Hétérogénéitéintra tumorale,!CTC!&!ctDNA … · 2017. 2. 22. · (IMENEO#study)% FC!Bidard*,#S#Michiels,#V#Mueller,#S#Riethdorf,LJ Esserman,A Lucci,B Naume,J Horiguchi,# RGisbert
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• Hétérogénéité intra-‐tumorale, CTC & ctDNA
• Quelques résultats récents du laboratoire des biomarqueurs tumoraux circulant
François-‐Clément Bidard, Dpt d’Oncologie Médicale
Détec;on CTC
1/ Enrichissement Sélection positive (CTC in) Sélection négative (blood cells out)
2/ Détection & décompte 3/ Eventuelle caractérisation moléculaire Cellules rares mais
« entières » : ADN, ARN, protéines… Analyse individuelle possible
CTC et hétérogénéité
Hétérogénéité : oui Validité Utilité
DETECT III (Allemagne): résultats en aBente
Revue: Bidard et al, Cancer Met Rev 2013
CirCe T-DM1
CirCe T-‐DM1 (France): résultats en aBente
Bidard et al, Nat Rev Clin Oncol 2013
Détec;on ctDNA
Bidard , La le@re du sénologue 2017
ctDNA et hétérogénéité
Nombreuses publications • Détection dans le sang de mutations présentes à un niveau sous-clonal (mais pas trop rare quand même…) è Gènes cibles ? è Hétérogénéité comme marqueur per se ? • Le sang est un « déversoir » de l’ensemble des sites tumoraux (mutations polyclonales…) è Vision « globale » è Mécanismes épistatiques : non évaluables
ctDNA et hétérogénéité
Cibles faciles: Mutations de résistance émergentes (stade IV): • Cancer colorectal è KRAS
• Cancer bronchique EGFR muté è EGFR T790M
• Cancer du sein è ESR1
POUMON
PopulaFon EGFRmut
Traitement TKI 1ère gen.
MutaFon de résistance EGFR T790M
polyclonale dans le sang ? non (autres gènes)
Fréquence esFmée >50%
Réversible sans pression ??
Traitement EGFR TKI 2ème gen.
POUMON CÔLON
PopulaFon EGFRmut KRASwt Traitement TKI 1ère gen. mAb anF-‐EGFR
MutaFon de résistance EGFR T790M KRAS
polyclonale dans le sang ? non (autres gènes) oui
Fréquence esFmée >50% # 20%
Réversible sans pression ?? oui
Traitement EGFR TKI 2ème gen. -‐
POUMON CÔLON SEIN
PopulaFon EGFRmut KRASwt RH+
Traitement TKI 1ère gen. mAb anF-‐EGFR DéprivaFon horm.
MutaFon de résistance EGFR T790M KRAS ESR1
polyclonale dans le sang ? non (autres gènes) oui oui
Fréquence esFmée >50% # 20% 30-‐40%
Réversible sans pression ?? oui ??
