Download Single Nucleotide Polymorphisms (SNP’s) in the p53, SMAD7

Why is Pancreatic Cancer so
Thrombogenic?
M. DICATO M.D., FRCP
Hematology- Oncology
Centre Hospitalier
L- 1210 Luxembourg
Total VTE Mortality per Year.
(Extrapolated to 25 EU Countries)
EU 25
DVT
684,019
PE
434,723
Mortality following VTE
543,454
• Deaths due to VTE :
543,4541
• More than double the combined deaths due to:
– AIDS
5,8602
– breast cancer
86,8312
– prostate cancer
63,6362
– transport accidents
53,5992
1Cohen
AT. Presented at the 5th Annual Congress of the European Federation of Internal Medicine; 2005.
statistics on health and safety 2001. Available from: http://epp.eurostat.cec.eu.int.
2Eurostat
Adapted from Dr A.T. Cohen’s presentation at the ISTH July 7,2007
Risk of DVT in Hospitalized Patients
• No prophylaxis + routine objective screening for DVT
Patient group
Medical patients
Major gyne/urol/gen surgery
Neurosurgery
Stroke
Hip/knee surgery
Major trauma
Spinal cord injury
Critical care patients
DVT incidence
10 - 20 %
15 - 40 %
15 - 40 %
20 - 50 %
40 - 60 %
40 - 80 %
60 - 80 %
15 - 80 %
Risk Factors for VTE
•
•
•
•
•
•
•
•
•
•
Previous venous thromboembolism
Increased age
Surgery
Trauma - major, local leg
Immobilization - bedrest, stroke, paralysis
Malignancy and its treatment (CTX, hormonal..)
Heart or respiratory failure
Estrogen use, pregnancy, postpartum, SERMs
Central venous lines
Thrombophilic abnormalities
Risk Factors for VTE
•
•
•
•
•
•
•
•
•
•
Previous venous thromboembolism
Increased age
Surgery
Trauma - major, local leg
Immobilization - bedrest, stroke, paralysis
Malignancy and its treatment (CTX, hormonal..)
Heart or respiratory failure
Estrogen use, pregnancy, postpartum, SERMs
Central venous lines
Thrombophilic abnormalities
Thrombophilia Mutations

In cancer patients with VTE, testing for
mutations [ VLeiden, PT, (MTHFR )] is
only useful if there is a previous personal
or family history of VTE
(M. Dicato et al. :Blood 2001,S1: 3984)
Relative Risk of VTE in Cancer
Patients
Stein, Am J Med, 2006
VTE Risk and Cancer
• Rate of growth and spread
• Sites: pancreas (rate 8.1%), kidneys & ovaries
(5.6%), stomach (4.9%)..
• Therapy: thalidomide, lenalidomide (?),
bevacizumab (2 fold arterial thrombosis p=
0.031, VTE none, posthoc analysis,
Scapatacci; meta-analysis: VTE RR 1.33, p<
0.001, Nalluri)
• ESA: RR 1.7
• RBC Transfusions vs none: 7.2 vs 3%
Risk factors for VTE in patients with cancer (2)
G. Lyman, Cancer 2011, 117: 1334- 49
MM SHAH JOP, 2010,11:331
• Patient- disease- treatment related risk factors
Is there are Biomarker?
•
-
?Biomarkers: Recent risk factors
Platelet count > 350.000
WBC >11.000
CRP
TF expression
D-dimers
Khorana et al.: ASCO Ed. Book, 2008
L. Plawny, M. Dicato: Thrombosis in Cancer in Mellar & Davis, p275-283
Physiopathology
TF, CP
Tumour
cells
TNF-IL-1
VIIA
Xa
TF
VIIa
monocytes
endothelial cells
Thrombin
Platelet aggregation
Pathways of activation of coagulation in cancer : TF (tissue factor) and CP
(cancer procoagulant) activate factors VIIa and Xa. TNF (tumour necrosis
factor), IL-1 (interleukin-1) induce TF expression on monocytes and on
endothelial cells.
Possible roles of TF activity in
cancer
• initiation of a hypercoagulable state and
thrombosis
• primary tumor growth – angiogenesis
• secondary tumor spread - metastasis
ASCO 2010: JCO 2010,28(suppl 15):4126
GWAS in VTE (www.genome.gov/gwastudies/)
• aPTT: decrease is risk of VTE: GWAS: Ile582Thr (in KNG1gene
encoding HMWK)
KNG1 Knock out mice have an increase aPTT and arterial
thrombosis
• PS: any SNP contributing to plasma variability, C’ and others; role
of inflammation in VTE
• vWF increase
• Other GWAS data:
Prot C level interference
Plasminogen activator inhibitor-1 (PAI-1), MPV: SNPs variability on
ABO: VTE, lipids, inflammatory markers, DM type 2 and CHD.
• Overall these risk are 1- 1.5. Multiple SNPs with modest effect
and rare variants with stronger impact; add DNA methylation
modif, histone modifications…
Physiopathology
TF, CP
Tumour
cells
TNF-IL-1
VIIA
Xa
TF
VIIa
monocytes
endothelial cells
Thrombin
Platelet aggregation
Pathways of activation of coagulation in cancer : TF (tissue factor) and CP
(cancer procoagulant) activate factors VIIa and Xa. TNF (tumour necrosis
factor), IL-1 (interleukin-1) induce TF expression on monocytes and on
endothelial cells.
