Lung Cancer Conference Luxembourg 2013
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Lung Cancer Conference Luxembourg 2013

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  • CTCs in patients with prostate cancer. Sampled by phlebotomy at the time when treatment is being considered, CTCs have the potential to provide tumor material for molecular profiling for biomarkers informative of tumor sensitivity to the targeted therapy being considered. FISH images are reproduced from Leversha et al. (53).
  • MKG-1866, Rev. 1 April 4, 2008 Notes are for internal training use only Introduction to the components.
  • MKG-1866, Rev. 1 April 4, 2008 Notes are for internal training use only

Lung Cancer Conference Luxembourg 2013 Lung Cancer Conference Luxembourg 2013 Presentation Transcript

  • 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
  • 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
  • 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
  • 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)
  • Microfluidics many approaches NIH funded • +/- dielectrophoresis • S Stott, X Zhang
  • CTC-CHIPS not enough clinical data yet • From LA to Wuhan • HR Tseng... B Xiong • 'nanovelcro'
  • EPIC (Scripps Research Institute, P Kuhn Lab, La Jolla) • From 2009, lung case • Concept of fluid biopsy and HD-CTCs • CECs...
  • FOR INTERNAL AND EXTERNAL USEMKG-1866, Rev. 1 8 CellSave Tube CellSearch™ Circulating Tumor Cell Kit Circulating Tumor Cell Control Kit CellSearch™ System VERIDEX, Immunicon, J&J CellTracks® AutoPrep® System MagNest® CellTracks® Analyzer II
  • FOR INTERNAL AND EXTERNAL USEMKG-1866, Rev. 1 9 Circulating Tumor Cell Y Anti-EpCAM Ferrofluid EpCAM Nucleus DAPI Y Anti- 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
  • Literature on CTCs PubMed 3/2013 • Breast (274) • Prostate (112) • Digestive (ColoRectal +...) (66) • Lung (<85, #45) • Others – Melanoma (16) %ProbabilityofSurvival 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 Logrank p < 0.0001 21.7 Months 11.5 Months Cox Hazard Ratio = 3.3 chi-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)
  • 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.)
  • 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.
  • Comparison CellSearch vs ISET Farace F Br J Cancer. 2011 Sep 6;105(6):847- 53.
  • CTMs: Circulating Tumour Microemboli Hou JM,.. Dive C J Clin Oncol 2012 Cho EH,.. Kuhn P Phys Biol. 2012 Feb;9(1):016001.
  • SCLC Cell 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
  • CTCs in SCLC and NSCLC • pharmacodynamic biomarker, in vivo and ex vivo • prognosis
  • 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 patients The 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].
  • CERONC/CIRCUBRONCH projects NSCLC preliminary results • Patients inclusion 31 – Sequential study 19
  • 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
  • CSF • Volume 150mL • Production #500mL per day, (3.7x) • Choroid plexuses • Lumbar puncture Berlin – Heinrich Ireneus Quincke Berl klin Wochenschr 1891;28:929 +965
  • 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.
  • 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
  • Media... • Huffington Post (03/06/2013) Valerie Harper • People – I think there's an opportunity to help people!
  • 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)
  • LM: Gold standard Dux 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
  • STA Ch 2: LCR mélanome CMC New Developments CSF vs BLOOD • Preservation: CSF paradox in Cell Save tubes! • Morphology, numbers and cell biology characteristics – Similarities: Breast – Discrepancies: Lung (+CTMs), Melanoma
  • CSFTCS Breast (BMC Clinical Pathology) CSFTCs Lung
  • 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
  • Sequential analysis of CSFTCs confirms repetability of numerations with two subgroups (high > 700/mL vs low) Sample number 1st 2nd 3rd 4th 5th Tumoralcells/5mLLCR 0,1 1 10 100 1000 10000 100000 DM CTC WA CTC CJ CTC DMB CTC VT CTC PV CTC BE CTC CS CTC HE CMC ST CMC DC CTC
  • 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
  • Melanoma CSFMCs Medical Oncology (in press) • CMC kit • Four patients • 9 points • Reproducibility
  • LUNG Cancer CSFTCs, 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%
  • LUNG Carcinoma meningitis • CSFTCs ---> • <---CSFTMs
  • 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
  • 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...
  • Acknowledgments EA 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