References. Valorization

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1 Valorization 179

2 Valorization 180

3 Valorization Colorectal cancer (CRC) is a major burden on the health care system with over 1,4millionnewlydiagnosedpatientsandalmost700,000deathsannually. 1 Becauseof these numbers, the global economic burden is substantial, with an estimated $US1422billion each year. Most of the costs occur in advanced stage CRC and are relatedtohospitalization,chemoandradiotherapy,treatmentofrelatedsideeffects andsupportivecare. 2 IntheNetherlands,CRCisoneofthemostfrequentlydiagnosed malignancies with over 15,000 new cases and over 5,000 cancerrelated deaths per year. 3 In 2011, 488 million were spent on health care of CRC patients in the Netherlands. 4,5 InordertodecreaseCRCratesandthusalsotheeconomicaswellasthe socialburden,itisgenerallyacceptedthatthemosteffectivestrategytomanagethe diseaseisearlydetection. 6 In addition to invasive screening methods, i.e. colonoscopy and sigmoidoscopy, severalnoninvasivemethodshavebeendevelopedsuchasthefecaloccultbloodtest (FOBT) and fecal immunochemical hemoglobin test (FIT). It has already been studied that populationbased screening using FOBT leads to a reduction in CRC mortality rates. 710 Since FIT achieves higher participation and CRC detection rates 1113, populationbased screening with this test is expected to improve the mortality rates even more. While FIT is costeffective and is expected to reduce CRC incidence and mortality, its performance can be improved since the test still misses approximately 20% of CRCs and up to 70% of advanced neoplasia. 11,14,15 Lowering the cutoff value increasesthedetectionofadvancedneoplasia,butresultsinadecreaseofthepositive predictive value leading to unnecessary patient anxiety and costs of follow up examinations. InordertoimproveCRCscreening,weidentifiedseveralpromotermethylation biomarkersinbloodand/orfeces.inchapter2,thepotentialofpromotermethylation detectionofgata4infecaldnaisinvestigated,reachingsensitivitiesandspecificities of 5171% and 8493%, respectively. Additionally, detection of GATA5 promoter methylationusingbloodbasedassaysasdescribedinchapter6,yieldedamethylation frequencyofonly18%withaspecificity99%.syne1andfoxe1obtainedrespectively detectionratesof47%and46%withspecificitiesof96%and93%.combiningsyne1 andfoxe1increasedthesensitivityto58%withaminimaldecreaseofthespecificityto 91%.Thoughtheseresultsarepromising,thereachedsensitivitiesandspecificitiesare notsufficientforincorporationintoaclinicalsetting.duetoimprovedfecalandblood DNAisolationanddetectiontechniques,theseresultsmightimproveinthefuture.In chapter4,weshowedthatdetectionofndrg4promotermethylationinstoolsamples identified 5361% of CRC patients, whereas almost no false positive results were obtained.beforeincorporationofanovelbiomarkerintoascreeningprogramcanbe considered, an optimal sensitivity and specificity should be reached. In addition, extensivevalidationwithintheintendedtargetpopulationtoconfirmtheinitialresults isrequired. 16 Combiningsensitivityandspecificity,NDRG4isoneofthebestsingleearly V 181

4 Valorization detection methylation markers published so far. This finding has been validated in independentstudies,demonstratingitsclinicalpotential NDRG4methylationasa diagnostic marker for CRC has been patented by our group and biomarker company MDxHealth (Irvine, USA, and was licensed to Exact Sciences (Madison,USA, a molecular maker test for CRC. Exact Sciences incorporated NDRG4 in their multi marker molecular diagnostic CRC screening test called Cologuard, which includes detection of KRAS mutations and NDRG4 and BMP3 promoter methylation together with a human hemoglobin immunoassay. 16 The United States Food and Drug administration (FDA) has approved Cologuard to screen an averagerisk adult populationof50yearsoldforcrc. 21 Additionally,manyhealthinsurancecompaniesin theunitedstatesofamericadecidedtocoverthecostsofcologuard. Asinmanyothercountries,apopulationbasedCRCscreeningprogramhasbeen introducedinthenetherlandssince2014,inwhichindividualsof5575yearsorolder are offered an immunochemical fecal occult blood test (FIT). If positive, a followup colonoscopy will be performed. The costs are funded by the national budget and thereforepaidwithtaxrevenues.thisdoesnotincludethecostsofthecolonoscopyin the case of a positive FIT, which is paid by the health insurance of the identified individual.comparisonofcologuard withfitinalargeprospectivestudy,showeda significantlyhigherdetectionrateof85%andaspecificityof95%withthecologuard test,whilethefitachievedlessfalsepositiveresults. 19 Althoughthesensitivityofthe Cologuard is promising, several adaptations are required before the test can be incorporated in countries such as the Netherlands, in which the logistic system is designedforscreeneesreceivingafitwhichonlyrequiresaminimalamountofstool andisfeasibleforathometesting.usingcologuard,wholestoolsampleshavetobe transportedtoalaboratorywhichisnotonlyalogisticandeconomicburdenbutalso requires adequate transportation material and preservation buffers. Improvement of Cologuard can be obtained by further development of athome testing on small amountsofstool.severalfactorsinfluencetheamountofdnaanditsquality,suchas samplecollection,storagebuffersanddnaisolation.inordertoincreasetheyieldof highqualitydna,thesefactorsshouldbeoptimized. In conclusion, one of the biomarkers identified in this thesis has been incorporated into a commercial biomarkerassay that detects more CRCs when compared to FIT. If this biomarker assay will be introduced in more CRC screening programs, we expect a decrease in CRC morbidity and mortality and consequently a decreaseofthesocialandeconomicburden. 182

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