Download - Lung Cancer Conference Luxembourg 2013
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CTCs and CSFTCs in metastatic Lung Cancer
• GC Faure, Q Tu, H Cai, M de Carvalho, C Kohler Immunologie
• C Clément-Duchêne, Y Martinet Pneumologie
• L Taillandier et al., Neurologie• E Le Rhun, COL, Lille
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CTCs... CSFTCs... ETCS?
• CTCs: A dream come true?– 1869, Thomas Ashworth– 2013, A new cell
biomarker• MRD a challenge in
oncohaematology:– Blood, Bone marrow
• MRD in solid oncology:– Prognosis– Personalized Medicine
– From DTCs to CTCs
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CTCs in patients with prostate cancer.
Danila D C et al. Clin Cancer Res 2011;17:3903-3912
©2011 by American Association for Cancer Research
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So many CTCs approaches post 3rd World CTC USA Boston
• Immunomagnetic (Cell Search, MagSweep..)• Cellular Size filtration (ISET, Screencell...)• Density gradient separation (Rarecell)• Dielectrophoresis (DepArray, Silicon Biosystem) • Microchip microfluidics (GEDI, Harvard SLS,
CTC-Chips... )• Multispectral imaging (on slide EPIC, flow
AMNIS)
• Functional properties CAM (VITATEX)• In vivo sampling (Gilupi)
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Microfluidicsmany approaches NIH funded
• +/- dielectrophoresis• S Stott, X Zhang
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CTC-CHIPSnot enough clinical data yet
• From LA to Wuhan• HR Tseng... B Xiong• 'nanovelcro'
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EPIC (Scripps Research Institute, P Kuhn Lab, La Jolla)
• From 2009, lung case
• Concept of fluid biopsy and HD-CTCs
• CECs...
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FOR INTERNAL AND EXTERNAL USEMKG-1866, Rev. 1 8
CellSave Tube
CellSearch Circulating Tumor Cell Kit
Circulating Tumor Cell Control Kit
CellSearch SystemVERIDEX, Immunicon, J&J
CellTracks AutoPrep System
MagNest
CellTracks Analyzer II
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FOR INTERNAL AND EXTERNAL USEMKG-1866, Rev. 1 9
Circulating Tumor CellY
Anti-EpCAMFerrofluid
EpCAM
NucleusDAPI
YAnti-CK-PE
CK
Immunomagnetic Labeling and Immunofluorescent Identification of Cells
Plus anti-CD45 do distinguish contaminant mononuclear cells
Enrichment of cells of interest with PROFILE Kit
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Literature on CTCs PubMed 3/2013
• Breast (274)• Prostate (112)• Digestive (ColoRectal +...) (66)• Lung (<85, #45)• Others
– Melanoma (16)%
Pro
babi
lity
of S
urvi
val
Time from Baseline Blood Draw (Months)0 2 4 6 8 10 12 14 16 18 22 24 26 28 30
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
20
Logrankp < 0.0001
21.7 Months
11.5Months
Cox Hazard Ratio = 3.3chi-square = 34.48(p-value < 0.0001)
CTC / 7.5mL Median OS in at Baseline N (%) Months (95% C.I.) <5 CTC 94 (43%) 21.7 (21.3 to ------) >5 CTC 125 (57%) 11.5 ( 9.3 to 13.7)
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Clinical research on CTCs in Lung Cancer (1)
• After initial molecular biology techniques
• Microchip (Haber Nature, 2007)• Cell Search
– Wu C et al (Beijing) J Thorac Oncol 2009 Jan;4(1):30-6.
– Okumura Y et al Pulmonary venous blood Ann Thorac Surg 2009 Jun;87(6):1669-75.
– Tanaka F et al Clin Canc Res 2009 Nov 15;15(22):6980-6.)
