d103 perspective for tailoring radiotherapy
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8/7/2019 D103 Perspective for Tailoring Radiotherapy
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Perspective for tailoring radiotherapyPerspective for tailoring radiotherapyaccording to prognosis in breast canceraccording to prognosis in breast cancer
Yazid Belkacémi, MD, PhDYazid Belkacémi, MD, PhDOn behalf of AROMEOn behalf of AROME
www.aromecancer.orgwww.aromecancer.org
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Conflict of interest
None
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Reduce or even no RT?Reduce or even no RT?
Change the paradigmChange the paradigmand tailor treatmentand tailor treatment
Do we need intensified RT?Do we need intensified RT?
Who need new strategies or modified sequence?Who need new strategies or modified sequence?
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Prognosis in breast cancerPrognosis in breast cancer
HostHost TumorTumor TreatmentsTreatments
PhysiologyPhysiologyImmunityImmunity
ClinicalClinicalPathologyPathologyLocal and distantLocal and distant
outcomeoutcome
PredictionPredictionPrognosisPrognosisBenefit / riskBenefit / risk
Micro environmentMicro environmentTumor biologyTumor biology
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History and paradigmsHistory and paradigms
Virchow (XIXth Century) : Breast anatomy description andVirchow (XIXth Century) : Breast anatomy description andparadigms:paradigms:“the diseases have their origin in cell abnormalities of the“the diseases have their origin in cell abnormalities of thebody” (1858)body” (1858) LocoLoco--regional extension: “regional extension: “ the metastases result from athe metastases result from a
Tumor and microenvironenment ?Tumor and microenvironenment ?
humoral diffusion”humoral diffusion”
Rudolf Virchow (1821Rudolf Virchow (1821--1902)1902)
Sappey CMP.Sappey CMP.
Anatomie, physiologie,Anatomie, physiologie,pathologie des vaisseauxpathologie des vaisseauxlymphatiques considéréslymphatiques considéréschez l’homme et leschez l’homme et lesvertébrés.vertébrés.A. Delahaye Paris; 1874.A. Delahaye Paris; 1874.
Prediction and prognosis ?Prediction and prognosis ?
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Prognostic factors from historic data
Middlesex hospital : 1905 to 1933
Advanced breast cancer (n = 250) 74% St IV, 23% St III
Median survival 2,7y
At 3y 44%At 5y 18%
At 10y 4%
At 5y: Death of all GIII patients
Bloom HJ. The natural history of untreated breast cancer.Bloom HJ. The natural history of untreated breast cancer. Ann N Y Acad Sci. 1964 ;114:747 Ann N Y Acad Sci. 1964 ;114:747--54.54.
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Prognostic factors from historic data
Rosen PP (1981) Ann Surg
Nodal involvement: impact of tumor size
Eighties and NinetiesEighties and Nineties
Sears HF (1982), Cancer
Kandalaft PL ( 1993), CancerPrognostic significance of IHC analysis of cathepsin
D in low-stage breast cancer.
-: re t ere g -r s o og c su popu at ons
Nixon AJ (1996), Cancer
Tumor grade to other pathologic featuresand to treatment
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30
35
Impact of RT on LR after conservative surgeryImpact of RT on LR after conservative surgery
45
NN-- (n = 6097)(n = 6097) N+ (n = 1214)N+ (n = 1214)
Meta analysisMeta analysis
0
5
10
15
20
25
5y 10y
CSCS + RT
Gain 5y: 16%Gain 5y: 16%
5y 10y
Gain 5y: 30%Gain 5y: 30%
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Meta analysis in the new eraMeta analysis in the new era
Surgery RadicalRadical toto CCCCADAD toto SNBSNB
Breast cancer management:Breast cancer management:Evolutions….Evolutions….
RTRT New technologyNew technologyNew concept: APBINew concept: APBIIMRT/GatingIMRT/Gating
SystemicSystemic AIAITaxanesTaxanesHerceptinHerceptin
…Revolution…Revolution
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Reduce or even no RT ?Reduce or even no RT ? Non aggressive T profiles and / or high intrinsic RS ofNon aggressive T profiles and / or high intrinsic RS ofnormal tissues that could need :normal tissues that could need :
oo Dose or volumes reductionsDose or volumes reductions
Change the paradigmChange the paradigm
oo New approaches : HypoF or APBINew approaches : HypoF or APBIoo No RTNo RT
Do we need intensified RT ?Do we need intensified RT ?
