IMENEO study
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![Page 1: IMENEO study](https://reader033.fdocument.pub/reader033/viewer/2022042906/58a798cd1a28ab5f6c8b65a1/html5/thumbnails/1.jpg)
International MEta-analysis
of circulating tumor cell detection
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-Martínez, W Onstenk, N Fujisawa, E Diaz-Rubio, FA Taran, MR Cappelletti, M Ignatiadis, 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 Cottu, JW Park, S Loibl, JY Pierga, K Pantel
* Medical Oncology, Institut Curie, Paris, France
This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
FC BidardResearch grant from Janssen Diagnostics to Institut Curie
K d'HollanderIDDI employee
Disclosures
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
Circulating Tumors Cells (CTCs)CTCs are the “seeds” of distant metastases
In metastatic BC patients- prognostic factor before & during therapy- dynamic changes of CTCs >> serum markersCristofanilli et al., N Engl J Med 2004; Bidard et al., Lancet Oncol 2014
In non-metastatic BC patients- prognostic factor before adjuvant therapyLucci et al., Lancet Oncol 2012; Rack et al., J Natl Cancer Inst 2014
CTCs can be counted with the FDA-cleared CellSearch® system
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
CTCs in neoadjuvant settingFirst study with CellSearch®, N=118 pts (REMAGUS02)
Numerous studies initiated worldwidevery few published / heterogeneous results
No significant association between CTC detection and pCR
Prognostic impact on:
Distant-Metastasis-Free SurvivalPierga et al., Clin Cancer Res 2008
Overall SurvivalBidard et al., Ann Oncol 2010
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
ObjectivesStudy objectives were pre-specified in a written protocol
Iry objective: Overall Survival (OS)
IIry objectives: - Association with baseline characteristics (includ. T4d vs non T4d)- Distant Disease-Free Survival (DDFS)- Locoregional Relapse-Free Interval (LRFI)- Association with pCR- Exploration of CTC-positivity thresholds- To measure the added value of CTC count to clinically-optimized prognostic models
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
Methods- literature & abstracts search up to Dec 2014- direct contact with all centers deemed to have eligible data:
CTC count by CellSearch® Early BC pts treated with neoadjuvant chemotherapy (NCT) Survival (published or not)
Non-overlapping CTC time points:○ [-5;0] weeks before NCT = baseline○ [1;8] weeks after start of NCT○ [-5;0] weeks before the surgery○ [1;52] weeks after surgery
StatisticsCox regression models (stratified by study) & landmark method Overfitting bias of multivariate prognostic models (used to report average increases in likelihood ratio) was limited by resampling procedures
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This presentation 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 collection
#2,000 potentially eligible pts from 18 centers
2 centersoff study
Letter of intent
call for data
2,239 pts data received
data cleaning 83 excluded
2,156 individual patients 21 studies 16 centers
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
N= 1,574 pts N= 290 pts
N= 1,200 ptsN= 285 pts
[-5;0]w before start of NCT[1;8w]w after start of NCT[-5;0]w before surgery[1;52]w after surgery
CTC data collected:
7.5ml of blood (1 tube) analyzedfor >95% of CTC points
Data collection
#2,000 potentially eligible pts from 18 centers
2 centersoff study
Letter of intent
call for data
2,239 pts data received
data cleaning 83 excluded
2,156 individual patients 21 studies 16 centers
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
N patients ≥1 CTC ≥2 CTC ≥5 CTC1574 25.2% 12.6% 5.9%Before NCT
CTC detection
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
N patients ≥1 CTC ≥2 CTC ≥5 CTC1574 25.2% 12.6% 5.9%
1200 15.1% 5.3% 1.0%
Before NCT
CTC detection
Before surgery
Decrease during NCT: p<.0001
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
N patients ≥1 CTC ≥2 CTC ≥5 CTC continuous1574 25.2% 12.6% 5.9%
cT size p<.0001 p<.0001 p<.0001 p<.0001cT1 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=.024cN0 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
HER2+ 365 (23.2%) 24.1% 11.0% 4.7%HR+ 800 (51.0%) 24.1% 11.5% 5.3%Triple Neg. 405 (25.8%) 28.4% 16.5% 8.4%
CTC detection & baseline characteristics
Before NCT
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
N patients ≥1 CTC ≥2 CTC ≥5 CTC continuous1370 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
HER2+ 292 (21.4%) 20.2% 8.9% 2.4%HR+ 738 (54.0%) 23.2% 11.0% 5.1%Triple Neg. 336 (24.6%) 24.4% 12.5% 4.8%
