BiologyofAnalSquamousCellCarcinoma

ProfEricRaymond,MD,PhDHôpitaux ParisSaint-Joseph

January2017

TrendsinAnalCancerIncidencebyAgeGroups

Source:SurveillanceEpidemiologyandEndResults– http://seer.cancer.gov/data Accessed8/18/2013

Thomison 2008,HumanPathology,39:154

HPVINFECTIONANDANALDYSPLASIAANDANALCANCER

PreventionofAnalCancerandotherHPVrelateddisease

• Merck– GardasilandGardasil-9arebothFDAapprovedforuseinmalesandfemales9– 26yrsofage

• Dosingis0.5mlattime0,1monthand6months• Bothgardasil vaccineshavebeenshowntopreventHPVrelatedcytologic changesduetotypespecificHPVsub-types

• GSK– Cervarix isonlyFDAapprovedforfemalesfromage9– 25yrs ofage• Dosingis0.5mlattime0,1monthand6months

• CondomusemayreduceHPVtransmissionbutsignificantleveloftransmissiondoesoccureveninthesettingofconsistentcondomuse

ClinCancerRes 2016

Molecularbiologyofanalsquamoous cellcarcinomas(ASCCs)

• AnalysisofseverallargecohortsofASCCshaveshownthatthemajorityofASCCsharborhumanpapillomavirus(HPV)

• HPVassociatedASCCshaveincreasedsensitivitytoCRTandimproveddiseaseoutcomescomparedtonon-HPVassociatedtumors

• KRAS,NRAS,andHRASmutationsareunfrequentlyobserved

• immunohistochemistry(IHC)revealedhighlevelsofEGFRexpressionandfrequentmutationsinthePIK3CA/AKTpathwaypriortotherapy

ClinCancerRes 2016

ManagementandPrognosisofAnalCancer• TreatmentforAnalCancer1

• ChemotherapywithMitomycin-Cand5-Flouro-uracilandRadiation

• Abdomino-PelvicResectiononlyforresidualdiseasepostChemo-RT

• FiveyearsurvivalratesofanalcancerinUS2• Localdisease– 78%• Regionaldisease– 56%• Distantdisease– 18%

1. Ajani JAetal;2008:JAMA299(16):1914-212. JohnsonLGetal;2004:Cancer;101:281- 288

Thenumberoftotalmutationsincreasesinrecurrenttumorsafterradiochemotherapy

ClinCancerRes 2016

Afterradiochemotherapy

• Atotalof2980somaticmutations,including1875missense,170nonsense,30frameshift,and785silentmutationswereidentified

• Thisincludes• knownactivatingmutationsinPIK3CA,• alterationsintheKEAP-1bindingdomainofNFE2L2,• mutationsinTP63andEP300,genesinvolvedinsquamouscelldifferentiation

• Inadditionotherbiologicalpatternswereobserved:• activatingMAPK1and• inactivatingPTENmutations

• Interestingly,• singleHPVnegativecasedidnothaveaTP53mutation• HPVpositivecasesharboredTP53mutations

ClinCancerRes 2016

Cellular&MolecularComponentsoftheCarcinomaMicroenvironment

EndothelialcellsPericytesVEGFR-PDGFR

Tcells(CD4-Treg)CD4:PD1-CTLA4-CD28Treg:CD73-CD39

DendriticcellsPDL1-PD1-MSHII-CD80/86

TumorassociatedmacrophagesCXCR4-TGFβR

TumorcellsTGFβR-MET-PDL1

FibroblastsFGFR

TGFβHGFFGF19IL8IL10

SDF1/CXCL12

MHC

PD-L1

PD-1

PD-1

T-cellreceptor

PD-L2

Tcell

NFκB

Other

PI3K

Tumorcell

IFNγ

IFNγR

Shp-2

Nivolumab

ImmuneCheckpointInhibitionbyNivolumab

• Nivolumab isafullyhumanIgG4anti-PD-1monoclonalantibodythatselectivelyblockstheinteractionbetweenPD-1andPD-L1/PD-L2,1 restoringT-cellimmuneactivitydirectedagainstthetumorcell

1. Topalian SL,etal.NEnglJMed.2012;366:2443-2454

CA209-040:Response KineticsORR:around15%- MedianDurationresponse17months

TimeSinceFirstDose,Months

Chan

geinTa

rgetLe

sion

From

Baseline,%

180

0 3 6 9 12 15 18 21

-100

-80

-60

-40

-20

0

20

40

60

80

100 Months,range

Uninfected(n=21)

HCV(n=11)

HBV(n=10)

TotalEvaluable(n=42)

DOR 7.2*– 12.5* 1.4*– 8.3* 11.9 1.4*– 12.5*

DurationofSD 1.1*– 17.3* 2.9† – 14.0 2.7*– 6.9* 1.1*– 17.3*

*Censored†Patient with resolved HCV infectionFirst occurrence of new lesion

11

+

AnthonyB.El-Khoueiry etal.ASCO2015

GeneticdriftsforASCCsfollowingtherapy

ClinCancerRes 2016

GeneticalterationsleadtomTOR pathwayactivation

ActivationofthemTOR pathwayClinCancerRes 2016

AnalogyAnalSquamousCellCarcinoma

Head&NeckSquamousCellCarcinoma

InHNSCC,thePI3K/mTORpathwayisactivated>70%oftumorsandyieldspoorprognosis

PI3k gene amplification (40-50%)

or mutation (11-40%)

Receptor activationEGFR >90%

PTEN Loss of function:

gene mutation (10-15%), deletion

or promoter methylation

Faivre etal.NatRevDrugDisc,2006

(No RAS mutation)

Everolimus

Conclusions

• Analsquamouscellcarcinomasareraretumorsofincreasingincidence• VaccinationofHPV16-18forcancerpreventioninimmunocompromisedpatients(HIV,chronicsteroids,immunosuppressivemedicationposttransplantation,…)

• Understandingtumorbiologyatthelevelofcancercellmutationsandchangesintumormicroenvironmentmayhelpidentifyingpoorprognosticpatientsanddevelopnovelanticancerdrugs

• Noveltherapeuticstrategiesmayinvolve:• Immunotherapies• mTOR inhibitors• Drugsinhibitingkeystepsinepithelial-to-mesenchymaltransition(MET,TGF-beta,CXCR4,etc…)