Transcript Cellular Signaling Pathways as Drug Targets

Therapy-Related Cardiac Toxicity in
Cancer Patients
JEAN-BERNARD DURAND, M.D., FCCP, FACC
ASSOCIATE PROFESSOR OF MEDICINE
MEDICAL DIRECTOR CARDIOMYOPATHY SERVICES
UNIVERSITY OF TEXAS
MD ANDERSON CANCER CENTER
HOUSTON, TEXAS
Jean-Bernard Durand, M.D.
Presenter Disclosure Information
I will not discuss off label use and/or investigational
use in my presentation.
I have the following financial relationships to
disclose:
– Astellas
– Employee of: University of Texas MD Anderson
Cancer Center
Overview
• Cardiovascular disease is the number two killer
of cancer survivors
• 108 million baby boomers will enter healthcare
industry by 2015
• By 2015 over 15 Million U.S. cancer survivors
– Many definitions of a cancer survivor
– Cardiologist viewpoint: survivorship starts at time of
diagnosis (Dr.Fitzhugh)
Overview
• Cancer treatment has shifted to targeted
therapies, with more than 30 new agents in the
past five years
– Life-saving drugs and cardiology approach should
support use; not interrupt use
– Limited randomized controlled trials on prevention of
cardiotoxicity
– Treatment is based on prevention, early detection,
prevention of progression heart failure
Late Mortality Among 5 Year Survivors
of Childhood Cancer CCSS
Armstrong GT et al. JCO.2009;27:2328-2338
N=20,483
Risk Factors for Heart Failure
•
•
•
•
•
•
CAD or history of MI
Hypertension
Diabetes
Alcoholism
Cardiotoxic drugs
Inherited
cardiomyopathies
• Sleep apnea
• Valvular heart disease
• Congenital heart defects
• Other:
– Obesity
– Age
– Reduced or falling vital
capacity
– Smoking
– High of low hematocrit
level
Dexrazoxane
Dexrazoxane
Two different Top2: a and b
Doxorubicin poisons both Top2a and Top2b.
Proliferating cells express Top2a.
However, the adult heart only expresses Top2b.
New Hypothesis
Doxorubicin-induced cardiotoxicity is mediated by Top2b
Acute Model
Top2b
Top2b
+/+
∆/∆
15 mg/kg Doxorubicin IP
∆/∆
+/+
Control
Top2b is required for doxorubicin-induced ROS production
Doxorubicin
Topoisomerase IIb
?
Reactive Oxygen Species
Top2b deletion prevents doxorubicin-cardiotoxicity
Yeh et al Nature 2012
Therapies for Prevention of Cardiotoxicity with Anthracyclines
RPCT-Valsartan for Prevention
of Cardiotoxicity
o Placebo
Valsartan
Cancer 2005; 104:2492-8
JACC Vol 58:2011
RPCT- Lipitor 40mg daily/Total dose doxo=251mg,one cycle per month X 6 months
Comparison of LVEF at Baseline
and After Chemotherapy
Data expressed as mean values.
Kalay et al. JACC. Dec 2006. 48:2258-62
Overcome Trial
JACC Apr 9 2013
N=90
Overcome Trial
JACC Apr 9 2013
N=90
Limited Time to Start Therapy
Journal of American College of Cardiology January 2010
Responders Have Less Cardiac Event Rates
Journal of American College of Cardiology January 2010
 703 patients (216 males)
 Age 47±12 years
 Treated with HDC
 Poor prognosis malignancies
♫ Follow-up = 48 months
♫ MACE incidence
 TnI serum determination:
 Baseline
= Before HDC
 Early
= soon after HDC (0,12,24,36,72 hours)
 Late
= 1 month after HDC
Circulation 2004
Cardiac Events
3.5 Year Follow-up
Negative
TnI
Sudden death
Cardiac death
Acute pulmonary edema
Heart failure
Asymptomatic LVEF >25%
Life-threatening arrhythmias
Conduction disturbances
requiring PM implantation
*= p<0.001 vs. TnI -
#= p<0.001 vs. TnI +-
Transient
TnI +
Persistent
TnI +
84%
* #
37% *
1%
Circulation 2004
Cardiac Risk Stratification
Persistent TnI+
=
Transient TnI+
=
Negative TnI
=
Positive predictive value = 84%
High risk
Intermediate risk
Low risk
Negative predictive value = 99%
Troponin I Early Positivity
443 pts
High-dose CT
TnI + = 114 pts (24%)
Enalapril
 n = 56 pts
 started 1 month after HDC
 continued for 1 year
Controls
 n = 58 pts
 physical examination, ECG, ECHO: b,1,3,6,12 months
Secondary End-points
Follow-up 12 months
Total
n=112
Sudden death
Cardiac death
Acute pulmonary edema
Heart failure
Life-threatening arrhythmias
CUMULATIVE EVENTS
Cardinale et al. Circulation 2006
ACEI
n=54
0 (0%) 0 (0%)
2 (2%) 0 (0%)
4 (2%) 0 (0%)
14 (12%) 0 (0%)
11 (10%) 1 (2%)
31 (28%) 1 (2%)
Controls
n=58
0 (0%)
2 (3%)
4 (3%)
14 (22%)
10 (16%)
30 (52%)
P
NS
NS
NS
<0.001
0.01
0.001
Heart Failure Specialist Perspective
Continuum of Cancer Intervention
Lymphoma Patient-R-Chop
Cycle 3
BNP/Troponin
Cycle 4
BNP/Troponin
(-) proceed,
(-) proceed,
(-) proceed,
(+) Echo(Strain),
Consider
Ace/BB?
