TRASTUZUMAB INDUCED CARDIOTOXICITY

INTRODUCTION
Trastuzumab is approved for use as either a single agent or in combination with paclitaxel
in patients with metastatic breast cancers that over-express the HER2 protein. The reported
incidence of congestive heart failure with single-agent trastuzumab is 7% and rises to 11% when
trastuzumab is combined with paclitaxel. The highest incidence (28%) was noted when
trastuzumab was given with an anthracycline. In the randomized phase III study of trastuzumab
in combination with chemotherapy (doxorubicin plus cyclophosphamide or with paclitaxel), the
incidence of cardiac dysfunction was 28% in patients receiving trastuzumab plus doxorubicin
plus cyclophosphamide versus 7% for doxorubicin/cyclophosphamide alone and 11% in those
receiving trastuzumab plus paclitaxel versus 1% for paclitaxel alone. The incidence of classes III
and IV (New York Heart Association Classification) cardiac failure was 19% for
trastuzumab/doxorubicin/cyclophosphamide versus 3% for doxorubicin/cyclophosphamide and
4% for trastuzumab/paclitaxel versus 1% for paclitaxel alone.

MECHANISM OF ACTION OF TRASTUZUMAB

Trastuzumab is a recombinant humanized monoclonal antibiotic that selectively binds to
HER-2 glycoprotein, a member of the epidermal growth factor family of cellular receptors
(EGFR). EGFR encodes its own tyrosine kinase which, upon receptorligand binding, normally
autophosphorylates the receptor causing downstream signalling which increases proliferation,
metastatic potential and evasion of apoptosis.
The antibody is an IgG1 kappa antibody that contains human framework regions and
murine complementarily determining regions that binds to HER-2. HER-2 is overexpressed in
about one-third of patients with breast cancer. Trastuzumab inhibits cell-cycle progression by
decreasing cells entering the S phase of the cell cycle, leading to downregulation of HER-2
receptors on tumor cells and decreased cell proliferation. Trastuzumab also leads to antibody
dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), along
with directly inducing apoptosis in cells overexpressing the HER-2 protein.
 The figure shows the mechanism of action of Trastuzumab

MECHANISM OF TOXICITY
Trastuzumab is cardiotoxic on its own and strikingly potentiates the cardiotoxic effects of
anthracyclines. The trastuzumab target, ErbB2, is expressed on cardiomyocytes, where it exerts a
protective effect on cardiac function. Both HER receptors and their ligands are expressed in the
heart and their activation creates a hypertrophic response. In addition, heregulinHER signalling
promotes cell survival and growth and protects against apoptosis. The ability of the heart to
withstand stress is due, at least in part, to a protein network leading to cell survival that is
activated by HER ligands and involves the activator protein-1 and the nuclear factor B.
Activator protein-1 regulates the expression of a group of cardiac proteins that are important in
the development of cardiac hypertrophy, and nuclear factor B regulates the genes that are
involved in the cellular response to stress and inflammation.
Cardiotoxicity is thought to be related to blocking of the normal physiologic action of
HER2 on cardiomyocytes, as well as potential effects on the function of resident cardiac stem
cells. In the absence of HER2 function, cardiomyocytes are unable to activate survival pathways
and reactive oxygen species (ROS) accumulate resulting in cardiac dysfunction. Similarly,
cardiac stem cells appear to lose their capacity for cardiogenic differentiation and formation of
microvascular networks.

PREVENTION
Currently, there are no standard guidelines for monitoring of patients on trastuzumab. We
recommend that patients with underlying cardiac disease should be closely monitored for signs
and symptoms of cardiac dysfunction. Patients who develop congestive heart failure or are
suspected of developing cardiac dysfunction should be evaluated by an ECG and an
echocardiogram. Further chemotherapy should be stopped, and management is supportive
depending on the degree of myocardial dysfunction. It is suggested that patients should not be
treated with trastuzumab when their LVEF is below 50-55%. There has been speculation that
angiotensin receptor blockers may also be beneficial in preventing trastuzumab cardiotoxicity.
Angiotensin is a down regulator of the ErbB system, which plays a pivotal role in cardiac
protection.
MANAGEMENT
Treatment of breast cancer with trastuzumab resulted in an unexpectedly high incidence
of cardiotoxicity, usually occurring as asymptomatic left ventricular ejection fraction (LVEF)
reduction or overt heart failure (HF). The toxicity seems to be direct and not dependent on
cumulative dose or treatment duration. In most patients, trastuzumab-induced cardiotoxicity
(TIC) is reversible in which left ventricular ejection fraction (LVEF) improves after trastuzumab
withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. No evidence-
based recommendations for the treatment of patients developing cardiac dysfunction after
trastuzumab therapy have been proposed. The evidence that support the use of ACE-I and BB in
this setting is limited to case series. Despite evidence, the potential efficacy of ACE-I and BB in
improving LVEF in patients receiving trastuzumab remains uncertain.
Management of trastuzumab-related cardiotoxicity has two distinct aspects: withdrawal
of trastuzumab therapy and treatment of cardiac dysfunction. The stopping/restarting rules used
in the adjuvant trials were effective and are recommended, with some modifications regarding
recommendations for a cardiology consult or treatment of cardiac dysfunction (or both) when
appropriate.

