Internalmammarynodeirradia.onin
earlynode-posi.vebreastcancer
LiseBJThorsen,MD,PhDDepartmentofOncology,AarhusUniversityHospital
May17th2017
Breastcancer
• Womenofthewesternworld• Life-Hmerisk>10%• 2012:500,000newcasesinEurope
• Origininbreast• Spreadtoregionalnodes• Spreadtodistantsites
Breastcancertreatment
• Loco-regional– Surgery
• Mastectomy• Breastconservingsurgery/lumpectomy
• N+:Axillarynoderemoval– Radiotherapy
• Systemictreatment– Chemotherapy– Endocrinetreatment– Targetedtreatment
Internalmammarynodes
• IMNmetastases– MoreoXenw.large/medialtumor/
axillaryN+disease• IMNmetastases:apoorprognosHcsign• 10-yearsurvival
• IMNN0&AxN0:76%• IMNN+&AxN+:25%
• 1960’s:Surgicalrandomizedcontrolledtrials:nobeneficialeffectofIMNdissecHon
• RetrospecHveanalysesofinternalmammarynodeirradiaHon:noconclusiveresults
DBCG
• DanishBreastCancerGroup(DBCG)iniHated1976
• NaHonalguidelinesondiagnosis&treatmentofbreastcancer
• NaHonalDBCGregistrysince1977– Aim:AllDanishpaHentswithprimaryinvasivebreastcancer
– InformaHon:Demography,disease,treatment,follow-up
• NaHonalclinicaltrials
DBCG1980’s
Internalmammarynode(IMN)RTforallN+breastcancer
paHents
1987
2000Anthracyclines
?Rightside+IMNRTLeXsideNoIMN-RT
2003
NoevidenceforeffectofIMN-RT
LeXsideheartdosehigh
Cuzick,etal.CancerTreatRep,1987
2003
Overallsurvival
DBCG
Rightside+IMNRT
↑Breastcancerdeath
↓Heartdeath
Le@sideNoIMN-RT
NaHon-wideprospecHvepopulaHonbased
cohortstudy
Hypotheses
InpaHentswithearlynodeposiHvebreastcancer,IMN-RT• Improvesoverallsurvival• Reducesbreastcancermortality• Reducestheriskofdistantrecurrence
StudypopulaHon
• Inclusion:– TreatedwithstandardRT[2003–2007]– UnilateralearlyBC– OneormoremacrometastaHcaxillarylymphnodes
– StageII-III– Nopriormalignancies– Age<70years
Materialsandmethods
Data-sources• DBCGregistry• TheDanishCivilRegistraHonsystem(CPR)• Registryoncausesofdeath(COD)• Hospitalrecords• Treatment-planningsystems• InformaHonfromgeneralpracHHoners
DBCG-IMN:Design
Right-sidedbreastcancer(n=1492)
LeX-sidedbreastcancer(n=1597)
Inclusioncriterianotmet(n=55)
Eligible(n=3089)
Assessedforeligibility(n=3377)• Registry:Early-stageN+breastcancer
ValidaHonofregistrydata(n=3322)• Consistencyonhistopathology+adjuvanttreatment• MissingdataacquiredfrompaHentfiles Inclusioncriteria
notmet(n=233)
Ineligible nNoornon-standardRT 134RecurrencebeforeRT 34Micrometastases 33Stage4diseaseatdiagnosis 38Inoperable 24Priormalignancy 21Bilateralcancer 4Total 288
PaHentandtumorcharacterisHcsIMNRT(n=1492) NoIMNRT(n=1597)
Medianage(range) 56(22-70) 57(27-70)
Pre-menopausal 612(41%) 649(41%)
EstrogenreceptorposiHve(%) 1207(81%) 1279(80%)
InvasiveductalcarcinomaInvasivelobularcarcinomaOther
1311(88%)135(9%)46(3%)
1356(85%)164(10%)77(5%)
GradeIGradeIIGradeIII
353(24%)715(48%)416(28%)
384(24%)747(47%)462(29%)
pT1pT2pT3
625(42%)773(52%)92(6%)
653(41%)836(52%)106(4%)
pN1pN2pN3
868(58%)401(27%)223(15%)
950(60%)417(26%)230(14%)
LateralMedial/central
907(61%)582(39%)
950(60%)644(40%)
DBCG-IMN:Treatment
IMNRT(n=1492) NoIMNRT(n=1597)
Radiotherapy:48Gy/24FIMN-RT(%)AxillarylevelII-III-IV(%)AxillarylevelI-II-III-IV(%)BoostaXerBCS(%)
1437(97%)1219(82%)273(18%)192(13%)
161(10%)1301(82%)296(18%)192(12%)
TypeofsurgeryMastectomy+AC(%)Breastconserving+AC(%)
962(65%)530(35%)
1054(66%)543(34%)
SystemictreatmentEndocrinetherapy(%)Chemotherapy(%)Endocrine+chemotherapy(%)
702(47%)276(18%)514(35%)
745(47%)310(19%)542(34%)
DBCG-IMN:Follow-up
• Follow-upevery6monthsfor5years,thenonceayearunHl10years• Dateandsiteofrecurrence• Contralateralbreastcancer• Othermalignantdisease• Deathandcauseofdeath
