BIOMARKERS OF THROMBOSIS IN CANCER PATIENTS

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1 BIOMARKERS OF THROMBOSIS IN CANCER PATIENTS Pr. Dominique Farge-Bancel Internal Medicine and Vascular Disease Unit UF 04, Hôpital St-Louis Hospital Paris Diderot University for the Groupe Francophone Thrombose et Cancer (GFTC ) / International Thrombosis and Cancer- Continuos Medical Education (ITAC-CME ) /

WHY$BIOMARKERS$for$VTE$in$cancer$pa9ents$?

$Venous$Thromboembolism$ (VTE=$VT,$PE$or$CAT)$ in$$4$n$20%$cancer$pts$ $ $VTE$at$autopsy$in$50%$of$cancer$pts $ VTE$ $20%$of$VTE$pts$

cancer A need for adequate biomarkers to identify patients at risk of VTE => primary VTE prevention based on risk stratification 2.#Farge#et#al.

2 WHY$BIOMARKERS$for$VTE$in$cancer$pa9ents$?$ Treatment(of(VTE(:(an(interna/onal(health(priority(in(countries(with(cancer(plan( $Thrombophylaxis$:$a$major$challenge$ Cancer$ $Venous$Thromboembolism$ (VTE=$VT,$PE$or$CAT)$ in$$4$n$20%$cancer$pts$ $ $VTE$at$autopsy$in$50%$of$cancer$pts $ VTE$ $20%$of$VTE$pts$ $have$ac9ve$cancer $ $4N12%$of$pts$with$idiopathic$VTE$ have$an$underlying$cancer, $ THE RISK of VTE and THE RISK OF BLEEDING vary according to cancer A need for adequate biomarkers to identify patients at risk of VTE => primary VTE prevention based on risk stratification 2.#Farge#et#al.#Thromb#Res#2010;125(Suppl2):S108.#2.#Falanga##&#Zacharski.#Ann#Oncol#2005;16:696.#3.#Monreal#et#al.#J#Thromb#Haemost# 2006;4:1950L1956.#4#Pabinger#I#et#al#Blood#2013;#122:2011#5#Hanna#D#et#al#Clin#Rev#Oncol#Hematol#2013;#88:#19# VENOUS$THROMBOEMBOLISM$AND$CANCER$Copyright$ $ $(OPIC$28/02/2012)$( 2

3 BIOMARKERS OF THROMBOSIS IN CANCER PATIENTS 1. Pathophysiology$of$Cancer$Associated$Thrombosis:$ Pa/ent s(characteris/cs,(tumor(histology/stage,(treatment(related( factors( Hypercoagulability(in(cancer(( 2. Poten9al$predic9ve$biomarkers:$ Blood(count(parameters( Platelets(and(cloAng(ac/va/on(markers( Micropar/cles(and(Tissue(Factor( CloAng(factors(Fibrinogen,(Factor(XIII,(factor(VIII( C(Reac/ve(Protein((CRP)((

4 1$Pathophysiology$of$Cancer$Associated$Thrombosis$ CANCER = INDEPENDANT RISK FACTOR for VTE CANCER case control study 625 pts Olmsted county 1 épisode VTE Heit Arch Int Med 2000; 160:

1$Pathophysiology$of$Cancer$Associated$Thrombosis$ THE$RISK$IS$NOT$EQUAL$according$to$cancer$type$:$OVERALL$INCIDENCE$ California Registry Cancer : 528,693 cancer pts (1993 to 1995)

5 1$Pathophysiology$of$Cancer$Associated$Thrombosis$ THE$RISK$IS$NOT$EQUAL$according$to$cancer$type$:$OVERALL$INCIDENCE$ California Registry Cancer : 528,693 cancer pts (1993 to 1995) Standardized International Ratio (SIR) adjusted for age, race, sex incidence rates during the year immediately preceeding the diagnosis of cancer 5 White Arch Intern Med 2005; 165: 1782

6 $ 1(Pathophysiology(of(Cancer(Associated(Thrombosis( THE(RISK(IS(NOT(EQUAL(ACCORDING(TO(CANCER(DISSEMINATION( Timp(Blood(2013( 6"

Hôtel-Dieu de Paris» 1865 Trousseau#A.#Phlegmasia#alba#dolens.