Locally aggressive T profiles : increased doses or largerLocally aggressive T profiles : increased doses or largervolumesvolumes
Who need new strategies or modified sequence ?Who need new strategies or modified sequence ?
T profiles with high risk of metastatic recurrenceT profiles with high risk of metastatic recurrence
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To tailor RT to prognosticTo tailor RT to prognostic
HostHost TumorTumor TreatmentsTreatments
PhysiologyPhysiologyImmunityImmunity
ClinicalClinicalPathologyPathologyLocal and distantLocal and distant
outcomeoutcome
PredictionPredictionPrognosticPrognosticBenefit / riskBenefit / risk
Micro environmentMicro environmentTumor biologyTumor biology
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AgeAge
« L’un des privilèges de la vieillesse,« L’un des privilèges de la vieillesse,c’est d c’est d ’avoir, outre son âge, tous les âges » ’avoir, outre son âge, tous les âges »
(Victor Hugo 1802(Victor Hugo 1802--1885)1885)
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Decrease of RT Observance after 65y
Observance of RT according to age
Observance
77%
50%
24%
12%
N de co-morbidities
0
≥≥≥≥ 2
Age
65-69y
≥≥≥≥ 80y
BallardBallard--Barbach, 1996Barbach, 1996
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# pts age stage TRT FU
(y)
LR
(%)
p
1. Fyles 386383
> 50< 50
T1-2T1-2
TAMTAM + RT
5.6 7.70.6
0.001
TAM vs TAM+RTTAM vs TAM+RTNEJM 2004NEJM 2004
2. Hughes 319317
> 70< 70
T1T1
TAMTAM + RT
5.6 41
0.001
1.1. Age > 60yAge > 60y < 10mm< 10mm HR+HR+LR at 5yLR at 5y 0%0% 1.2%1.2% p = 0.16p = 0.16MetastasesMetastases 4%4% 4.5%4.5%
2.2. Beast C death 3 3Other causes 54 53
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APBI Concept
Reduce the treated volumeIncrease the dose per fraction
Use of HDR
New concept for new profiles
Reduce the RT durationIncrease observance and QoL
Pending questionsIdeal profile for APBI: tumor, age…
Limited FU in published studies
Randomized trials: ongoing
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APBI consensus statement from the ASTRO
Based on 645 original research articles4 published randomized clinical trials
“Suitable” group “Cautionary” group “Unsuitable” group
Smith BD et al. IJROBP 74: 987Smith BD et al. IJROBP 74: 987--1001, 20091001, 2009
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“Suitable” Age > 60
No BRCA 1-2mutations T1
IDC, mucinous, tubular,
colloid DCIS not allowed EIC not allowed
Any grade No LVI ER pos Unicentric Unifocal
ssoc a e a owe
pN0 (i -; i +) SN Bx or ALND
No neo-adjuvant CT
Smith BD et al. IJROBP 74: 987Smith BD et al. IJROBP 74: 987--1001, 20091001, 2009
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To tailor RT to prognosticTo tailor RT to prognostic
HostHost TumorTumor TreatmentsTreatments
PhysiologyPhysiologyImmunityImmunity
ClinicalClinicalPathologyPathologyLocal and distantLocal and distant
outcomeoutcome
PredictionPredictionPrognosticPrognosticBenefit / riskBenefit / risk
environment environmentTumor biologyTumor biology
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Is it possible to define particularIs it possible to define particular
populations at risk using biology?populations at risk using biology?
