AnnalsofHepatology18(2019)786–787
ContentslistsavailableatScienceDirect
Annals
of
Hepatology
j o ur na l ho me p ag e:w w w . e l s e v i e r . e s / a n n a l s o f h e p a t o l o g y
Opinion
Hepatocellular
carcinoma,
a
unique
tumor
with
a
lack
of
biomarkers
Jose
D.
Debes
a,b,∗,
Enrique
Carrera
c,
Angelo
Z.
Mattos
d,
Jhon
E.
Prieto
e,
Andre
Boonstra
a,
On
behalf
of
ESCALON
investigators
1aDepartmentofGastroenterologyandHepatology,ErasmusMC,UniversityMedicalCenterRotterdam,TheNetherlands bDepartmentofMedicine,UniversityofMinnesota,Minneapolis,MN,USA
cUniversidadSanFranciscodeQuito,HospitalEugenioEspejo,Quito,Ecuador dUniversidadeFederaldeCiênciasdaSaúdedePortoAlegre,PortoAlegre,RS,Brazil eCentrodeEnfermedadesHepaticasyDigestivas(CEHYD),Bogota,Colombia
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Availableonline26August2019 Keywords:
HCC Biomarkers Blood
a
b
s
t
r
a
c
t
Hepatocellularcarcinoma(HCC)isoneoftheleadingcausesofcancer-relateddeathworldwide. Inter-estingly,thegreatmajorityofindividualsaffectedbythetumorhaveunderlyingliverdisease,therefore narrowingthepopulationtobescreened.Still,however,thereisaclearlackofbloodbiomarkers,and surveillanceinthoseatriskisperformedbyfrequentimagingoftheliver.Avarietyofmultinational col-laborationsarecurrentlyinvestedinfindingbiomarkersforHCCbasedonliver-producedproteins.Anew approachwithassessmentofperipheralproteinsmightbenecessaryforthesuccessfulearlydetection ofthismalignancy.
©2019Fundaci ´onCl´ınicaM ´edicaSur,A.C.PublishedbyElsevierEspa ˜na,S.L.U.Thisisanopenaccess articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Opinion
Elsa(nother realname) is 36 years old.In December 2017 shewasdiagnosedwithcirrhosissecondarytohepatitisB infec-tion(HBV), afterbeing referred to a tertiary hospital in Quito, Ecuadorduetoagastrointestinalbleedfromesophagealvarices. Shehassince remainedstable and on treatmentfor HBV. Due toherHBV-relatedcirrhosis shewasadvisedtoundergo hepa-tocellularcarcinoma(HCC)surveillancewithultrasound,thegold standard,every6months.ElsalivesinTepapare,Pastazaprovince, intheEcuadorianAmazon.TocomplywithherHCCsurveillance sheundertakesa6–8hcanoetripthroughtheAmazonRiver, fol-lowedbya5-hbusridetoQuito.Althoughuntilpresenttimeshe hasfollowedhersurveillanceinstructionsproperly,herprimary hepatologistinQuitoisunsurethatshecanundertakesucha com-muteforalongperiodoftime.Elsa’sexampleisnotisolated,but arathercommonscenarioofindividualswithcirrhosisresidingin ruralsettingsinmanyregionsoftheworld.
HCCisthemostfrequentmalignancyoftheliverandthesecond mostcommoncauseofcancer-relateddeathworldwide.HCChas aspecificparticularity:itdoesrarely-to-neveroccurinahealthy liver.ThegreatmajorityofHCCsoccurinasettingofunderlying
∗ Correspondingauthor:420
E-mailaddress:debes003@umn.edu(J.D.Debes). 1 SeeAppendix.
cirrhosis.Indeed,individualswithlivercirrhosis,dependingonthe initialcauseofliverdisease,haveanapproximate50%riskofHCC overa10yearperiod[1].