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Clinical research on CTCs in Lung Cancer (2)
• Filtration methods (ISET)– Vona G... P Paterlini-Brechot Amer J Pathol 2000, 156,
57-63
– Hofman V et al, Clin Cancer Res. 2011 Feb 15;17(4):827-35
– Hou JM...Dive C Am J Pathol. 2011 Mar;178(3):989-96;
– Hou JM et al J Clin Oncol. 2012 Feb 10;30(5):525-32.
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ComparisonCellSearch vs ISET
Farace F Br J Cancer. 2011 Sep 6;105(6):847-53.
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CTMs: Circulating Tumour Microemboli
Hou JM,.. Dive C J Clin Oncol 2012 Cho EH,.. Kuhn P Phys Biol. 2012
Feb;9(1):016001.
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SCLCCell Search
Hou JM et al Am J Pathol 2009 Aug;175(2):808-16;
Hou JM et al J Clin Oncol. 2011 Apr 20;29(12):1556-63
Naito T et al J Thorac Oncol. 2012 Mar;7(3):512-9
Hiltermann N et al Ann Oncol. 2012 Nov;23(11):2937-42
Boshuizen R al J Thorac Dis. 2012 Oct;4(5):456-8 PK
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CTCs in SCLC and NSCLC
• pharmacodynamic biomarker, in vivo and ex vivo
• prognosis
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Metaanalysis
Metaanalysis of circulating tumor cells
as a prognostic marker in lung cancer
Ma XL, Xiao ZL, Liu L, Liu XX, Nie W, Li P, Chen NY, Wei YQ.
Asian Pac J Cancer VOLUME 13, 2012 Issue Number 4 , 1137-1144
12 + 15 articles, 2615 patientsThe hazard ratio (HR) for OS predicted by pro-
treatment CTCs was 2.61 [1.82, 3.74], while the HR for PFS was 2.37 [1.41, 3.99].
The HR for OS predicted by post-treatment CTCs was 4.19 [2.92, 6.00], while the HR for PFS was 4.97 [3.05, 8.11].
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CERONC/CIRCUBRONCH projectsNSCLC preliminary results
• Patients inclusion 31 – Sequential study 19
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After CTCs............ CSFTC
• A new acronym– CSF:volume 150 mL vs blood (4,5L)– Another biological fluid– From choroid plexuses
• A new gold standard for carcinoma meningitis definition
• A new frontier for cancer research– Metastatic processus– Therapeutic approaches
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CSF
• Volume 150mL• Production #500mL per day, (3.7x)• Choroid plexuses • Lumbar puncture Berlin
– Heinrich Ireneus Quincke Berl klin Wochenschr 1891;28:929 +965
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CSFTCs: a new frontier in Cancer?
- L. Nayak, M. Fleisher, R. Gonzalez-Espinoza et al. (MSK, NY) Immunomagnetic platform technology (IMPT) for the diagnosis of leptomeningeal metastasis in solid tumors (LMST) 2010 ASCO Poster Discussion Session, Abstract Number: 2032.
Neurology 2013
- Patel et al Hershey (Oncotarget 2011 Oct;2(10):752-60.)
- Burns TF, Wolff AC (Johns Hopkins, Baltimore) Cell Cycle. 2012 Jan 15;11(2):203-4. Epub 2012 Jan 15. Detection of circulating tumor cells in the cerebrospinal fluid: a new frontier.
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Leptomeningeal Metastasis
• Clinique– Very sick: seizures, severe
headaches, blurry vision, mental status changes, inability to walk or perform everyday tasks.. completely incapacitated
• Diagnosis– Imaging (MRI)
• Meningeal enhancement
– Cytology– Biomarkers
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Media...
• Huffington Post (03/06/2013) Valerie Harper
• People– I think there's an opportunity to help
people!