Why is Pancreatic Cancer so
Thrombogenic?
• Location: retroperitoneal, bedridden..
• Thrombophilic state:TF, Thrombin,
GWAS…
• Decrease in inhibitors: AT, Prot C&S,
thrombomodulin..
• Platelet aggregation increase..Mucin
• Inflammation: TGF, TNF,…
• KRAS- mdm2/p53
ASCO 2010, Riess H. et al.: Prospective randomised trial of
simultaneous pancreatic cancer treatment with enoxaparin
and chemotherapy: Final results of the CONKO-004 trial,
JCO 2010, 28( Suppl.15): 4033
Limitations of vitamin K antagonists
(VKAs)
Ansell et al., Chest 2004; Hirsh et al., Chest 2004
Warfarin thrombosis
Narrow
therapeutic
window
Dose
Bleeding
Warfarin bleeding
Thrombosis
• Unpredictable pharmacology
• Narrow therapeutic window
– Difficult to keep within
therapeutic range
• Multiple drug–drug and
food–drug interactions
• Dosing problems in the
initial phase of therapy
• Increased risk of major and
minor bleeding
What is New?
Clinic:
• Prevention of VTE: Semuloparin
• Real life VTE
Research:
• Genome wide association studies
Oral Anticoagulants:
• Coumarinics:
Pharmacogenetics: CYP2C9
VKORC1
• Antithrombins:
Ximelagatran: hepatotoxicity, off market EMEA 2008
Dabigatran
• Anti Xa:
Rivaroxaban (Xarelto) marketed 2008/2009; VTE med. 2011
Dabigatran (Pradaxa)
Apixaban
Thank You
1/3
2/3
3/3
Back- up slides
ASCO Guideline: Recommendations for Venous
Thromboembolism Prophylaxis and Treatment in
Patients with Cancer
G.H. Lyman et al.: JCO 2007, 25:5490 - 5505
1. Should hospitalized patients with cancer
receive anticoagulation for VTE prophylaxis?
• Recommendation: hospitalized patients with
cancer should be considered candidates for
VTE prophylaxis in the absence of bleeding
or other anticoagulant contraindications
JCO 2007
2. Should ambulatory patients with cancer
receive anticoagulation for VTE prophylaxis
during systemic chemotherapy?
• Routine prophylaxis not recommended
• Thalidomide or lenalidomide with chemotherpy or
dexamethasone is a high risk and warrants
prophylaxis
• Randomised controlled studies needed
• Research identifying better risk markers needed
JCO 2007
3. Should patients with cancer undergoing
surgery receive perioperative VTE prophylaxis?
• All patients should be considered for prophylaxis
• Laparotomy, laparoscopy or thoracotomy of >30’
should receive prophylaxis unless contraindicated
• Prophylaxis should be started preoperatively or as soon
as possible postoperatively
• Mechanical methods may be added
• Prophylaxis to be continued for at least 7-10 days, up
to 4 weeks to be considered in major abdominal or
pelvic surgery for cancer with high-risk (residual
malignant disease, obesity) and with a history of
previous VTE
JCO 2007
4.What is the best treatment for patients with cancer
with established VTE to prevent recurrent VTE?
• LMWH for initial 5-10 days
• LMWH for at least 6 months is preferred. VKA with a target INR
of 2-3 is acceptable, when LMWH not available
• After 6 months consider indefinite anticoagulation for selected
patients with active cancer
• Vena cava filter is only indicated for patients with
contraindications to anticoagulant therapy and recurrence
needing long term treatment
• For patients with CNS malignancies anticoagulation is
recommended as for other cancer patients. To be avoided in
active intracranial bleeding, recent surgery, bleeding diathesis
• For elderly patients as for other patients with close monitoring
5. Should patients with cancer receive anticoagulants
in the absence of established VTE to improve survival
• Anticoagulants are not recommended to improve
survival in patients with cancer without VTE
• Patients with cancer should be encouraged to
participate in clinical trials designed to evaluate
anticoagulant therapy as an adjunct to standard
anticancer therapy
G. Lyman, Cancer 2011, 117: 1334
Acquired APC Resistance (1/2)
ASCO 2006:  8563 : adriamycin and epirubicin
downregulate endothelial Protein C receptor and
impair the APC (activated protein C) pathway. The
conversion of Protein C to APC is hampered.
 After the treatment with these anthracyclins 25 % of
patients had a low APC.
Conclusion : This might be one of the contributing
factors of chemotherapy induced thrombophilia.
Acquired APC Resistance (2/2)
 -62 patients with MM (Blood Coag.
Fibrinolys.:2002,13: 187)
– 23% APC resistance at baseline: 50% developed
VTE. Increase of VTE with thalidomide, ++ Dexa &
ADR
 -1178 patients (Br. J. Haem. 2006, 134: 399)
– 109 patients APC resistance, 36 V Leiden
– 30/31 acquired APC resistance normalised after
Rp
G. Lyman, Cancer 2011, 117: 1334