What is hot in breast cancer brain metastases?

Dieta Brandsma, Department of Neuro-oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

8th Annual Brain Metastases Research and Emerging Therapy Conference, Marseille 2018

- 15-20%ofmetastaticbreastcancerpatients- incidenceBMdependsonbreastcancersubtype

incidenceBM medianOS

hormonereceptorpositiveandHER2negative

14% 9-10months

HER2positive 30-50% 11-18months

triplenegative 46% 5months

Arebrainmetastasesaprobleminbreastcancer?

1.definitiveroleanduseofsystemictherapy

2.newtreatmentstrategiesinmetastaticbreastcancer-PARPinhibitors

-CDK4/6inhibitors

-immunecheckpointinhibitors

3.translationalresearch:a.BMdifferfromprimarytumorb.liquidbiopsiesinBM(sessionyesterday)

Whatishotinbreastcancerbrainmetastases(BCBM)?

May 2018 August 2018

4coursesofcapecitabin+trastuzumab

Case

woman,60,metastaticHER2+breastcancerdysphasiaandright-sidedsensomotorsymptoms

capecitabin+lapatinibinHER2+BMpatients

LANDSCAPEtrial:

Phase2studyoncapecitabin+lapatinibinHER2+metastaticbreastcancerwithpreviouslyuntreatedBM(n=45,60%symptomatic)

Results:objectiveresponse:66%,allPRmediantimetoCNSprogression=6monthsmediantimetoRT=8months

Discussion:authorsproposeRCTofupfrontcapecitabin+lapatinibvsWBRT

Bachelotetal.,Landscapetrial.LancetOncol2013Jan;14(1):64-71

DM1=emtansin,cytotoxicactivity,microtubule-inhibitoryagent

T-DM1

T-DM1=trastuzumablinkedtoDM1

EMILIAtrial,randomizedclinicaltrialin991patients

T-DM1inmetastaticHER2+breastcancer

Vermaetal.NEnglJMed2012Nov8;367(19):1783-91

T-DM1 lapatinib+capecitabin

Pvalue

objectiveresponserate 44% 31% P<0.001

PFS 10months 6months P<0.001

OS 31months 25months P<0.001

Conclusion:T-DM1leadstoabetterresponserate,PFSandOS

exploratoryanalysisEMILIAtrial

T-DM1inHER2+breastcancerwithtreated,asymptomaticCNSmetastases

T-DM1(n=45)

lapatinib+capecitabin(n=50)

statisticalsignificance

CNSprogression 22% 16%

PFS 6months 6months P=1.000

OS 27months 13months P=0.008

Conclusion:significantbetterOSwithT-DM1probablyduetobetterresponseofsystemicmetastases

Kropetal.AnnOncol2015Jan;26(1):113-9

woman,44,HER2+breastcancer,symptomaticBM

atdiagnosis 4monthsafterWBRT

6monthsafterWBRT

3monthsT-DM1

treatment

JNeurooncol.2016Apr;127(2):401-3.

retrospectiveanalysisT-DM1inHER2+breastcancerwith(andwithout)BM

Fabietal.Breast2018Oct;41:137-143.Epubaheadofprint:2018Jul.

withBM(n=87)

withoutBM(n=216)

P-value

intracranialresponse(n=45)- complete- partial

25%4%21%

---

extracranialresponse 35% 38% NS

mediancumulativePFS 7months 8months P=0.06

mediancumulativeOS 14months 32months P<0.001

Conclusion:T-DM1isactiveinBMfromHER2+breastcancerandfurtherstudiesarewarranted

Phase3trialoncarboplatinvsdocetaxelinadvancedtriplenegativebreastcancer:theTNTTrial(n=376)

Results:- overallresponseratecarboplatin=68%vsdocetaxel=33%inBRCA1/2mutatedmetastatictriplenegativebreastcancer(p=0.03)

-±50%cross-over→noconclusiononOS

Tuttetal.NatMed2018May;24(5):628-637.

WhatisnewonsystemictherapyintriplenegativeBCin2018?

BReastCAncer-1and-2mutations

-BRCAproteinsneededforhomologousrecombinationtorepairdoubleDNAstrandbreaks-5%breastcancerpatients:BRCAmutation

BReastCAncer(BRCA)-1and-2mutations

BRCA1:triplenegativebreastcancer

BRCA2:estrogenpositivebreastcancer

lifetimeriskbreastcancer

lifetimeriskovariancancer

BRCA1 60-80% 35-45%

BRCA2 60-80% 10-20%

1.definitiveroleanduseofsystemictherapy

2.newtreatmentstrategiesinmetastaticbreastcancer-Poly(ADP-Ribose)Polymerase=PARPinhibitors

-CDK4/6inhibitors

-immunecheckpointinhibitors

3.translationalresearch:a.BMdifferfromprimarytumorb.liquidbiopsiesinBM(sessionyesterday)

Whatishotinbreastcancerbrainmetastases(BCBM)?