(+) Echo(Strain),
Consider Ace/BB?
(+) Echo(strain),
Consider
Ace/BB?
Continue Chemo
Continue Chemo
Cycle 1
Cycle 2
Baseline ECG
BNP/Troponin
Echo/Strain
Troponin
BNP
Continue Chemo
ECG HR<60 (Qtc)
Any symptoms
Stop dox LVEF<40%
Echo Versus MUGA?
Echo
• Valvular heart disease
• Wall motion
abnormalities
• Pulmonary pressures
• Hemodynamics
• Diastology
• Strain
MUGA
• Accurate for low
ejection fraction
• Less accurate with
rhythm disorders
• No information on
valvular disorders
• Little information on
wall motion
abnormalities
Class I Indications Assessment of
LV Function
•
•
•
•
•
•
•
Suspected cardiomyopathy or CHF
Edema with clinical signs of increased CVP
Dyspnea or clinical signs of heart disease
Unexplained hypotension
Exposure to cardiotoxic agents
“Pre-chemo”
Re-evaluation change in status or Rx
ACC/AHA/ASE Guidelines of Echo 2003
Cardiotoxicity occurs earlier than change in EF
Doxorubicin was given IV every 3 to 4 weeks.
Biopsy specimens were taken approximately 3 weeks following last therapy.
3
Mean Biopsy Grade
Mackay
5%
Billingham
2
n=7
— MDAH
n=22
n=8
n=3
— Stanford
n=8
n=18
1
*
0
*Risk of CHF
200 –400
401 – 500
Cumulative Doxorubicin Dose (mg/m2)
Adapted from Ewer et al. J Clin Oncol 1984;2:112-117.
>500
Committee for Proporietary Medicinal Products .
The European Agency for the Medicinal Products .London 17th Dec 1997.
http://www.emea.eu.int/pdfs/human/swp/098696en.pdf
Termination of T-wave; In the Eyes
of the Beholder
Cancer patients: risks for
prolonged QTc .
ECG
Percent
Reference
Prolonged QTc
10.6%
Barbey et al 2003
Borderline or
prolonged QTc
15%
Vaterasian, et al. 2003
any ECG anomaly
36%
Barbey et al 2003
•molecularly targeted agents with  QTc
•adjuvant regimens, long treatment periods
• survival  emphasis toxicity reduction
WHEN TO WORRY ABOUT QT?
• More than 25% prolongation of QTc interval from
the baseline or a QTc interval longer than 500 ms
increases the risk of precipitation of drug-induced
torsade de pointes
• More than 90% of incidences of drug-induced
torsade de pointes occur with QTc values of more
than 500 ms
Bednar MM et al. Am. J. Cardiol 2002;89:1316–1319
Gowda RM et al. Int J Cardiol 2004;96:1-6
TREATMENT
• Discontinuation of the offending agent: Any
offending agent should be withdrawn.
Predisposing conditions such as hypokalemia,
hypomagnesaemia, and bradycardia should be
identified and corrected.
• (>90% of time, we just stop supportive cast of
medications)
PROGNOSIS
• Because Long QT interval is primarily an
electrical disorder, in the absence of structural
heart disease and LV dysfunction, the long-term
prognosis is good as long as the offending agents
and risk factors are corrected and arrhythmia is
controlled.
Things to Consider
• More than 500 known tyrosine kinases from
Human Genome Project
– Over 250 of these tyrosine kinases are cloned,
and expressed
– 7 Tyrosine kinases are FDA approved
– 4 Tyrosine kinases targeted (17 kinases in vivo)
– How many kinases in the human genome are
cardiac specific?
Selective vs. Non-Selective
Kinase Binding Profiles
Kinase-binding profiles of the ABL inhibitors imatinib (upper panel), dasatinib (middle panel), and bosutinib (bottom panel) across
a set of protein kinases simultaneously identified from K562 cells. The bars indicate the IC50 values, defined as the concentration
of drug at which half-maximal competition of kinobead binding is observed.
