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

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

The Outcome for Anthracycline Cardiomyopathy is Poor

Felker et. al. NEJM. 2000. 342: 1077-1084.

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

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

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.

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

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

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.

“For every complex

problem there is a

simple solution, and

it’s wrong.”

H.L. Mencken

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

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

Primary Prevention

Kaya et al. Int J Cardiol 2013

Primary Prevention

Bosch, et al. J Am Coll Cardiol

2013

Primary Prevention

p=0.03

Seicean, et al. J Am Coll Cardiol 2013

Primary Prevention

Kalam, et al. Eur J Cancer 2013

Beta

Blocker

ACEi

Recovery of LV dysfunction with

standard HF therapy

Jensen, et al. Annals of Oncology. 2002. 13:499-709.

Resp

on

ders

(%

)

(n = 130) (n = 71)

Cardinale, et al. JACC 2010

For effective cardioprotection, timing is the key . . .

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?

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

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]

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

Thank

You M. Felker, MD

M. Khouri, MD