Traitement EGFR TKI 2ème gen. -‐ Agent ciblant le RE (SERD)
Cancer colorectal: essai OPTIPRIME Les an;-‐EGFR “raisonnés”
Diaposi;ve de JB Bachet (CHU Pi;é Salpêtrière)
Cancer du poumon EGFR muté: essai APPLE Introduc;on précoce (ctDNA) vs tardive (PD) d’osimer;nib
Diaposi;ve de J Remon Masip (VHIO); EORTC lung group, B Besse (IGR)
Cancer du sein RH+ : Introduc;on précoce (ctDNA) vs tardive (PD) de fulvestrant
• Hétérogénéité intra-‐tumorale, CTC & ctDNA
• Quelques résultats récents du laboratoire des biomarqueurs tumoraux circulant cancer du sein neoadjuvant CTC è IMENEO (oral San Antonio 2016) ctDNAè Riva et al, Clin Chem 2017 + ctDNA HPV
Interna;onal MEta-‐analysis
of circula;ng tumor cell detec;on
in early breast cancer pts
treated by NEOadjuvant chemotherapy (IMENEO study)
FC Bidard*, S Michiels, V Mueller, S Riethdorf, LJ Esserman, A Lucci, B Naume, J Horiguchi, R Gisbert-‐Criado, S Sleijfer, M Toi, JA Garcia-‐Saenz, A Hartkopf, D Generali, F Rothé, J Smerage, L Muinelo, J Stebbing, P Viens, M Magbanua, CS Hall, O Engebraaten, D Takata, J Vidal-‐Marinez, W Onstenk, N Fujisawa, E Diaz-‐Rubio, FA Taran, MR Cappellek, M IgnaFadis, C Proudhon, D Wolf, J Bowman Bauldry, E Borgen, R Nagaoka, V Carañana, J Kraan, M Maestro, SY Brucker, K Weber, F Reyal, D Amara, MG Karhade, RR Mathiesen, H Tokiniwa, A Llombart-‐Cussac, K d'Hollander, P Co@u, JW Park, S Loibl, JY Pierga, K Pantel
* Medical Oncology, Ins;tut Curie, Paris, France
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
Data collec;on
#2,000 poten;ally eligible pts from 18 centers
2 centers off study
LeBer of intent
call for data
2,239 pts data received
data cleaning 83 excluded
2,156 individual pa;ents 21 studies 16 centers
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
N pa;ents ≥1 CTC ≥2 CTC ≥5 CTC 1574 25.2% 12.6% 5.9%
1200 15.1% 5.3% 1.0%
Before NCT
CTC detec;on
Before surgery
Decrease during NCT: p<.0001
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
N pa;ents ≥1 CTC ≥2 CTC ≥5 CTC con;nuous 1574 25.2% 12.6% 5.9%
cT size p<.0001 p<.0001 p<.0001 p<.0001 cT1 122 (7.9%) 18.9% 8.2% 3.3%
cT2 770 (49.8%) 22.3% 10.3% 3.5%
cT3 343 (22.2%) 24.2% 12.2% 6.1%
cT4a-‐c 108 (7.0%) 28.7% 16.7% 8.3%
cT4d 204 (13.2%) 41.2% 24.5% 15.7%
cN status p=.051 p=.021 p=.009 p=.024 cN0 656 (41.9%) 22.7% 10.4% 4.1%
cN+ 911 (58.1%) 27.1% 14.4% 7.2%
Subgroup p=.23 p=.028 p=0.54 p=.12
HR+ 365 (23.2%) 24.1% 11.0% 4.7%
HER2+ 800 (51.0%) 24.1% 11.5% 5.3%
Triple Neg. 405 (25.8%) 28.4% 16.5% 8.4%
CTC detec;on & baseline characteris;cs
Before NCT
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
N pa;ents ≥1 CTC ≥2 CTC ≥5 CTC con;nuous 1370 22.9% 10.8% 4.4%
cT size p=.31 p=.15 p=.049 p=.21
cT1 122 (9.1%) 18.9% 8.2% 3.3%
cT2 770 (56.9%) 22.3% 10.3% 3.5%
cT3 343 (25.5%) 24.2% 12.2% 6.1%
cT4a-‐c 108 (8.0%) 28.7% 16.7% 8.3%
cT4d EXCLUDED
cN status p=.22 p=.19 p=.24 p=.17
cN0 604 (44.3%) 21.4% 9.6% 3.6%
cN+ 760 (55.7%) 24.2% 12.0% 5.1%
Subgroup p=.44 p=.36 p=.13 p=.37
HR+ 292 (21.4%) 20.2% 8.9% 2.4%
HER2+ 738 (54.0%) 23.2% 11.0% 5.1%
Triple Neg. 336 (24.6%) 24.4% 12.5% 4.8%
CTC detec;on & baseline characteris;cs, T4d excluded
Before NCT
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
