***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: Abstract Background : Systematic evaluation and validation of new prognostic and predictive markers , technologies and interventions for colorectal cancer ( CRC ) is crucial for optimizing patients ’ outcomes . With only 5–15 % of patients participating in clinical trials , generalizability of results is poor . Moreover , current trials often lack the capacity for post-hoc subgroup analyses . For this purpose , a large observational cohort study , serving as a multiple trial and biobanking facility , was set up by the Dutch Colorectal Cancer Group ( DCCG ) . Methods / design : The Prospect i ve Dutch ColoRectal Cancer cohort is a prospect i ve multidisciplinary nationwide observational cohort study in the Netherl and s ( yearly CRC incidence of 15 500 ) . All CRC patients ( stage I – IV ) are eligible for inclusion , and longitudinal clinical data are registered . Patients give separate consent for the collection of blood and tumor tissue , filling out question naires , and broad r and omization for studies according to the innovative cohort multiple r and omized controlled trial design ( cm RCT ) , serving as an alternative study design for the classic RCT . Objectives of the study include : 1 ) systematic ally collected long-term clinical data , patient-reported outcomes and bio material s from daily CRC practice ; and 2 ) to facilitate future basic , translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods , even for studies with stringent inclusion criteria . Results : Seven months after initiation 650 patients have been enrolled , eight centers participate , 15 centers await IRB approval and nine embedded cohort- or cm RCT - design ed studies are currently recruiting patients . Conclusion : This cohort provides a unique multidisciplinary data , biobank , and patient-reported outcomes collection initiative , serving as an infrastructure for various kinds of research aim ing to improve treatment outcomes in CRC patients . This comprehensive design may serve as an example for other tumor types PURPOSE Fluoropyrimidines are frequently prescribed anticancer drugs . A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase ( DPD ; ie , DPYD*2A ) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity . This study determined the feasibility , safety , and cost of DPYD*2A genotype-guided dosing . PATIENTS AND METHODS Patients intended to be treated with fluoropyrimidine-based chemotherapy  were prospect ively genotyped for DPYD*2A before start of therapy . Variant allele carriers received an initial dose reduction of ≥ 50 % followed by dose titration based on tolerance . Toxicity was the primary end point and was compared with historical controls ( ie , DPYD*2A variant allele carriers receiving st and ard dose described in literature ) and with DPYD*2A wild-type patients treated with the st and ard dose in this study . Secondary end points included a model-based cost analysis , as well as pharmacokinetic and DPD enzyme activity analyses . RESULTS A total of 2,038 patients were prospect ively screened for DPYD*2A , of whom 22 ( 1.1 % ) were heterozygous polymorphic . DPYD*2A variant allele carriers were treated with a median dose-intensity of 48 % ( range , 17 % to 91 % ) . The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73 % ( 95 % CI , 58 % to 85 % ) in historical controls ( n = 48 ) to 28 % ( 95 % CI , 10 % to 53 % ) by genotype-guided dosing ( P < .001 ) ; drug-induced death was reduced from 10 % to 0 % . Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the st and ard dose ( 23 % ; P = .64 ) and by similar systemic fluorouracil ( active drug ) exposure . Furthermore , average total treatment cost per patient was lower for screening ( € 2,772 [ $ 3,767 ] ) than for nonscreening ( € 2,817 [ $ 3,828 ] ) , outweighing screening costs . CONCLUSION DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity . DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient . On a population level , upfront genotyping seemed cost saving UNLABELLED In February 2010 , the Medical Advisory Secretariat ( MAS ) began work on evidence -based review s of the literature surrounding three pharmacogenomic tests . This project came about when Cancer Care Ontario ( CCO ) asked MAS to provide evidence -based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario . Evidence -based analyses have been prepared for each of these technologies . These have been completed in conjunction with internal and external stakeholders , including a Provincial Expert Panel on Pharmacogenomics ( PEPP ) . Within the PEPP , subgroup committees were developed for each disease area . For each technology , an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative ( THETA ) and is summarized within the reports . THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT : www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER : An Evidence -Based and Economic Analysis Epidermal Growth Factor Receptor Mutation ( EGFR ) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor ( TKI ) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer : an Evidence -Based and Economic Analysis K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer : an Evidence -Based and Economic Analysis . OBJECTIVE The objective of this systematic review is to determine the predictive value of KRAS testing in the treatment of metastatic colorectal cancer ( mCRC ) with two anti-EGFR agents , cetuximab and panitumumab . Economic analyses are also being conducted to evaluate the cost-effectiveness of KRAS testing . CLINICAL NEED CONDITION AND TARGET POPULATION Metastatic colorectal cancer ( mCRC ) is usually defined as stage IV disease according to the American Joint Committee on Cancer tumour node metastasis ( TNM ) system or stage D in the Duke 's classification system . Patients with advanced colorectal cancer ( mCRC ) either present with metastatic disease or develop it through disease progression . KRAS ( Kristen-RAS , a member of the rat sarcoma virus ( ras ) gene family of oncogenes ) is frequently mutated in epithelial cancers such as colorectal cancer , with mutations occurring in mutational hotspots ( codons 12 and 13 ) of the KRAS protein . Involved in EGFR-mediated signalling of cellular processes such as cell proliferation , resistance to apoptosis , enhanced cell motility and neoangiogenesis , a mutation in the KRAS gene is believed to be involved in cancer pathogenesis . Such a mutation is also hypothesized to be involved in resistance to targeted anti-EGFR ( epidermal growth factor receptor with tyrosine kinase activity ) treatments such as cetuximab and panitumumab , hence , the important in evaluating the evidence on the predictive value of KRAS testing in this context . KRAS MUTATION TESTING IN ADVANCED COLORECTAL CANCER : Both cetuximab and panitumumab are indicated by Health Canada in the treatment of patients with metastatic colorectal cancer whose tumours are WT for the KRAS gene .  