7 1(Pathophysiology(of(Cancer(Associated(Thrombosis( HYPERCOAGULABILITY IN CANCER Jean-Baptiste Bouillaud ( ) «De l oblitération des veines» 1823 Armaud Trousseau ( ) «Clinique Médicale de L Hôtel-Dieu de Paris» 1865 Trousseau#A.#Phlegmasia#alba#dolens.#Clinique#médicale#de#l HôtelLDieu#de#Paris,#Paris:#Ballière:1865;654# Pabinger#I#et#al#Blood#2013;#122:2011# # #Hanna#D#et#al#Clin#Rev#Oncol#Hematol#2013;#88:#19#

1$Pathophysiology$of$Cancer$Associated$Thrombosis$ Acquired hypercoagulability and cancer: 3 HYPERCOAGULABILITY 1821-1902 Intinsic factors Extrinsic factors (antitumour treatment) 1 VENOUS BLOOD

8 1$Pathophysiology$of$Cancer$Associated$Thrombosis$ Acquired hypercoagulability and cancer: 3 HYPERCOAGULABILITY Intinsic factors Extrinsic factors (antitumour treatment) 1 VENOUS BLOOD STASIS Hospitalization, Immobilization (surgery) Extrinsic compression(tumour) Virchow triad 2 ENDOTHELIAL LESIONS. Tumor cells effraction Surgery Central Venous Catheter Chemotherapy Surgery Radiotherapy Combination : blood stasis or skeletal immobility + vessel wall insult + blood hypercoagulabilty

9 PHYSIOLOGIC COAGULATION PATHWAY - initiated when TF and F VII mediate FX activation Introduction à l étude de l hémostase et de la thrombose,b. Boneu et J.P Cazenave

HYPERCOAGULABILITY IN CANCER : inflammation + thrombosis + cancer! Inflammation:! ff VIII, Fibrinogen, CRPa! Cytokines! Adhesion molecules! VTE associated with:!

10 HYPERCOAGULABILITY IN CANCER : inflammation + thrombosis + cancer! Inflammation:! ff VIII, Fibrinogen, CRPa! Cytokines! Adhesion molecules! VTE associated with:! TNF-α, IL-8, IL-6, CRP (Fox, 2005)! F VIII and VWF (Tsai, 2002)! activity ADAMTS 13 (Mannucci, 2003) Rodger L. Bick, M.D., Ph.D. Cancer-Associated Thrombosis NEJM ; 2003: 349;2

11 2. POTENTIAL PREDICTIVE BIOMARKERS! Blood count parameters : particular interest since assessed regularly! Leukocytosis! Khorana et al Cancer 2005 : ANC study risk CAT VTE: x 2 fold! RIETE study 380r cancer pts: risk CAT VTE: x 1.6 fold! High platelet count risk CAT supported by several studies! Not(to(be(used(as(a(single(parameter(for(risk(predic/on,(rather(within(RAMs Cancer type N pt Cut off HR/OR for VTE during follow-up 95% CI Khorana 2005 Various G/L 2.8 (HR) Simanek 2010 Various 665 > 443G/LL 3.5 (HR)

2 POTENTIAL CAT BIOMARKERS : P-selectin Inflammation, Thrombosis and Cancer! CD62P, member of the selectin family of cell adhesion moelcules:! Expressed on platelets and endothelial cells!

12 2 POTENTIAL CAT BIOMARKERS : P-selectin Inflammation, Thrombosis and Cancer! CD62P, member of the selectin family of cell adhesion moelcules:! Expressed on platelets and endothelial cells! Mediates heterotypic cell-cell interactions! Interact with PSGL-1 on the surface of monocytes TF expression = release of TF bearing MP Fibrin + thrombus formation " sp-selectin in pts with acute VTE + associated with risk of VTE in pts without cancer. Bann JTH 2000; Gremmel. J Vasc Surg Ay Clin Chem 2007 " CATS prospective study cancer pts, biomarker CAT:! 6.4%pts (n+44) with VTE within 415 days FU! Adjusted for age, sex, chemotherapy, surgery, radiotherapy, palteletts, tumor type, cancer types! Predictor VTE : HR 2.3 (p=0.009) risk of VTE. Ay et al. Blood 2008 Chen et al.arch Immunol Ther Exp 2005 Andre et al. PNAS 2000 Prandoni Lancet Oncol 2007

DNDimers$ Cancer Entity n Cutoff HR/OR for VTE during Follow- Up 95% CI Ay 2008 Various 821 1.44 µg/ml 2.2 (HR) 1.3-3.6 Arpaia 2009 Various 124 > 0.65µg/mL 4 (HR) 1.2-13.

13 DNDimers$ Cancer Entity n Cutoff HR/OR for VTE during Follow- Up 95% CI Ay 2008 Various µg/ml 2.2 (HR) Arpaia 2009 Various 124 > 0.65µg/mL 4 (HR) Stender 2009 Colorectal 176 > 0.3µg/mL 6.5 (HR) Kodarma 2010 Gynecologic 291 > 5µg/mL 1.2 (OR) Ferroni2012 Lung 108 > 1.5µg/mL 11 (HR) Ay et al 2008

14 Thrombin$Genera9on$poten9al$ HR, 2.0; 95% CI, 1.3 to 3.2 P.003

15 2. POTENTIAL PREDICTIVE BIOMARKERS MARKERS OF PLATELETS and CLOTTING ACTIVATION Rickles et al. Chest 2003

16 Possible Effects of Low-Molecular- Weight Heparins on Tumor Biology. Journal of Pathophysiology of Haemostasis and Thrombosis. 2006;

