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Maximizing Cardiac Function on HER2-
Targeted Therapy: Proactive Use of ACE
Inhibitors or Beta Blockers
Hyman B. Muss, MD
31th Miami Breast Cancer Conference 2014
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Anthracyclines
• Anthracyclines: CHF < 2% early; 5% late?
50%+ some cardiac dysfunction at 10-20 yrs
Dose dependent (.14% < 400/m v 7% > 550)
Modest with AC x 4
TAC or FEC higher
• Prevention
> 6 hour infusions
Liposomal preparations
Dexrazoxane
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The Outcome for Anthracycline Cardiomyopathy is Poor
Felker et. al. NEJM. 2000. 342: 1077-1084.
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Trastuzumab
• CHF 2.5% (meta-analysis 12,000 pts)
• Not clearly related to cumulative dose
• Increased risk with anthracyclines
• Increases with increasing age
• Baseline LVEF and then every 3 months
Follow trial guidelines (Romond NEJM 2005)
• Consider prevention for high risk
Older, lower LVEF prior to Rx
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Monitoring for Cardiac Toxicity • Echocardiogaphy
More information
Diastolic dysfunction 25-97% with Anthracyline
• Value uncertain; may predict late toxicity
• Nuclear imaging (MUGA) – simple %
• MRI validated method – may be best
• Not ready for prime time
Natriuretic peptides: B-type,BNP; N-terminal
ProB, NT-proBNP; atrial natriuretic peptide
Troponins; more specific than NPs? Predictive? Davis and Witteles; Semin Oncol 2013
Colombo et al Curr Treat Opin Cardiovasc Med 2013
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Subclinical cardiac disease with anthracyclines
These subclinical abnormalities of LV function are associated with 2-4 fold increases in CV events.
Hundley WG. Circulation 2010.
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MRI methods (left ventricle)
A multi-phase, multi-slice cine white blood
sequence was used to measure LV volumes
and ejection fraction using a modified
Simpson’s Rule Method
Mean, mid-wall circumferential strain
using tissue tagging
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Early gadolinium enhancement in a patient with breast cancer receiving adjuvant
trastuzumab therapy referred with concern of cardiotoxicity.
Thavendiranathan P et al. Circ Cardiovasc Imaging.
2013;6:1080-1091
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SEER: ~8,000 age 66-80 with adjuvant Rx over 7 years
- CHF Medicare billing codes ranged from 29% to 38%
depending on the cancer treatment regimen received.
CHF in breast cancer survivors
Pinder MC, et al. JCO 2007;25(25):3808-3815.
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“For every complex
problem there is a
simple solution, and
it’s wrong.”
H.L. Mencken
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Issues with Monitoring
• Trastuzumab
Toxicity can occur quickly
Results in delays or discontinuation
May be hard to convince pt to restart
• Anthracyclines and CHF
Can occur very late – mths to years after Rx
Cannot tell if drug related
Likely to shorten survival
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Prevention Strategies
Intervention Mechanism of
Protection Adverse Effects
ACEI/ARBs Biomechanical effects
Antioxidant properties
BP lowering symptoms
(worse w/ chemo)
Beta-blockers
Biomechanical effects
Antioxidant properties
(Carvedilol, Nebivolol)
BP lowering symptoms
(worse w/ chemo)
Fatigue
Statins Antioxidant properties Muscle, Hepatic
Dexrazoxane
Top 2β inhibition
Antioxidant properties
Myelosuppression
? Reduced tumor response rates
Exercise Improving CV reserve
Antioxidant effects
Value when drug chemo or
trastuzumab induced uncertain
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Primary Prevention
Kaya et al. Int J Cardiol 2013
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Primary Prevention
Bosch, et al. J Am Coll Cardiol
2013
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Primary Prevention
p=0.03
Seicean, et al. J Am Coll Cardiol 2013
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Primary Prevention
Kalam, et al. Eur J Cancer 2013
Beta
Blocker
ACEi
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Recovery of LV dysfunction with
standard HF therapy
Jensen, et al. Annals of Oncology. 2002. 13:499-709.
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Resp
on
ders
(%
)
(n = 130) (n = 71)
Cardinale, et al. JACC 2010
For effective cardioprotection, timing is the key . . .
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Prevention
• Involve cardiologist
Make sure they are familiar with issues
• Key ACEi/ARBa and beta-blockers
lisinopril best studied ACE
carvedilol best studied beta-blocker
• ACEi/ARB usually started first
• May work for anthracyclines also
Should we consider long term monitoring?
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Agents
• Beta-blockers
Carvedilol
• Block alpha-1, beta 1 and 2 adrenergic rcp
• Vasodilatory and antioxidant
• Small studies show prtotective value
Others; nebivolol, metoprolol, bisoprolol.
• ACE inhibitors
Lisinopril
Others: captopril, enalapril
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Ongoing Trials • MANTICORE 101-Breast (NCT01016886) - Open
Bisoprolol, perindopril, or placebo on MRI indices of LV remodeling/serum biomarkers:159 women HER2+ early breast cancer. [U. Alberta]
• NCT01009918 – Open Carvedilol, lisinopril, or placebo on LVEF at 52 weeks in 468 women
with HER2+ early breast cancer [U. South Florida]
• PRADA (NCT01434134) - Open Metoprolol vs. placebo; Candesartan vs. placebo on LVEF by MRI in
120 breast cancer patients receiving anthracyclines or trastuzumab [U. Oslo]
• NCT00806390 - terminated Metoprolol vs. placebo on LVEF by MUGA in 188 breast cancer
patients receiving anthracyclines or trastuzumab [U. Maryland]
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Summary • ACE inhibitors or Beta blockers are recommended
after detection of cardiotoxicity by LVEF decline
• Timing is key
Promising data for ACEI’s, B-Bl’s (emerging for statins)
However, large randomized / prospective trials needed • Optimal timing of intervention? What detection method is best?
• Primary prevention? Revisit use of Dexrazoxane?
• Duration of therapy?
• Intra-class differences among beta blockers, ACE inhibitors, etc.?
• Studies needed to evaluate exercise as intervention
• Future Steps
Genetic profiling to characterize risk • Personalized cardio-protection is likely coming
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Thank
You M. Felker, MD
M. Khouri, MD