D103 Perspective for Tailoring Radiotherapy

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



Conflict of interest

None



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?



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



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 ?



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.



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



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%



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



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



To tailor RT to prognosticTo tailor RT to prognostic




outcomeoutcome

PredictionPredictionPrognosticPrognosticBenefit / riskBenefit / risk




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)



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



# 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



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



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



“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



To tailor RT to prognosticTo tailor RT to prognostic




outcomeoutcome

PredictionPredictionPrognosticPrognosticBenefit / riskBenefit / risk

environment environmentTumor biologyTumor biology



Is it possible to define particularIs it possible to define particular

populations at risk using biology?populations at risk using biology?



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--



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



N = 2985, FUP: 12y, LR n = 325 & LRR n = 227N = 2985, FUP: 12y, LR n = 325 & LRR n = 227



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



Are HER2 cells radioresistant?Are HER2 cells radioresistant?



Trastuzumab : specific radiosensibilisation HER2+ cell lines

SKBR3MCF7



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



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



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)



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



Is it possible to define particularIs it possible to define particular

populations at risk using gene profils?populations at risk using gene profils?



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



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



Prognosis in breast cancerPrognosis in breast cancer



outcomeoutcome



PredictionPredictionPrognosisPrognosisBenefit / riskBenefit / risk

Means, social, cultural issuesMeans, social, cultural issues



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



C l iC l i



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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D103 Perspective for Tailoring Radiotherapy

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