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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 (France): résultats en aBente CirCe T-DM1
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 ? Fréquence esFmée Réversible sans pression Traitement non (autres gènes) >50% ?? EGFR TKI 2ème gen. POUMON CÔLON PopulaFon EGFRmut KRASwt Traitement TKI 1ère gen. mAb anF-­‐EGFR MutaFon de résistance EGFR T790M KRAS non (autres gènes) oui >50% # 20% ?? oui EGFR TKI 2ème gen. -­‐ polyclonale dans le sang ? Fréquence esFmée Réversible sans pression Traitement POUMON CÔLON SEIN PopulaFon EGFRmut KRASwt RH+ Traitement TKI 1ère gen. mAb anF-­‐EGFR DéprivaFon horm. MutaFon de résistance EGFR T790M KRAS ESR1 non (autres gènes) oui oui >50% # 20% 30-­‐40% ?? oui ?? EGFR TKI 2ème gen. -­‐ Agent ciblant le RE (SERD) polyclonale dans le sang ? Fréquence esFmée Réversible sans pression Traitement 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 San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 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 [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 Data collec;on LeBer of intent #2,000 poten;ally eligible pts from 18 centers call for data 2 centers off study 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 [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 CTC detec;on Before NCT Before surgery N pa;ents 1574 ≥1 CTC 25.2% ≥2 CTC 12.6% ≥5 CTC 5.9% 1200 15.1% 5.3% 1.0% Decrease during NCT: p<.0001 This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 CTC detec;on & baseline characteris;cs Before NCT cT size N pa;ents 1574 ≥1 CTC 25.2% p<.0001 ≥2 CTC 12.6% p<.0001 ≥5 CTC 5.9% p<.0001 cT1 cT2 cT3 cT4a-­‐c 122 (7.9%) 770 (49.8%) 343 (22.2%) 108 (7.0%) 18.9% 22.3% 24.2% 28.7% 8.2% 10.3% 12.2% 16.7% 3.3% 3.5% 6.1% 8.3% cT4d 204 (13.2%) 41.2% 24.5% 15.7% p=.051 p=.021 p=.009 22.7% 27.1% 10.4% 14.4% 4.1% 7.2% p=.23 p=.028 p=0.54 24.1% 24.1% 28.4% 11.0% 11.5% 16.5% 4.7% 5.3% 8.4% cN status cN0 cN+ 656 (41.9%) 911 (58.1%) Subgroup HR+ HER2+ Triple Neg. 365 (23.2%) 800 (51.0%) 405 (25.8%) con;nuous p<.0001 p=.024 p=.12 This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 CTC detec;on & baseline characteris;cs, T4d excluded Before NCT cT size cT1 cT2 cT3 cT4a-­‐c cT4d N pa;ents 1370 122 (9.1%) 770 (56.9%) 343 (25.5%) 108 (8.0%) 604 (44.3%) 760 (55.7%) Subgroup HR+ HER2+ Triple Neg. ≥2 CTC 10.8% p=.31 p=.15 ≥5 CTC 4.4% p=.049 18.9% 22.3% 24.2% 28.7% 8.2% 10.3% 12.2% 16.7% 3.3% 3.5% 6.1% 8.3% p=.22 p=.19 p=.24 21.4% 24.2% 9.6% 12.0% 3.6% 5.1% p=.44 p=.36 p=.13 20.2% 23.2% 24.4% 8.9% 11.0% 12.5% 2.4% 5.1% 4.8% con;nuous p=.21 EXCLUDED cN status cN0 cN+ ≥1 CTC 22.9% 292 (21.4%) 738 (54.0%) 336 (24.6%) p=.17 p=.37 This presentaFon is the intellectual property of the presenter. contact [email protected] 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 CTC before NCT pCR 374 (24.0%) No pCR 1183 (76.0%) CTC before surgery pCR 300 (26.3%) No pCR 841 (73.7%) ≥1 CTC p=.076 