Onewouldassumethatwithsuchaspecificpopulationtotarget, thescientificcommunitywouldhavedevelopedscreening tech-nologiesforearlyidentificationofHCCinthoseatrisk.Sadly,this isnotthecase:inthecurrentstandardofcareindividuals with advanced liverdiseaseareadvisedtoreturn totheclinicevery 6monthstoundergoultrasonographic examinationoftheliver withthegoalof“visually”identifyingatumorsmallenoughtobe amenabletocurativetreatment.Despitethenon-invasivenatureof ultrasound,thefrequencyofthetesting,time-consuming appoint-mentsandpreparation(individualshavetostopeatingordrinking hoursbeforethetest)leadtopooradherenceasindividualsgrow tired and miss appointments. This explains whyEdenvik et al. reportedthat only30%of HCCdiagnosesoccurthrough surveil-lanceinSweden,andSingaletal.reported24%propersurveillance forHCCintheUnitedStates,whichimprovedto47%onlyafter specificeffortsinreachingpatientswereattempted[2,3].These issuesaremoreprevalentinLatinAmericawhereaccessto hospi-talsforimaging islimited,workpermitsformedicalexamsare scarceand culturalfactors lead toindividuals shying from fre-quent health visits.A recent analysisfromtheSouth American Liver Research Network(SALRN) of morethan 1300HCC cases revealedthatoverhalfofthemwerediagnosedoutsideof surveil-lance[4].
https://doi.org/10.1016/j.aohep.2019.07.009
1665-2681/©2019Fundaci ´onCl´ınicaM ´edica Sur,A.C.PublishedbyElsevierEspa ˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).
J.D.Debesetal./AnnalsofHepatology18(2019)786–787 787
Thereisaclearandobviousneedfornewbiomarkersinorderto easilydetectearlyHCC.Thesebiomarkersshouldbesensedinblood andideallyinintervalslongerthan6months.Thescientific commu-nityandindustry,aswellasthehepatologycommunityasawhole, arefullyawareofthisandeffortshavebeenplacedtoachieveearly HCCdetectionviabloodtests.Nonetheless,biomarkersthathave sofarbeenidentifieddonotreliablypredictthedevelopmentof HCCinthoseatrisk.
AcommonlyusedbiomarkerforHCCisalpha-fetoprotein(AFP). However,thesensitivityandspecificityofthisproteinisquitelow andthemostimportantprofessionalsocietiesforliverdiseasedo notadvocateitsuseinisolationaslevelsshowsignificant varia-tioninindividualswithandwithoutHCC[5].TheGALADmodel (whichcombinesage,genderand3bloodbiomarkers)hasshown promise,butitisunclearhowitperformsindifferentpopulations. Otherbiomarkersthathavebeenstudiedorproposedwith vari-abledegreesofsuccessareglypican-3,alpha-glucosidase,AFP-L3 anddes-gamma-carboxyprothrombin(DCP)[6–8].However,none ofthesearereadyforprimetimeandwestillrelyonultrasoundfor surveillanceandearlydetection.
TherationalefortheproposedbiomarkersforHCCscreening (mentionedabove)isbased ontheunderstandingthat atumor willproducea proteinthatcan bedetectedin blood.However, HCCpresentsanarrayofcomplexities,suchasahighlyvariable geneticcomponentandvariableproteinproductionsdependingon thecauseofunderlyingliverdisease.OneotherparticularityofHCC isthatitdevelopsfromaninflammatoryenvironmentinthe major-ityofcases(theenvironmentthatleadstocirrhosis).Therefore,the immunesystemintheseindividualsisinter-relatedtothe forma-tionofthetumorlikelyfromveryearlystages,evenwhenthetumor isnotdetectablebyimaging.Interestingly,arecentstudyfromour groupinasmallcohortofHCVpatientsfoundthatimmune mark-ersdetectedinbloodcouldpredictHCCdevelopmentupto2years inadvance[9].Itiswiththisinmind,thatagroupofcliniciansand researchersfromEurope,NorthAmericaandSouthAmericajoined forcestoformESCALON(European-SouthAmericanConsortiumto AssessLiver-OriginatedNeoplasia).Oneofthemaingoalsofthis multinationalinitiativeistovalidateimmune-relatedmarkersthat couldpredictHCCearlyon,withabloodtest.Theconceptissimple, albeitimportant:“tousetheimmunereactionofthebodyto pre-dictearlytumordevelopment”.Weexpectthatthisapproachwill eventuallyallowproviderstodetectHCCearlierthana“6-month period”likelyextendingsurveillancetimetoonceayearormore andalsominimizingdiscomfortbysubjectingapatienttoasimple blooddraw.BesidesESCALON,othermultinationalinitiativesare studyingnovelbiomarkersforHCC.Thecommongoalamongstof allofthemisthesame:thattheElsasofthisworlddon’thaveto endureheroichurdlestoundergocancersurveillance.