PARPinhibitioninBRCAmutatedcancer

singlestrandDNAbreak

doublestrandDNAbreak

repairedDNA

BRCAmutatedcancersareinparticularsensitivetoPARPinhibition

PARPinhibitioningermlineBRCAmutatedHER2negativemetastaticbreastcancer-Olympiadtrial

Robsonetal.NEnglJMed2017Aug10;377(6):523-533

olaparib(n=205)

single-agentchemotherapy(n=97)

P-value

responserate 60% 29%

medianPFS 7months 4months P<0.001

medianOS 17months(estimate)

17months(estimate)

notsignificantHR0.90;95%CI0.63-0.91

Conclusion:significantbenefitolaparibmonotherapyovernon-platinumsingle-agentchemotherapy

PARPinhibitioningermlineBRCAmutatedmetastaticHER2negativebreastcancer-EMBRACAtrial

Littonetal.NEnglJMed2018Aug23;379(8):753-763

talozoparib(n=287)

single-agentchemotherapy(n=144)

P-value

responserate 63% 27% P<0.001

medianPFS 9months 6months P<0.001

medianOS 22months 19months P=0.11(HR0.7695%CI=0.55-1.06)

Conclusion:significantbenefittalozoparibovernon-platinumsingle-agentchemotherapy

PARPinhibitionandbreastcancerBM

- PhaseItrial:veliparib+WBRTinBMfromprimarysolidtumors*30%fatigue,20%nausea,nonewtoxicities*medianOSbreastcancergroup,n=25:8months(2.8-15.0)*nomogram-model-predicted4.9months(4.2-5.5)

-noongoingtrialsonPARPinhibitorsinBMofbreastcancer

Mehtaetal.VeliparibincombinationwithWBRTinpatientswithbrainmetastases:resultsofaphaseIstudy.JNeurooncol2015Apr;122(2):409-417.

1.definitiveroleanduseofsystemictherapy

2.newtreatmentstrategiesinmetastaticbreastcancer-PARPinhibitors

-CDK4/6inhibitors

-immunecheckpointinhibitors

3.preclinicalresearch:a.BMdifferfromprimarytumorb.liquidbiopsiesinBM(sessionyesterday)

Whatishotinbreastcancerbrainmetastases(BCBM)?

CDK4/6inhibitioninhormonereceptorpositivebreastcancerleadstocellcyclearrest

efficacyofCDK4/6inhibitorsinhormonereceptorpositivemetastaticbreastcancer

6randomizedclinicaltrials(2015-2018):

PALOMA:palbociclib+fulvestrantvsfulvestrantMONALEESA:ribociclib+letrozolevsletrozoleMONARCH:abemaciclib+fulvestrantvsfulvestrantConclusion:consistentdoublingofPFSin1stand2ndlinetreatment,noeffectonOS(yet)

→CDK4/6inhibitorsusedinclinicalpractice

CDK4/6inhibitionandbreastcancerBM

-phaseIandphaseIIstudy:abemaciclibinCSFsimilartoplasma

-open-labelphaseIIstudyinhormonereceptorpositivemetastaticbreastcancerwithBM(n=23):2PR(9%)

-3ongoingtrialswithCDK4/6inhibitorsinbreastcancerBM(NCT02896335,NCT02774681,NCT02308020)

Shebjametal.ASCOmeetingabstract2016;34(suppl):526

1.definitiveroleanduseofsystemictherapy

2.newtreatmentstrategiesinmetastaticbreastcancer-PARPinhibitors

-CDK4/6inhibitors

-immunecheckpointinhibitors

3.translationalresearch:a.BMdifferfromprimarytumorb.liquidbiopsiesinBM(sessionyesterday)

Whatishotinbreastcancerbrainmetastases(BCBM)?

AnnouncementRochedd.July2018:

PhaseIIIImpassion130studyonatezolizumab+paclitaxelvsplacebo+paclitaxelinmetastatictriplenegativebreastcancer:

- significantincreasePFSinintention-to-treatandPD-L1positivegroup

- encouragingoverallsurvival(OS)benefitforPD-L1positivegroupatinterimanalysis

Immunecheckpointinhibitorsinmetastaticbreastcancer

ImmunecheckpointinhibitorsinbreastcancerBM

OngoingclinicaltrialofdurvalumabinpatientswithBMfromepithelial-derivedtumorsincludingbreastcancer(NCT02669914)

- geneticdifferencesbetweenBMandprimarybreastcancer*mutationsinCDK-andPI3K/AKT/mTORpathway(Brastianosetal.,CancerDiscovery2015)*geneexpressionprofiles(Vareslijaetal.JNatlCancerInst2018)

- morehomologousrecombinantdeficiencyinBMcomparedtoprimarybreastcancer(Diossyetal.,AnnOncol2018)

- immunemicro-environment:*fewerTILsinBMthaninprimarybreastcancer(Ogiyaetal.Oncotarget2017)

translationalresearchBMdifferfromprimarytumor

THE FUTURE - BREAST CANCER BRAIN METASTASES

- increaseduseofupfrontsystemictherapy

- furtherdataoneffectofPARP-,CDK4/6-andimmune-checkpointinhibitorsinBM

-differencesBMandprimarytumormaytailorfuturetreatment

Thank you for your attention!

8th Annual Brain Metastases Research and Emerging Therapy Conference, Marseille 2018

DNArepairviaexchangeofnucleotidesbetween

homologouschromosomes

chromosome

homologouschromosome

homologousrecombinationduringmitosis:repairofdoublestrandDNAbreaks

morehomologousrecombinationdeficiencyinnon-BRCAmutatedBCBM

Diossyetal.,Breastcancerbrainmetastasesshowincreasedlevelsofgenomicaberrationbasedhomologousrecombinationdeficiencyscoresrelativetocorrepondingprimarytumors.AnnOncolJun2018,Epubaheadofprint.

Translationalstudyinnon-BRCAmutatedbreastcancer(n=37)

-significantincreaseofHRDinBMrelativetoprimarytumor-increasedHRDlevel87.5%ofBMvsprimarytumor-56%ofBM=HRDdeficient

Question:shouldHRDmeasurementbeusedforstratificationofpatientsforPARPinhibition?