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Molecular subtypes and local controlMolecular subtypes and local control
Period of TRT: 1998Period of TRT: 1998--20012001 Median FU : 70m (n = 793)Median FU : 70m (n = 793)Age :Age : > 55y: 50%> 55y: 50% > 65y: 25%> 65y: 25%
MarginsMargins -- : 97%: 97% No trastuzumabNo trastuzumabRL at 5y : 1.8%RL at 5y : 1.8%
Nguyen PL et al. JCO 2008;26:2373Nguyen PL et al. JCO 2008;26:2373--88
Luminal ALuminal A 0.8% (0,30.8% (0,3--2,2)2,2)RE+/RP+ HER2RE+/RP+ HER2--
Luminal BLuminal B 1.5% (0,21.5% (0,2--10)10)RE+/RP+ HER2+RE+/RP+ HER2+
Her2Her2 8.4% (2,28.4% (2,2--30)30)RERE--/RP/RP-- HER2+HER2+
Triple NEGTriple NEG 7.1% (37.1% (3--16)16)RERE--RPRP--HER2HER2--
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HER2 and LR riskHER2 and LR risk
Higher risk of LR is associated with:Higher risk of LR is associated with:
Multivariate analysisMultivariate analysis
Luminal A as referenceLuminal A as reference
Nguyen PL et al. JCO 2008;26:2373Nguyen PL et al. JCO 2008;26:2373--88
FactorsFactors adjusted HRadjusted HR ICIC--95% 95% p p--valuevalue
HERHER--22 9.29.2 1.61.6--5151 0.0120.012
Triple NEGTriple NEG 7.17.1 1.61.6--3131 0.0090.009
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N = 2985, FUP: 12y, LR n = 325 & LRR n = 227N = 2985, FUP: 12y, LR n = 325 & LRR n = 227
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Press MFPress MFJCO 1997JCO 1997
HER 2 is a poor prognostic factorHER 2 is a poor prognostic factor
NN324324
HER2+HER2+18%18%
SituationSituationNN--
SurvivalSurvival LR&LR&DR DR
Rakkhit R Rakkhit R SABCS 2008SABCS 2008
10651065 23%23% pT1apT1a--bb
Amplification of HER2 is an independent unfavorable Amplification of HER2 is an independent unfavorable
prognostic factor in Nprognostic factor in N-- tumors and/or < 1cm of sizetumors and/or < 1cm of size
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Are HER2 cells radioresistant?Are HER2 cells radioresistant?
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Trastuzumab : specific radiosensibilisation HER2+ cell lines
SKBR3MCF7
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MCF7 transfected by HER2 :- Increase of radioresistance (clonogenic survival)
- Resistance to radiation-induced apoptosis
Mol Cancer Ther (2003)
Increased dose of RxIncreased dose of RxAt 4Gy survival (0;55 vs 0.42)At 4Gy survival (0;55 vs 0.42) At 8Gy: 0.14 vs 0.02 & 0.04At 8Gy: 0.14 vs 0.02 & 0.04
PI3-K/Akt & MEK/MAPK pathways are involved in HER2
cells radioresistance
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Traitement : n = 22 pts Her2+Traitement : n = 22 pts Her2+
HR HR (n = 15)(n = 15) CT resistants (n=7)CT resistants (n=7)RT : Accelerated aand HypoFRT : Accelerated aand HypoFAmifostine : 1g en S/CAmifostine : 1g en S/CTrastuzumab : 4m /k /2semTrastuzumab : 4m /k /2sem
High risk BC ou CTHigh risk BC ou CT--resistantresistant
Koukourakis MI. Am J Clin Oncol 2005; 28 : 495Koukourakis MI. Am J Clin Oncol 2005; 28 : 495--500.500.
CT (n=13): Doxo25 mg/m² or TXT 40 mg/m²/ 2semCT (n=13): Doxo25 mg/m² or TXT 40 mg/m²/ 2sem
RÉSULTATS :RÉSULTATS :
Feasibility of the combined TRTFeasibility of the combined TRT•• No increase of toxicityNo increase of toxicity•• CT resistant tumors: CR in 5/7 casCT resistant tumors: CR in 5/7 cas•• No recurrence after 3No recurrence after 3--26 m of FUp26 m of FUp
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N = 19 Endpoint: pCRTreatment: Weekly trastuzumab (2 mg/kg IV), concurrent RT 50Gy in 25f (breast &nodes) 7 RT alone and 12 following protocol
(11 T4)(11 T4)
Surgery :Surgery :
2/7 had pCR2/7 had pCR1/7 pTmic1/7 pTmic
Total:Total:43% vs historical control 5%43% vs historical control 5%
(p=0.02)(p=0.02)(Huang E et al. IJROBP 2002)(Huang E et al. IJROBP 2002)
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HER2 RadioresistanceHER2 Radioresistance
QuestionQuestion
Are Are HERHER 22 cellscells radioresistant?radioresistant?