Funding
ThisprojecthasreceivedfundingfromtheEuropeanUnion’s Horizon2020researchandinnovationprogramundergrant agree-mentNo.825510,theRobertWoodJohnsonFoundation,AFMDP andNIH-NCIR21CA215883-01A1toJDD.
Appendix. ESCALONinvestigators
Firstname,middleinitial Lastname
JoseD. Debes Andre Boonstra AngeloZ. Mattos Marco Arrese Domingo Balderramo JuanC. Roa JuanW. Valle JesusM. Banales Enrique Carrera PabloA. Romagnoli JhonE. Prieto BettinaE. Hansen Esteban Gonzalez-Ballerga MelinaR. Ferreiro Arndt Vogel Angela Lamarca References
[1]Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012;379:1245–55.
[2]EdenvikP,DavidsdottirL,OksanenA,IsakssonB,HultcrantzR,StålP.Application ofhepatocellularcarcinomasurveillanceinaEuropeansetting.Whatcanwe learnfromclinicalpractice?LiverInt2015;35:1862–71.
[3]SingalAG,TiroJA,MarreroJA,McCallisterK,MejiasC,AdamsonB,etal.Mailed outreachprogramincreasesultrasoundscreeningofpatientswithcirrhosisfor hepatocellularcarcinoma.Gastroenterology2017;152,608–615.e604. [4]DebesJD,ChanAJ,BalderramoD,KikuchiL,GonzalezBallergaE,PrietoJE,etal.
HepatocellularcarcinomainSouthAmerica:evaluationofriskfactors, demo-graphicsandtherapy.LiverInt2018;38:136–43.
[5]ShermanM,BruixJ,PoraykoM,TranT,CommitteeAPG.Screeningfor hepato-cellularcarcinoma:therationalefortheAmericanAssociationfortheStudyof LiverDiseasesrecommendations.Hepatology2012;56:793–6.
[6]JohnsonPJ,PirrieSJ,CoxTF,BerhaneS,TengM,PalmerD,etal.The detec-tionofhepatocellularcarcinomausingaprospectivelydevelopedandvalidated modelbasedonserologicalbiomarkers.CancerEpidemiolBiomarkersPrev 2014;23:144–53.
[7]XuD,SuC,SunL,GaoY,LiY.Performanceofserumglypican3indiagnosisof hepatocellularcarcinoma:ameta-analysis.AnnHepatol2019;18:58–67. [8]SugimotoH,TakedaS,InoueS,KanekoT,WatanabeK,NakaoA.
Des-gamma-carboxyprothrombin(DCP)ratio,anovelparametermeasuredbymonoclonal antibodiesMU-3and19B7,asanewprognosticindicatorforhepatocellular carcinoma.LiverInt2003;23:38–44.
[9]DebesJD,VanTilborgM,GroothuisminkZMA,HansenBE,SchulzeZurWiesch J,vonFeldenJ,etal.Levelsofcytokinesinserumassociatewithdevelopment ofhepatocellularcarcinomainpatientswithHCVinfectiontreatedwith direct-actingantivirals.Gastroenterology2018;154,515–517.e513.