Results
PaLernofrecurrenceMedianFU=8.0years
IMNRT(n=1492)
NoIMNRT(n=1597)
Localrecurrence
29(1.9%) 21(1.3%)
Regionallymphnoderecurrence
10(0.7%) 15(0.9%)
Contralateralbreastcancer
39(2.6%) 36(2.3%)
010
2030
40
Cumulativeincide
nce(%)
Distantrecurrence
1586 1401 1229 1075 500NoIMNRT1485 1322 1193 1043 521IMNRT
Atrisk
0 1 2 3 4 5 6 7 8
Yearssinceradiotherapy
Distantrecurrence
29.7%27.4%AdjustedHR:0.89(0.78;1.01)P=0.07
Difference:2.3%
Events AllIMNRT 417 1492NoIMNRT 478 1597
No.AtriskIMNRTNoIMNRT
Breastcancermortality
CauseofdeathMedianFU=8yrs
IMNRT(n=1492)
NoIMNRT(n=1597)
Breastcancer 329 400Cardiovascular 9 9Othermalignancy 26 39Other 21 32Unknown 0 3
010
2030
40
Cumulativeincide
nce(%
)
Breastcancerd
eath
1586 1507 1352 1246 790NoIMNRT1485 1406 1299 1203 782IMNRT
Atrisk
0 1 2 3 4 5 6 7 8
Yearssinceradiotherapy
Breastcancermortality
23.4%20.9%AdjustedHR:0.85(0.73;0.98)P=0.03
Difference:2.5%
Events AllIMNRT 329 1492NoIMNRT 400 1597
No.AtriskIMNRTNoIMNRT
025
5075
100
Alive(%
)
1586 1507 1352 1246 790NoIMNRT1485 1406 1299 1203 782IMNRT
Atrisk
0 1 2 3 4 5 6 7 8
Yearssinceradiotherapy
75.9%72.2%AdjustedHR:0.82(0.72;0.94)P=0.005
Primaryendpoint:OverallSurvival
Difference:3.7%
Events AllIMNRT 385 1492NoIMNRT 483 1597
No.AtriskIMNRTNoIMNRT
Thorsenetal.JClinOncolfeb2016
AssociaHon:ü-Causality?
• IncreasingriskofIMNmetastaseswith:– IncreasingnumberofposiHveaxillarylymphnodes
– Medial/centraltumorlocaHon
SubgroupanalysisEndpoint:Overallsurvival
Thorsenetal.JClinOncolfeb2016
Hypotheses
InpaHentswithearlynodeposiHvebreastcancer,IMN-RT
• Improvesoverallsurvival
• Reducesbreastcancermortality
• Reducestheriskofdistantrecurrence
PP(P)
Consequence
New2014radiotherapyguidelines:• AllDanishpaHentswithnode-posiHveearlybreastcancerareofferedinternalmammarynodeirradiaHonaspartofadjuvantradiotherapy
• Treatmentisprovidedusingorgan-sparingradiotherapytechniques
Resultsincontext
Whelanetal.:MA.20,2000-2007• 1832pts.ThemajoritystageI-IIbreastcancer,randomisedtowhole
breastirradiaHon(WBI)versusWBI+regionalRT.MFU9.5years• Improveddiseasefreesurvivalanddistantdiseasefreesurvival• BreastcancerspecificsurvivalandOSnotsignificantPoortmansetal.:EORTC22922-10925,1996-2004• 4004pts.withstageI-IIIbreastcancer.Medial/centraltumorand/or
N+diseaserandomisedtomedialsupraclavicular(MS)andIMN-RT.MFU10.9years
• Improveddiseasefreesurvival,distantdiseasefreesurvivalandbreastcancerspecificsurvivalwithMS+IMN-RT
• Overallsurvivalborderlinesignificant
FutureperspecHvesInfavorofIMN-RT:• Consistenteffectacross
studies:Improvessurvival• NewRT-techniques:Low
dosestoorgansatrisk:âriskoftoxicity
• Developmentsintreatmentofcardiovasculardisease:AmelioraHonoftoxicity?
AgainstIMN-RT:• Efficientsystemictherapy:
• ârecurrencerates• âabsolutegainsw.RT
• EarlydetecHon:ChangingbiologyàLessaggressivedisease?
• Riskofcardiacdamageandsecondcancer*
*GrantzauT,RadiotherOncol.2015Jan;114(1):56-65
FutureperspecHves
• WhoneedsIMN-RT?– IdenHficaHonofsub-groupswithlargereffectofIMN-RT
– DetecHonofIMN-metastases(SenHnelnode?PET?)
• WhodoesnotneedIMN-RT?– GeneHcprofilesmaypredictlackofbenefitfromradiotherapyinbreastcancer*
• Methodsforweighingbenefitsagainstharm– Personalizingtreatment
*TrammTetal:ClinCancerRes.2014Oct15;20(20):5272-80
Acknowledgements
Thisworkwassupportedby:• TheDanishCancerSociety• CIRRO–theLundbeckFoundaHonCenterforIntervenHonalResearchinRadiaHonOncology
• TheBreastFriendsCancerCampaign• MaxandIngerWørznersMemorialFoundaHon