ConclusionConclusion
HER HER22 cellscells areare radioresitantradioresitant inin experimentalexperimental modelsmodels (in(invitrovitro andand inin vivo)vivo) ResistanceResistance toto radiationradiation--inducedinduced apoptosisapoptosis
IncreasedIncreased DNADNA repairrepair ClinicalClinical datadata supportsupport increasedincreased riskrisk of of LR LR andand LRR LRR inin HER HER22++ BCBC asas comparedcompared toto luminalluminal phenotypephenotype NeedNeed of of furtherfurther investigationsinvestigations toto definedefine optimaloptimal strategiesstrategies
andand sequencessequences inin HER HER22++ patientspatients
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Is it possible to define particularIs it possible to define particular
populations at risk using gene profils?populations at risk using gene profils?
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Luminal A tumors (HR+ HER2Luminal A tumors (HR+ HER2--))
n = 227 (n = 138)n = 227 (n = 138) Clinicla, pathologic dataClinicla, pathologic data(1992(1992--2004)2004) Kinome (PK genes)Kinome (PK genes)
GEP evaluated by 16 gènes (mitosis)GEP evaluated by 16 gènes (mitosis)
Luminal ALuminal A BasalBasal(n = 80)(n = 80) (n = 58)(n = 58)
Luminal AaLuminal Aa Luminal AbLuminal Ab
Pc +Pc + PcPc --High mitotic indexHigh mitotic indexScore PK Score PK
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Local recurrence after BCT +/Local recurrence after BCT +/-- RTRT
n = 143n = 143 NN--, margins, margins ––
ER+ER+ subgroup GEP distinguish patientssubgroup GEP distinguish patientsLR after RTLR after RT No LR or No RTNo LR or No RT pp
NiméusNiméus--Malström E et al. Br Cancer Res 2008Malström E et al. Br Cancer Res 2008
..
ER ER-- subgroupsubgroup NSNS
Conclusion:Conclusion:GEP provides added value to conventional markers inGEP provides added value to conventional markers inpredicting LR despite RTpredicting LR despite RT
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Prognosis in breast cancerPrognosis in breast cancer
HostHost TumorTumor TreatmentsTreatments
ClinicalClinicalPathologyPathologyLocal and distantLocal and distant
outcomeoutcome
Micro environmentMicro environmentTumor biologyTumor biology
PhysiologyPhysiologyImmunityImmunity
PredictionPredictionPrognosisPrognosisBenefit / riskBenefit / risk
Means, social, cultural issuesMeans, social, cultural issues
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Adequate guidelines..?
Disparities…!!!
Cobalt 60 LASyria
Damas 1 0Haleb 0 1 (Private)Morocco 9 1
Israel 1 20Italy 43 226
Data in 2008Data in 2008
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C l iC l i
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Reduce volumes or even omit RTReduce volumes or even omit RT Define subpopulation of aged patients with very low riskDefine subpopulation of aged patients with very low riskand non aggressive T profiles :and non aggressive T profiles :
HypofractionationHypofractionation
ConclusionConclusionPerspectives to change the paradigmPerspectives to change the paradigm
HT alone for ER+HT alone for ER+
More intensified RT scheduleMore intensified RT schedule Locally aggressive T profiles and young patientsLocally aggressive T profiles and young patients
Increased doses: young boost trialIncreased doses: young boost trial
Need of new strategies or modified sequenceNeed of new strategies or modified sequence T profiles with high risk of metastatic recurrenceT profiles with high risk of metastatic recurrence
HER2+, triple negative and screening by genomicsHER2+, triple negative and screening by genomics
Ob i d !
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