17 2 POTENTIAL PREDICTIVE BIOMARKERS for CAT : CLOTTING FACTORS: Fibrinogen, F XIII and F VIII Fibrinogen with arterial thrombosis but not with VTE Polymorphims F XIII associated with VTE in non cancer pts but not in CAT F VIII levels established risk factor for VTE in non cancer pt and also in CATS study CRP : acute phase reactant protein Induces TF on monocytes, SMSC and endothelial cells CTAS study predictive on univariate but not in multivariate

18 $ 2.$POTENTIAL$PREDICTIVE$BIOMARKERS$ Regula/on(of(tumor(cell(and(endothelial(cell(procoagulant(func/ons( TUMOR CELL : = > Cys protease = CP = > cleaves FX = FFX a FXa + FVa : a complex on platelet surface Prothrombin => Thrombin 2 forms of TISSUE FACTOR: - 1 associated with Microparticles MP - 1 non MP, expressed on platelets, leucocytes and enothtelial cells Rickles FR, Falanga A. Thrombosis Research 2001;102:

19 PLASMA COAGULATION TISSUE FACTOR VII FT VIIa Ca++ IX Sous-endothélium PL PL IXa VIIIa Ca++ X PL X II Ca++ Xa PL Va Thrombine (IIa) Fibrinolyse (Plasmine) Fibrinogen Fibrine

20 2. TF expression on cancer cells SOJ-6 BxPC-3 MiaPaCa-2 Panc1 Human cell lines FT Contrôle- (Irrelevant) Panc02 LLC1 Murine cell lines FT Contrôle- (Irrelevant) Plasma levels of TF bearing MP in cancer patients MP as a cancer biomarkers? Dubois$,$Frere,$Marseille$;$Copyright$ $ $(OPIC$28/02/2012)$(

2 POTENTIAL CAT BIOMARKERS : Microparticles subµmvesicles (0.

Derived from membrane vesiculation during cell maturation Jimenez

Surface express Phosphatidylserine PL (-), AG originating cell AG

MP expressing TF then express platelet-selectin (P selectin)

21 2 POTENTIAL CAT BIOMARKERS : Microparticles subµmvesicles (0.1-1µm); proteins + phospholipids! Derived from membrane vesiculation during cell maturation Jimenez et al. 2003! Surface express Phosphatidylserine PL (-), AG originating cell AG Langer et al. 2008, TF Hron"et"al." Tromb"Haemost2007","Tilley"et"al."Tromb"Res,"2008""Del"Conde"et"al."J"Thromb"Haemost"2007"! MP expressing TF then express platelet-selectin (P selectin) glycoprotein ligand (PSGL-1), which binds P-selectin on the surface of activated endothelial cells (= catalytic surface for TF expression)! Prothrombo9c$phenotype$in$cancer$mouse$Thomas et al. J Exp Med 2009 Panc02-GFP 2µm

22 2 POTENTIAL CAT BIOMARKERS TF activity expressed by cancer cells and cancer MP TF activity per surface unit X 100 on cancer MPs? MP traverse from tumor to blood stream through leaky vessels? Cancer indirectly stimulate host cells to produce more vesicles Thomas et al. J Exp Med 2009

26 3. RAMs: 2 DIFFERENT RISK ASSESSMENT MODELS for indentification of Cancer patients at risk for VTE Khorana#AA##et#al##Blood#2008#;#11:#4902##low (score 0), intermediate, (score 1-2), and high risk (score 3) CATS study AY 2008 ; Pabinger et al Blood 2013; 122:: 2011 ##

Relations ship between tumor growth and biomarkers #

// metastasis evolutio, # Microparticules (MP): All

27 Relations ship between tumor growth and biomarkers # Tissu factor (TF): triiger coagulation, blood clotting // metastasis evolutio, # Microparticules (MP): All dosage tecnhiques: MP + onset VTE in cancer The best biomarkers for CAT biomarqueurs? LIMITS: Detection des MPs par FACS, Sampling (stability), MPs life duration in vivo

Venous Thromboembolism and Cancer: A New Focus for Better Patient Outcomes Continuing Medical Education Grant Request Submitted on behalf of: ITAC-CME 1 Av Claude Vellefaux Hôpital St Louis Médecine

28 Venous Thromboembolism and Cancer: A New Focus for Better Patient Outcomes Continuing Medical Education Grant Request Submitted on behalf of: ITAC-CME 1 Av Claude Vellefaux Hôpital St Louis Médecine interne et vasculaire Paris / Program Administrator: Lynn Heywood-McLean Lynn@ITAC-CME.com This proposal is submitted in the strictest of confidence by ITAC-CME for the purpose of developing continuing medical education programs. VENOUS THROMBOEMBOLISM AND CANCER )

Primary Exam Physiology lecture 5. Haemostasis

Primary Exam Physiology lecture 5 Haemostasis Haemostasis Body s response for the prevention and cessation of bleeding. Broadly consists of: Primary Haemostasis - vascular spasm and platlet plug formation