Nature Biotechnology 25(9)2007
Drug-Induced HF of FDA Approved
Targeted Cancer Therapies
Drug
Approval
Action
CHF
Sorafenib
2007
VEGF1,2,3/PDGF
1%
Dasatinib
2006
BCR-ABL/SRC
C-Kit, PDGF
4%
Sunitinib
2006
VEGF/PDGF/
C-KIT
3-14%
Bevacizumab
2004
VEGF
2-14%
Trastuzumab
2000
ErbB-2/TKI
3-27%
Imatinib
2001
C-ABL, C-Kit
1%
FDA Approved Targeted Therapies
Drug
HTN/CMP
Responds to
ACE/BB
SHF/DHF
Sorafenib
CMP
Yes
SHF
Dasatinib
CMP
Yes
SHF
Sunitinib
HTN/CMP
Yes
SHF/DHF
Bevacizumab
HTN/CMP
Yes
SHF/DHF
Trastuzumab
CMP
Yes
SHF
Imatinib
CMP
Yes
SHF
Hypertension is a Biomarker of Efficacy
in Patients with Metastatic Renal Cell
Carcinoma Treated with Sunitinib
BI Rini,1 DP Cohen,2 DR Lu,2 I Chen,2 S Hariharan,3 RA
Figlin,4
MS Baum,5 RJ Motzer5
1Cleveland
Clinic Taussig Cancer Institute, Cleveland, OH;
Pfizer Oncology, 2La Jolla, CA, 3New York, NY;
4City of Hope National Medical Center, Duarte, CA;
5Memorial Sloan-Kettering Cancer Center, New York, NY, USA
38
Clinical Outcome by HTN Status
Objective response, n (%)
Progression-free survival,
months
Overall survival, months
Objective response, n (%)
Progression-free survival,
months
Overall survival, months
Max. SBP
≥140 mmHg
(n=441)
Max. SBP
<140 mmHg
(n=93)
P-value
241 (54.6%)
9 (9.7%)
<0.0001
12.5
30.5
2.5
7.8
<0.0001
<0.0001
Max. DBP
≥90 mmHg
(n=362)
Max. DBP
<90 mmHg
(n=172)
P-value
207 (57.2%)
43 (25.0%)
<0.0001
13.4
5.3
<0.0001
32.1
15.0
<0.0001
39
Probability of overall survival
Median OS by Use of Anti-HTN Agents, HTNinduced Dose Reductions and HTN Status as
Defined by
Maximum SBP ≥140 mmHg on Sunitinib
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Dose reduction only
Anti-HTN drug only
Both
Neither
No HTN
0
5
10
15
20
25
30
35
Time (months)
40
45
50
40
Binding to specific adrenergic receptors, β-blockers inhibit cancer cell migration and
metastasis, suggesting a novel targeted therapeutic application in protecting against
breast cancer disease progression
Powe, D. G. & Entschladen, F. Nature Reviews Clinical Oncology 8, 511-512 (2011)
J Clin Oncol 29;2645-2652
Baseline Hypertensive BC Patients Treated
with Beta Blockers Live Longer
Oncotarget 2010; 1:628-638
Heart Success
• Organizations for future:
• Conquer, MD Anderson Cancer Center, 2001
• Cardiology Oncology Partnership Vanderbilt
USA, 2004
• International Society for Cardioncology, Milan,
Italy, 2009
• Brazilian Cardiology Oncology, Sao Paulo,
Brazil, 2009
• Canadian Cardioncology, 2010
Conclusions
• Cardiologists and oncologists must collaborate
• Exciting new cancer therapies are being discovered,
however, in order to maximize their potential, cardiac
toxicities need to be identified and addressed upfront
• Although recent clinical experience has shown significant
cardiotoxicity post-trial with cancer therapies, we have
also seen resolution of toxicity using evidence-based
cardiology guidelines (beta blockers need further study)
• More collaborative work with biomarkers/cardiac imaging
for early detection and treatment
Thank you!
• Twitter
Jean-Bernard Durand@oncocardiology
[email protected]
Carvedilol Dose-Response Trial (MOCHA*):
Effect on Ejection Fraction and Mortality
Changes in LVEF
‡
8
7
 LVEF (EF units)
‡
6
‡
5
4
3
2
1
0
Placebo
6.25 mg bid
12.5 mg bid
25 mg bid
Carvedilol
Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months; placebo (n=84), carvedilol (n=261).
*Multicenter Oral Carvedilol Heart Failure Assessment.
Adapted from Bristow MR et al. Circulation. 1996;94:2807–2816.
‡P<.05
vs placebo.