Serial LVEF assessments are required to guide treatment, and a high degree of
reproducibility is essential. Left ventricular ejection fraction is a dynamic physiological function
varying from day to day depending on heart rate and loading conditions, but every effort must be
made to provide an accurate and precise assessment of LVEF to guide clinical decisions about
trastuzumab therapy.
Table 1: Recommendations for continuation or withdrawal of trastuzumab therapy in
asymptomatic patients based on serial measurements of left ventricular ejection fraction (LVEF)

Figure 1: Algorithm for Continuation and Discontinuation of Trastuzumab Based on LVEF

Assessments
Symptomatic left ventricular (LV) dysfunction
Symptomatic left ventricular (LV) dysfunction must be treated per recommendations for heart
failure treatment. Patients developing signs and symptoms of heart failure such as dyspnea,
increased cough, peripheral edema, S3 gallop, and reduced ejection fraction should have their
trastuzumab treatment interrupted All patients with heart failure and a LVEF below 40% should
be treated with an ACE inhibitor in combination with a beta-blocker unless a specific
contraindication exists (class I, level A evidence). Symptomatic left ventricular dysfunction due
to trastuzumab responds well to ACE inhibitors and -blockers, which are considered the
mainstay of cardiotoxicity treatment. Some members of the panel also felt that, to prevent further
degradation of LVEF or the development of clinical heart failure, an ACE inhibitor should be
considered if the patients LVEF is between 40% and 50%.

Figure 2: for
Whereas treatment Algorithm for management
asymptomatic of symptomatic
LV dysfunction is: heart failure.
 If the LVEF decreases to 0.40, trastuzumab should be interrupted, as significant left
ventricular systolic dysfunction (LVSD) has occurred. ACE inhibitors should be used in all
asymptomatic patients with LV dysfunction and an ejection fraction below 40% . The LVEF
measurement should be repeated after 68 weeks. Trastuzumab may be re-initiated if the LVEF
is restored to a level above the lower limit of normal (LLN).

Beta-blockers should be considered in all patients with asymptomatic LV dysfunction and

a LVEF below 40%. If the LVEF decreases to below the LLN but > 0.40, trastuzumab may be
continued, but an ACE inhibitor should be initiated. If this decrease occurs despite pre-existing
ACE inhibitor therapy, the patient should be referred to a cardiologist.

Initiation of pharmacotherapy for trastuzumab related cardiotoxicity must be carried out

on an accelerated schedule, because the normal titration schedules can take several months to
reach the optimal therapeutic dosage.

Table 2: Initiating heart failure medication

Navigation through these recommendations may be facilitated by the adoption of a traffic light
system:

1) A green light indicates LVEF above the LLN, no signs or symptoms of CHF and any
trastuzumab-related LVEF decrease being o0.10.
2) An amber light indicates LVEF between the LLN and 0.40, with no signs or symptoms of
CHF, or a trastuzumab-related LVEF reduction of 0.1 or more.
3) A red light indicates LVEF p0.40 or symptoms and signs of cardiac failure.

During trastuzumab , green is an indication to continue treatment. Amber is also an indication

to continue treatment, but patients should also be taking an ACE inhibitor. Patients who drop into
the amber range while on an ACE inhibitor should be referred for a cardiology opinion. Red is an
indication to interrupt trastuzumab, start on an ACE inhibitor if applicable, and refer for a
cardiology opinion. Patients whose trastuzumab is interrupted (red light) should not restart until
LVEF is within the normal range (green light)
Post-chemotherapy, green indicates go. Amber indicates defer until green. Red indicates that it is
unlikely to be safe to start trastuzumab. Both amber and red are indications for the initiation of
ACE inhibitors and referral to cardiology for the optimisation of cardiac function. It is
recommended that LVEF is reassessed after 3 months, and that trastuzumab is not commenced
unless LVEF is within normal limits at that point.

REFERENCES:
 Shakir, D. K., &Rasul, K. I. (2009). Chemotherapy Induced Cardiomyopathy:
Pathogenesis, Monitoring and Management. Journal of Clinical Medicine Research.
Saidi, A., &Alharethi, R. (2012). Management of Chemotherapy Induced
Cardiomyopathy. Current Cardiology Reviews, 7(4), 245-249.
Volkova, M., & Russell, R. (2012). Anthracycline Cardiotoxicity: Prevalence,
Pathogenesis and Treatment. Current Cardiology Reviews, 7(4), 214-220.
Alldredge, B. K. (n.d.). Koda-Kimble and young applied therapeutics: the clinical use of
drugs. Philadelphia, PA: Lippincott Williams & Wilkins, 2012.
Jones, A. L., Barlow, M., Barrett-Lee, P. J., Canney, P. A., Gilmour, I. M., Robb, S. D., &
Verrill, M. W. (2009). Management of cardiac health in trastuzumab-treated patients with
breast cancer: updated United Kingdom National Cancer Research Institute
recommendations for monitoring. British journal of cancer, 100(5), 684-692.
Perik, P. J., Alexander de Korte, M., Van Veldhuisen, D. J., Gietema, J. A., Sleijfer, D. T.,
& De Vries, E. G. (2007). Cardiotoxicity associated with the use of trastuzumab in breast
cancer patients. Expert review of anticancer therapy, 7(12), 1763-1771.