Cetuximab may be offered as monotherapy in patients intolerant to irinotecan-based chemotherapy or in patients who have failed both irinotecan and oxaliplatin-based regimens and who received a fluoropyrimidine .  It can also be administered in combination with irinotecan in patients refractory to other irinotecan-based chemotherapy regimens . Panitumumab is only indicated as a single agent after failure of fluoropyrimidine- , oxaliplatin- , and irinotecan-containing chemotherapy regimens . In Ontario , patients with advanced colorectal cancer who are refractory to chemotherapy may be offered the targeted anti-EGFR treatments cetuximab or panitumumab . Eligibility for these treatments is based on the KRAS status of their tumour , derived from tissue collected from surgical or biopsy specimens . It is believed that KRAS status is not affected by treatments , therefore , for patients for whom surgical tissue is available for KRAS testing , additional biopsies prior to treatment with these targeted agents is not necessary . For patients that have not undergone surgery or for whom surgical tissue is not available , a biopsy of either the primary or metastatic site is required to determine their KRAS status . This is possible as status at the metastatic and primary tumour sites is considered to be similar . RESEARCH QUESTION To determine if there is predictive value of KRAS testing in guiding treatment decisions with anti-EGFR targeted therapies in advanced colorectal cancer patients refractory to chemotherapy . RESEARCH METHODS LITERATURE SEARCH The Medical Advisory Secretariat followed its st and ard procedures and on May 18 , 2010 , search ed the following electronic data bases : Ovid MEDLINE , EMBASE , Ovid MEDLINE In-Process & Other Non-Indexed Citations , Cochrane Central Register of Controlled Trials , Cochrane Data base of Systematic Review s and The International Network of Agencies for Health Technology Assessment data base . The subject headings and keywords search ed included colorectal cancer , cetuximab , panitumumab , and KRAS testing . The search was further restricted to English- language articles published between January 1 , 2009 and May 18 , 2010 result ing in 1335 articles for review . Excluded were case reports , comments , editorials , non  systematic review s , and letters . Studies published from January 1 , 2005 to December 31 , 2008 were identified in a health technology assessment conducted by the Agency for Healthcare Research and Quality ( AHRQ ) , published in 2010 . In total , 14 observational studies were identified for inclusion in this EBA : 4 for cetuximab monotherapy , 7 for the cetuximab-irinotecan combination therapy , and 3 to be included in the review for panitumumab monotherapy INCLUSION CRITERIA English- language articles , and English or French- language HTAs published from January 2005 to May 2010 , inclusive . R and omized controlled trials ( RCTs ) or observational studies , including single arm treatment studies that include KRAS testing . Studies with data on main outcomes of interest , overall and progression-free survival . Studies of third line treatment with cetuximab or panitumumab in patients with advanced colorectal cancer refractory to chemotherapy . For the cetuximab-irinotecan evaluation , studies in which at least 70 % of patients in the study received this combination therapy . EXCLUSION CRITERIA Studies whose entire sample was included in subsequent publications which have been included in this EBA . Studies in pediatric population s . Case reports , comments , editorials , or letters . OUTCOMES OF INTEREST Overall survival ( OS ) , medianProgression-free-survival ( PFS ) , median . Response rates . Adverse event rates . Quality of life ( QOL ) . SUMMARY OF FINDINGS OF SYSTEMATIC REVIEW : CETUXIMAB OR PANITUMUMAB MONOTHERAPY : Based on moderate GRADE observational evidence , there is improvement in PFS and OS favouring patients without the KRAS mutation ( KRAS wildtype , or KRAS WT ) compared to those with the mutation . CETUXIMAB-IRINOTECAN COMBINATION THERAPY : There is low GRADE evidence that testing for KRAS may optimize survival benefits in patients without the KRAS mutation ( KRAS wildtype , or KRAS WT ) compared to those with the mutation . However , cetuximab-irinotecan combination treatments based on KRAS status discount any effect of cetuximab in possibly reversing resistance to irinotecan in patients with the mutation , as observed effects were lower than for patients without the mutation . Clinical experts have raised concerns about the biological plausibility of this observation and this conclusion would , therefore , be regarded as hypothesis generating . ECONOMIC ANALYSIS Cost-effectiveness and budget impact analyses were conducted incorporating estimates of effectiveness from this systematic review . Evaluation of relative cost-effectiveness , based on a decision-analytic cost-utility analysis , assessed testing for KRAS genetic mutations versus no testing in the context of treatment with cetuximab monotherapy , panitumumab monotherapy , cetuximab in combination with irinotecan , and best supportive care . Of importance to note is that the cost-effectiveness analysis focused on the impact of testing for KRAS mutations compared to no testing in the context of different treatment options , and does not assess the cost-effectiveness of the drug treatments alone . CONCLUSIONS KRAS status is predict 
    Output:
    
Model-based cost-effectiveness analyses of systemic mCRC treatments have adopted varied modelling methods and structures , result ing in substantially different outcomes .
As models generally focus on first-line treatment without consideration of downstream treatments , there is a profound source of structural uncertainty implying that the cost-effectiveness of treatments across the mCRC pathway remains uncertain