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LM: Epidemiology... Prognosis 3 to 5% of cancer patients, incidence up to 9.6% (J Clin
Oncol 2004;22:2865) Up to 19% of autopsied patients with cancer and
neurological symtoms (Glass, 1979)– Breast cancer (5%), lung (11%), melanoma (20%)
Increasing incidence – Better survival of cancer patients– New molecules for systemic disease have bad
meningeal diffusion Very Bad prognosis (4 weeks to 6 months) and bad
quality of life– But promise of new intrathecal drugs (MTX,
trastuzumab...) and trials (Chamberlain)
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LM: Gold standardDux et al, J Neurol Sci, 1994; 121; 74-78
CSF volume– 3.5mL: 68% positivity – 10.5mL: 97% positivity
Time interval between sampling and analysis Cell viability 30 mns 50%; 60 mns 20%; 90 mns 10%
Good sensitivity requires First LP 40% Second LP 80%, Third LP to reach 90-95%
No reliable quantification– Response at 50% threshold
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STA Ch 2: LCR mélanome CMCNew DevelopmentsCSF vs BLOOD
• Preservation: CSF paradox in Cell Save tubes!
• Morphology, numbers and cell biology characteristics
– Similarities: Breast– Discrepancies: Lung (+CTMs), Melanoma
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CSFTCS Breast (BMC Clinical Pathology)
CSFTCs Lung
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First Results Specificity: no contaminating ependymal cells
in controls Sensitivity: Detection and quantification in all
established LM patients studied– Initial point of follow-up
• From 1 to >10000 cells– Sequential study in 9 patients from
Deposein with #30 assays High homogeneity (and reproducibility) of
images in patients according to primitive cancer types
High purity compared to blood samples Presence of CTM in lung cancer
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Sequential analysis of CSFTCs confirms repetability of numerations with two subgroups (high > 700/mL vs low)
Sample number
1st 2nd 3rd 4th 5th
Tu
mora
l ce
lls
/ 5 m
L L
CR
0,1
1
10
100
1000
10000
100000
DM CTCWA CTCCJ CTCDMB CTCVT CTCPV CTCBE CTCCS CTCHE CMCST CMCDC CTC
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Melanoma Leptomeningeal metastasis
• CMCs are not so easy to detect in blood
• Meningitis is underdiagnosed with severe prognosis
• L Harstad et al: Neuro Oncol 2008; 10: 1010-8 MD
Anderson
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Melanoma CSFMCsMedical Oncology (in press)
• CMC kit• Four patients• 9 points• Reproducibility
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LUNG CancerCSFTCs, CSFTMs
• Samples (13) • Numerous CSFTCs
– One sequential follow-up (3)– Cell galleries might differentiate SCLC
(1), adenocarcinoma (2), NSCLC (3)....
– Aspects of apoptosis, autophagy...
• Numerous CTMs in some NSCLC patients up to 80%
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LUNG Carcinoma meningitis
• CSFTCs --->
• <---CSFTMs
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CSFTCs: a new frontier!
• Tumoral (epithelial) cells can be detected and quantified in CSF with the CellSearch® technology (CSFTCs)
• Their numbers can be sequentially followed-up in breast, lung and other cancers
– allowing to evaluate the efficacy of treatments (intrathecal and/or systemic)
• Tumoral cell population is more homogeneous and somehow different from blood CTCs, allowing further studies of metastatic properties
• CSFMCs can also be detected and quantified in CSF
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Participants:
• Centre Oscar Lambret (Lille)• CHU (Nancy)
– Pôle Laboratoires (Immunologie)– Pôle Neurologie (L Taillandier, Internes:
Marie, Maud?, Basile...)• Université Lorraine: SIGRETO (F Plenat), CRAN
CNRS UMR 7039 (D Wolff)• Hôpital Zhongnan (ZHOU Yunfeng, TU
Jiancheng, XIONG Bin Wuhan University• NENO Network
– Amiens, Besançon, Colmar, Reims, Strasbourg... Luxembourg, Liège...
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AcknowledgmentsEA 4369 RHEM UMR CNRS 7039
• GC Faure• M de Carvalho• MC Béné (Nantes)• Wuhan PhD students (Chen Min, Cai
Huili, Tu Qian)
• Laboratoire d'Immunologie, CHU Nancy, Pôle Laboratoires et Faculté de Médecine, Université Lorraine