CTC detec;on: associa;on with pCR
pCR was defined as ypT0/isN0 in 92.5% of pa;ents (N=1916/2072)
pCR was observed in 24.3% of pa;ents (N=503/2072)
N pa;ents ≥1 CTC ≥2 CTC ≥5 CTC con;nuous p=.076 p=.65 p=.90 p=.10
pCR 374 (24.0%) 21.7% 12.0% 6.1% No pCR 1183 (76.0%) 26.3% 13.0% 5.9%
p=.45 p=.13 p=.53 p=.52 pCR 300 (26.3%) 13.7% 7.0% 1.3% No pCR 841 (73.7%) 15.7% 4.6% 1.0%
CTC before NCT
CTC before surgery
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
N pts % Events Hazard Ra;o 0 CTC 1175 9.8% 1 1 CTC 199 10.6% 1.09 [0.65-‐1.69] 2 CTC 59 23.7% 2.63 [1.42-‐4.54]
3-‐4 CTC 47 29.8% 3.84 [2.08-‐6.66] ≥ 5 CTC 93 46.2% 6.25 [4.34-‐9.09]
Stra;fied p value <.0001
months
CTC before NCT & Overall Survival
Same HR observed without T4d tumors No interac;on found with tumor subtype
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
CTC before NCT & Distant Disease-‐Free Survival
N pts % Events Hazard Ra;o 0 CTC 1175 14.6% 1 1 CTC 199 18.1% 1.19 [0.81-‐1.69] 2 CTC 59 33.9% 2.44 [1.47-‐3.84]
3-‐4 CTC 47 38.3% 3.44 [1.96-‐5.55] ≥ 5 CTC 93 58.1% 5.00 [3.57-‐7.14]
Stra;fied p value <.0001
months Same HR observed without T4d tumors No interac;on found with tumor subtype
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
CTC before NCT & Locoregional Relapse-‐Free Interval
N pts % Events Hazard Ra;o 0 CTC 1175 6.7% 1 1 CTC 199 6.0% 0.89 [0.46-‐1.61] 2 CTC 59 15.3% 2.43 [1.12-‐4.76]
3-‐4 CTC 47 4.3% 1.23 [0.20-‐4.00] ≥ 5 CTC 93 22.6% 4.16 [2.32-‐6.66]
months
Stra;fied p value <.0001
Same HR observed without T4d tumors No interac;on found with tumor subtype
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
Overall clinical validity (threshold ≥2 CTC) Mul;variate analyses Time point OS DDFS LRFI
HR p HR p HR p
CTC at baseline (landmark analysis)
4.19 [2.97-‐5.88]
<.0001 3.79 [2.84-‐5.03]
<.0001 3.20 [1.93-‐5.19]
<.0001
CTC [-‐5;0]w before surgery (landmark analysis)
2.56 [1.45-‐4.23]
.0020 2.69 [1.67-‐4.12]
<.0001 1.05 [0.32-‐2.55]
.92
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
Added value to comprehensive prognos;c models
Model (1) Model (2) Endpoint Average increase in Chi2 [95% CI]
P value
Baseline (resampling procedure)
Baseline + CTC baseline
OS 28.9 [13.3-‐44.1] <.0001 DDFS 38.7 [21.9-‐58.5] <.0001 LRFI 8.7 [2.4-‐19.2] .003
Baseline + CTC baseline + pCR (resampling & landmark)
Baseline + CTC baseline + pCR + CTC before surgery
OS 3.1 [0.03-‐11.3] .07
DDFS 3.1 [0.02-‐9.7] .07
LRFI 0.9 [0.00-‐3.5] .34
Likelihood ra;o tests
This presentaFon is the intellectual property of the presenter. contact fcbidard@curie.fr for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-‐10, 2016
Conclusion
CTC number-‐dependent impact on OS, DDFS and LRFI
significant above ≥2 CTC/7.5ml
Post-‐neoadjuvant survival does not exclusively rely on breast cancer
characteris;cs & pCR
CTC complements (but not dupplicates) usual prognos;c factors
Next steps: -‐ clinical u;lity trials (e.g. post-‐neoadjuvant therapy)
-‐ further biological characteriza;on
HPV-‐induced cancers
Cabel et al, in preparaFon
Diagnosis of relapse
Response to systemic therapy
PHRC 2016 obtenu Anger Besançon Curie Paris Curie St Cloud Paris (Tenon)
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