CTC detection & baseline characteristics, T4d excluded
Before NCT
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This presentation 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 detection: association with pCR
pCR was defined as ypT0/isN0 in 92.5% of patients (N=1916/2072)
pCR was observed in 24.3% of patients (N=503/2072)
N patients ≥1 CTC ≥2 CTC ≥5 CTC continuousp=.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=.52pCR 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
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
N pts0 CTC 11751 CTC 1992 CTC 59
3-4 CTC 47≥ 5 CTC 93
CTC before NCT & Overall Survival
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
N pts % Events Hazard Ratio0 CTC 1175 9.8% 11 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]
Stratified p value <.0001
months
CTC before NCT & Overall Survival
Same HR observed without T4d tumors No interaction found with tumor subtype
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This presentation 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
N pts % Events Hazard Ratio0 CTC 1175 14.6% 11 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]
Stratified p value <.0001
monthsSame HR observed without T4d tumors No interaction found with tumor subtype
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This presentation 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
N pts % Events Hazard Ratio0 CTC 1175 6.7% 11 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
Stratified p value <.0001
Same HR observed without T4d tumors No interaction found with tumor subtype
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This presentation 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)Multivariate analysesTime point OS
HR p
CTC at baseline(landmark analysis)
4.19 [2.97-5.88]
<.0001
cT T3-T4T4d
1.49 2.94
.0023
cN cN1 1.65 .0045Subgroup HER2+
Triple Neg1.69 5.24
<.0001
pCR No 5.88 <.0001
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This presentation 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)Multivariate analysesTime 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
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
Changes during therapy; ≥2 CTC
Distant Disease-Free SurvivalLandmark analysis
Overall SurvivalLandmark analysis
N
<2 / <2 CTC 609
<2 / >2 CTC 21
>2 / <2 CTC 103
>2 / >2 CTC 11
N
<2 / <2 CTC 606
<2 / >2 CTC 21
>2 / <2 CTC 103
>2 / >2 CTC 10
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This presentation is the intellectual property of the presenter. contact [email protected] for permission to reprint/ distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
Changes during therapy; ≥2 CTC
Distant Disease-Free SurvivalLandmark analysisStratified p value p<.0001
Overall SurvivalLandmark analysisStratified p value p<.0001
N HR
<2 / <2 CTC 609 1
<2 / >2 CTC 21 3.57>2 / <2 CTC 103 4.29>2 / >2 CTC 11 9.68
N HR
<2 / <2 CTC 606 1
<2 / >2 CTC 21 3.89>2 / <2 CTC 103 4.18>2 / >2 CTC 10 4.94
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This presentation 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 prognostic models
Model (1) Model (2) Endpoint Average increase in Chi2 [95% CI] P value
Baseline
(resampling procedure)
Baseline + CTC baseline
OS
DDFS
LRFI
Baseline+ CTC baseline+ pCR(resampling & landmark)
Baseline+ CTC baseline+ pCR+ CTC before surgery
OS
DDFS
LRFI
Likelihood ratio tests
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This presentation 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 prognostic 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 ratio tests
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This presentation 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
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
characteristics & pCR
CTC complements (but not dupplicates) usual prognostic factors
Next steps: - clinical utility trials (e.g. post-neoadjuvant therapy)
- further biological characterization
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San Antonio Breast Cancer Symposium – December 6-10, 2016
S MichielsJY PiergaP CottuC ProudhonF ReyalP Viens
B NaumeE BorgenO EngebraatenRR Mathiesen
S SleijferJ KraanW Onstenk
D GeneraliMR Cappelletti
Thank you
K d'HollanderE Coart
K PantelA HartkopfS LoiblV MuellerS RiethdorfSY BruckerFA TaranK Weber
J HoriguchiM ToiN FujisawaR NagaokaD TakataH Tokiniwa
JA Garcia-SaenzR Gisbert-CriadoL MuineloV CarañanaE Diaz-RubioA Llombart-CussacM MaestroJ Vidal-Martínez
LJ EssermanA LucciJ SmerageD AmaraJ Bowman BauldryCS HallD HayesMG KarhadeM MagbanuaJW ParkD Wolf
M IgnatiadisF Rothé
J Stebbing