Theimportanceofbiomarkersforpeoplewithcancer

NicolaNormanno

ISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI

FONDAZIONE G. Pascale – NAPOLISC Biologia Cellulare e Bioterapie

CENTRO RICERCHE ONCOLOGICHEMERCOGLIANO (AV)

Laboratorio di Farmacogenomica

Molecular alterations incancercells offerpotential fortherapeutic intervention with

"target-based agents"

Hanahan &Weinberg Cell 2011

Theefficacy of targeted therapy depends on

TUMOR HETEROGENEITY

Burrell Nature2013

Target-basedagents+predictivebiomarkers:PRECISIONMEDICINE

WITHOUTBIOMARKERS

WITHBIOMARKERS

What arecancerbiomarkers?

Abiomarkeris“acharacteristicthatisobjectivelymeasuredandevaluatedasanindicatorofnormalbiologicalprocesses,pathogenicprocesses,or

pharmacologicresponsestoatherapeuticintervention”

Precisionmedicine(preferred term)/personalised medicine.….Incancer,thetermusuallyreferstotheuseoftherapeuticsthatareexpectedtoconferbenefittoasubsetofpatientswhosecancerdisplaysspecificmolecularorcellularfeatures(mostcommonlygenomicchangesandgeneorproteinexpressionpatterns).Nevertheless,thetermalsoincludestheuseofprognosticmarkers,predictorsoftoxicitiesandanyparametersuchasenvironmentalandlifestylefactorsthatleadstotreatmenttailoring.

Most commonpredictive biomarkersforsolid tumors

Drug Biomarker Tumortype

Cetuximab(Erbitux),Panitumumab(Vectibix) AbsenceofRASmutations

Colorectalcarcinoma

Crizotinib(Xalkori),Ceritinib(Zykadia),Alectinib(Alecensa)

PresenceofALKrearrangements

Non-smallcelllungcancer

Gefitinib(Iressa),Erlotinib(Tarceva),Afatinib(Giotrif),Osimertinib(Tagrisso)

PresenceofEGFRmutations

Non-smallcelllungcancer

Trastuzumab(Herceptin) PresenceofHER2amplification

Breastandgastriccancer

Vemurafenib(Zelboraf),Dabrafenib(Tafinlar),Trametinib(Mekinist)

PresenceofBRAFmutations

Melanoma

Pembrolizumab ExpressionofPD-L1 Non-smallcelllungcancer

Testing forbiomarkers

Ø Biomarker testing is usually performed on tumor fragments obtained by biopsies, but can also be performed on blood samples (liquid biopsy)

Ø The liquid biopsy can be used for biomarker testing, butnot for the diagnosis of tumor that requires a tissuesample

Apatientstoryin2010• OnNovember2010,a41-year-oldman,formerlightsmoker(5pack-

years),wasadmittedtoourInstitution.• Criticalclinicalconditions:massivepericardialeffusion,disseminated

intravascularcoagulation,renalandhepaticfailure(ECOGPS4).• CTscanshowedtwolunglesionsintheupperrightlobe(24and21mm),

rightpleuraleffusion,ametastaticlesionoftherightventricleoftheheart(16x22mm),multiplehepaticlesions(20mm),thrombosisoftheportalsystem,ascites,multiplebonemetastases(sternum,cervical,dorsalandlumbarspine,pelvis).

• Thecytologic evaluationofthepericardialeffusionwaspositiveforlungadenocarcinoma.

• MutationalanalysisoftheEGFRwasrequestedonacytologic specimencontainingonly20neoplasticcells.

Morabito JTO 2012

EGFRmutational analysis of CTCs,serum andplasmaby using PNA-clamp

168bpDNADEL

35 CTCs

STANDARD

0 CTCs

2 CTCs

183bpDNA WT

168bpDNADEL

STANDARD

183bpDNA WT

168bpDNA DELSTANDARD

PLASMA- PNA

+ PNASTANDARD

STANDARD

183bpDNA

WT

168bpDNA DEL

SERUM- PNA

+ PNA

*: obtained from the same patient at different time points during the treatment

Samplesanalysed

Tumor EGFRstatus

Sourceoftumor DNA

EGFRmutations

Ex19Del L858R

1*c.2235_2249del15p.E746_A750del

CTC(35) Mut WT

Serum Mut WT

Plasma Mut WT

2*c.2235_2249del15p.E746_A750del

CTC(0) WT WT

3*c.2235_2249del15p.E746_A750del

CTC(2) Mut WT

Serum Mut WT

Plasma Mut WT

Morabito JTO 2012

December 2010 March 2011 July 2011

• On December 15, we started therapy with gefitinib 250 mg/day, with a progressive and dramatic improvement of clinical conditions. After two weeks of treatment, renal and hepatic functions were normalized

• The PET scan after 3 months of gefitinib showed only a minimal tracer accumulation at the basis of the right lung (SUV 3.3), but became negative after 7 months of therapy, indicating a complete response

• Response to gefitinib was mantained for 11 months, until November 2011 when an hepatic progression occurred

• The patient died on March 2012

Morabito JTO 2012

“Actionable”somaticalterationsidentifiedindifferenttumortypes

Zehir Nat Med 2017

Challenges inbiomarker testingandprecision oncology

Inordertopromoteprecisiononcologywemust:Ø GuaranteeaccesstobiomarkerstocancerpatientsinallEuropean

countries.Ø Promotetechnologicalevolutiontowardsinnovativetestingmethods

(nextgenerationsequencing)thatallowtheidentificationofseveralmarkersforanalysis.

Ø IdentifyreferencecenterswithadequateexperienceandtechnologicalequipmentthroughouttheEuropeanterritory.

Ø Facilitatenationalandinternationalcollaborationstoassessthepredictiveroleofraremutations.

Ø Guaranteeaccesstonewdrugsavailableinclinicalpracticeorthroughclinicaltrials.

Ø Ensurethatthequalityofthetestsreceivedbycancerpatientsishigh.

Mission• Internationalmulti-stakeholderexpertgroup

forimprovingqualityofclinicalbiomarkertestinginpathology

Organisation• Non-profitassociation(network)• EQAprovidermembers• CorporatesponsorsActivities• Publications,guidelines&training:AdvocateEQA/PT&education

• Multi-stakeholderCommunication:WorkingGroups,Workshops

• BestpracticeforEQA:Schemebadging• Verification/endorsement:Badging standards,controls,tools

• EQAdatasharingforresearchinEQAdesign:Database

InternationalQuality NetworkforPathology

Normanno J Cell Biochem 2013

Thefutureofbiomarker testing incancer

Garraway JCO 2013

SurgeonEndoscopistRadiologist

SurgeonEndoscopistRadiologist

MedicalOncologist

MedicalOncologist

Pathologist,Geneticist,Molecular Biologist

MedicalOncologist

SurgeonRadiotherapist

PrecisionOncology