect the sensitivity to chemotherapy and the risk of side-effects and therefore survival in stage III and possibly stage IV colon cancer . It could be a future predictive factor in the choice of a treatment regimen PURPOSE To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase ( DPYD ) , thymidylate synthase ( TYMS ) , and methylene tetrahydrofolate reductase ( MTHFR ) and of nongenetic factors for severe leukopenia , diarrhea , and mucositis related to  fluorouracil ( FU )  treatment . PATIENTS AND METHODS A multicenter prospect i ve clinical trial included 683 patients with cancer treated with FU monotherapy .  Toxicity was documented according to World Health Organization grade s. DPYD , TYMS , and MTHFR genotypes were determined , and DPYD was resequenced in patients with severe toxicity . RESULTS Grade 3 to 4 toxicity occurred in 16.1 % of patients . The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5 % ( 95%CI , 0.02 to 0.11 ) , with a positive predictive value of 0.46 ( 95 % CI , 0.19 to 0.75 ; P = .01 ) . Inclusion of additional DPYD variants improved prediction only marginally . Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia , whereas TYMS was associated with diarrhea . Genotype , female sex , mode of FU administration , and modulation by folinic acid were identified as independent risk factors by multivariable analysis . A previously unrecognized significant interaction was found between sex and DPYD , which result ed in an odds ratio for toxicity of 41.8 for male patients ( 95 % CI , 9.2 to 190 ; P < .0001 ) but only 1.33 ( 95 % CI , 0.34 to 5.2 ) in female patients . Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold ( 95 % CI , 1.08 to 2.22 ; P = .02 ) . CONCLUSION DPYD , TYMS , and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients . Toxicity risk assessment should include sex , mode of administration , and folinic acid as additional predictive factors The present study aim ed at investigating whether the simultaneous evaluation of pharmacokinetic , pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy . One hundred and thirty consecutive , B2 and C Duke 's stage colorectal cancer patients were prospect ively enrolled .  5FU pharmacokinetics was evaluated at the first cycle . Thymidylate synthase ( TYMS ) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase ( MTHFR ) C677 T and A1298C polymorphisms were assessed in peripheral leukocytes . Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity , disease-free survival ( DFS ) and overall survival ( OS ) . Multivariate analysis showed that : ( a ) low 5FU clearance was an independent predictive factor for severe toxicity ( OR=7.32 ; P<0.0001 ) ; ( b ) high-5FU clearance predicted poorer DFS ( HR=1.96 ; P=0.041 ) and OS ( HR=3.37 ; P=0.011 ) ; ( c ) advanced age was associated with shorter DFS ( HR=3.34 ; P=0.0008 ) and OS ( HR=2.66 ; P=0.024 ) ; ( d ) the C/C genotype of the MTHFR C677 T polymorphism was protective against grade 3–4 toxicity ( P=0.040 ) ; ( e ) none of the TYMS polymorphisms could explain 5FU  toxicity or clinical outcome Capecitabine is a drug that requires the consecutive action of three enzymes : carboxylesterase 2 ( CES 2 ) , cytidine deaminase ( CDD ) , and thymidine phosphorylase ( TP ) for transformation into 5-fluorouracil ( 5FU ) . The metabolism of 5FU requires the activity of thymidylate synthase ( TS ) and dihydropyrimidine dehydrogenase ( DPD ) among other enzymes . The present study prospect ively examined the possible relationship between the toxicity and efficacy of capecitabine and 14 different polymorphisms in CES 2 , CDD , TS and DPD . Between 2003 and 2005 , a total of 136 patients with advanced breast or colorectal cancer treated with capecitabine were prospect ively enrolled . The presence of two polymorphisms ( CDD 943insC and CES 2 Exon3 6046 G/A ) were associated with a non-statistically significant higher incidence of grade 3 h and -foot syndrome ( HFS ) ( p=0.07 ) and grade 3 - 4 diarrhoea ( p=0.09 ) , respectively . Patients heterozygous or homozygous for the polymorphism CES 2 5'UTR 823 C/G exhibited a significantly greater response rate to capecitabine , and time to progression of disease ( 59 % , 8.7 months ) than patients with the wild type gene sequence ( 32 % , p=0.015 ; 5.3 months , p=0.014 ) . For the first time , an association between a polymorphism in the CES2 gene and the efficacy of capecitabine has been described , providing preliminary evidence of its predictive and prognostic value Purpose : Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs , particularly fluoropyrimidines . Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines , including capecitabine , are thymidylate synthase ( TS ) , methylenetetrahydrofolate reductase ( MTHFR ) , and dihydropyrimidine dehydrogenase ( DPD ) . Experimental design : The aim of this prospect i ve pilot study was to analyze the effect of TS , MTHFR , and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy . Germinal polymorphisms of TS ( 6 bp deletion in the 3′ region and 28 bp repeats , including G > C mutation in the 5′ region ) , MTHFR ( 677C > T and 1298A > C ) , and DPD ( IVS14 + 1G > A ) were determined in 105 consecutive patients . Results : A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele ( 50 % versus 19 % versus 13 % respectively , P = 0.064 ) . The sole patient bearing the DPD IVS14 + 1G > A mutation ( heterozygous ) deceased from hematologic toxicity . The median response duration was 5.8 months ( 95 % confidence interval , 4.3 - 7.2 ) . Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others ( P = 0.037 ) . Conclusions : The present data suggest that 3RG3RG breast cancer patients are not good c and i date s for capecitabine therapy . In addition , attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine . These preliminary data require further confirmation on a larger number of patients The primary end point of the study was the analysis of associations between polymorphisms with putative influence on  5-fluorouracil/irinotecan activity and progression-free survival ( PFS ) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy .  Peripheral blood sample s from 146 prospect ively enrolled patients were used for genotyping polymorphisms in thymidylate synthase ( TS ) , methylenetetrahydrofolate reductase ( MTHFR ) , excision repair cross-complementation group-1 ( ERCC 1 ) xeroderma pigmentosum group-D ( XPD ) , X-ray cross-complementing-1 ( XRCC 1 ) , X-ray cross-complementing-3 ( XRCC 3 ) and uridine diphosphate-glucuronosyltransferases-A1 ( UGT1 A1 ) . TS 3′-UTR 6+/6 + and XRCC3 - 241 C/C genotypes were associated with adverse PFS . Hazard ratio for PFS achieved 2.89 ( 95 % confidence interval=1.56–5.80 ; P=0.002 ) in 30 patients ( 20 % ) with both risk genotypes . Risk for Grade III – IV neutropenia was significantly associated with UGT1A1 * 28 7/7 genotype . These promising findings deserve further investigations and their validation 
    Output:
    
There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy .
No good evidence of association with toxicity was found for the remaining polymorphisms , including several currently included in predictive kits .
A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above .
We estimate this test could provide 26 % sensitivity , 86 % specificity , and 49 % positive predictive value-better than most available commercial kits , but suboptimal for clinical use .
The test panel might be extended to include additional , rare DPYD variants functionally equivalent to * 2A and 2846A , though insufficient evidence supports its use in bolus , infusional , or combination FU .