Perspective for tailoring r adiotherapy Perspective for tailoring r adiotherapy according to prognosis in breast cancer according to prognosis in breast cancer Y azid Belkacémi, MD, PhD Y azid Belkacémi, MD, PhD On behalf of AROME On behalf of AROME www.aromecancer.org www.aromecancer.org
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8/7/2019 D103 Perspective for Tailoring Radiotherapy
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
8/7/2019 D103 Perspective for Tailoring Radiotherapy
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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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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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
8/7/2019 D103 Perspective for Tailoring Radiotherapy
« 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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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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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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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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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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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 !
8/7/2019 D103 Perspective for Tailoring Radiotherapy