21.7% 26.3% p=.45 13.7% 15.7% ≥2 CTC p=.65 12.0% 13.0% p=.13 7.0% 4.6% ≥5 CTC p=.90 6.1% 5.9% p=.53 1.3% 1.0% con;nuous p=.10 p=.52 This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 CTC before NCT & Overall Survival 0 CTC 1 CTC 2 CTC 3-­‐4 CTC ≥ 5 CTC N pts 1175 199 59 47 93 % Events 9.8% 10.6% 23.7% 29.8% 46.2% Hazard Ra;o 1 1.09 [0.65-­‐1.69] 2.63 [1.42-­‐4.54] 3.84 [2.08-­‐6.66] 6.25 [4.34-­‐9.09] Same HR observed without T4d tumors No interac;on found with tumor subtype Stra;fied p value <.0001 months
This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 CTC before NCT & Distant Disease-­‐Free Survival 0 CTC 1 CTC 2 CTC 3-­‐4 CTC ≥ 5 CTC N pts 1175 199 59 47 93 % Events 14.6% 18.1% 33.9% 38.3% 58.1% Hazard Ra;o 1 1.19 [0.81-­‐1.69] 2.44 [1.47-­‐3.84] 3.44 [1.96-­‐5.55] 5.00 [3.57-­‐7.14] Same HR observed without T4d tumors No interac;on found with tumor subtype Stra;fied p value <.0001 months
This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 CTC before NCT & Locoregional Relapse-­‐Free Interval 0 CTC 1 CTC 2 CTC 3-­‐4 CTC ≥ 5 CTC N pts 1175 199 59 47 93 % Events 6.7% 6.0% 15.3% 4.3% 22.6% Hazard Ra;o 1 0.89 [0.46-­‐1.61] 2.43 [1.12-­‐4.76] 1.23 [0.20-­‐4.00] 4.16 [2.32-­‐6.66] Same HR observed without T4d tumors No interac;on found with tumor subtype Stra;fied p value <.0001 months
This presentaFon is the intellectual property of the presenter. contact [email protected] 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 CTC at baseline (landmark analysis) CTC [-­‐5;0]w before surgery (landmark analysis) OS DDFS LRFI HR p HR p HR p 4.19 <.0001 3.79 <.0001 3.20 <.0001 2.56 .0020 2.69 <.0001 1.05 .92 [2.97-­‐5.88] [1.45-­‐4.23] [2.84-­‐5.03] [1.67-­‐4.12] [1.93-­‐5.19] [0.32-­‐2.55] This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 Added value to comprehensive prognos;c models Likelihood ra;o tests Average increase in Chi2 [95% CI] P value OS 28.9 [13.3-­‐44.1] <.0001 DDFS 38.7 [21.9-­‐58.5] <.0001 LRFI 8.7 [2.4-­‐19.2] .003 3.1 [0.03-­‐11.3] .07 3.1 [0.02-­‐9.7] .07 0.9 [0.00-­‐3.5] .34 Model (1) Model (2) Endpoint Baseline (resampling procedure) Baseline + CTC baseline Baseline + CTC baseline + pCR (resampling & landmark) Baseline OS + CTC baseline DDFS + pCR + CTC before surgery LRFI This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. San Antonio Breast Cancer Symposium – December 6-­‐10, 2016 Conclusion Post-­‐neoadjuvant survival does not exclusively rely on breast cancer characteris;cs & pCR CTC number-­‐dependent impact on OS, DDFS and LRFI significant above ≥2 CTC/7.5ml CTC complements (but not dupplicates) usual prognos;c factors Next steps: -­‐ clinical u;lity trials (e.g. post-­‐neoadjuvant therapy) -­‐ further biological characteriza;on This presentaFon is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute. HPV-­‐induced cancers Response to systemic therapy Diagnosis of relapse PHRC 2016 obtenu Anger Besançon Curie Paris Curie St Cloud Paris (Tenon) Cabel et al, in preparaFon