Lyons, Tomás G.

Morris, Patrick G.

PubMed

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EBioMedicine 2 (2015) 802–803
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EBioMedicine
j ourna l homepage: www.eb iomed ic ine.comCommentaryHow can clinical research help our understanding of
trastuzumab-related cardiotoxicity?Tomás G. Lyons, Patrick G. Morris⁎
Cancer Clinical Trials and Research Unit, Beaumont Hospital, Dublin 9, Ireland
It has been recognised that up to 25% of breast cancer overexpresses The major strength of this report by Reijers et al. is the fact that
the transmembrane human epidermal growth factor receptor 2 (HER2),
which, in the absence of treatment, is associated with an adverse prog-
nosis for patients Hudis, 2007. The monoclonal antibody trastuzumab,
which targets the HER2 receptor, has signiﬁcantly improved both over-
all and disease-free survival for patients with advanced and early stage
disease Slamon et al., 2001; Moja et al., 2012. However, an unexpected
ﬁnding during the clinical trials of trastuzumab was the development
of cardiotoxicity, mostly manifested as a decline in left ventricular ejec-
tion fraction (LVEF) and, more rarely, congestive heart failure. Despite
extensive research, the mechanisms underlying trastuzumab-related
cardiotoxicity remain poorly understood.
Against this background, the article in this issue of EBioMedicine by
Reijers et al. Reijers and Burggraaf, 2015, investigated the effects of
trastuzumab administration on a group of healthy male volunteers
and its impact on cardiac function. This report focuses, in part, on a
clinical trial, in which a developmental trastuzumab drug product was
shown to have bio-equivalence to the currently approved formulation
of trastuzumab (Herceptin®) Wisman et al., 2014. As part of this
study, volunteers (n = 118) underwent serial measurements of body
weight and biomarkers, including haemoglobin, haematocrit, albumin,
total protein, cardiac Troponin (cTn)-T and N-terminal pro-peptide of
B-type natriuretic peptide (NT-proBNP), along with assessments of
cardiac function by echocardiography. The current report focuses more
narrowly on cardiac function in 54/118 men who received either
trastuzumab (n = 46) or placebo (n = 8). Mean haemoglobin
(−0.3mM), haematocrit (−0.013 L/L), total protein (−2 g/dL) and albu-
min (−2 g/dL) all signiﬁcantly decreased post exposure to trastuzumab
compared with placebo. There was also a corresponding increase in
body weight (+0.4 kg), although this result was not statistically signiﬁ-
cant (p = 0.226) and the time for change to return to baseline was not
reported. There was no detectable increase in the cardiac speciﬁc blood
parameters, NT-proBNP and cTn-T in either trastuzumab-treated volun-
teers (n=46) or thosewho received placebo (n=6). In a further subset
analysis, there was no signiﬁcant difference in LVEF in volunteers who
received trastuzumab (n = 9) compared to placebo (n = 8) at either
4 or 63 days. No cardiac events were reported in the study, which is
not unexpected, given the small number of subjects and exposure to
trastuzumab was only a single dose.DOI of original article: http://dx.doi.org/10.1016/j.ebiom.2015.05.002.
⁎ Corresponding author.
http://dx.doi.org/10.1016/j.ebiom.2015.07.021
2352-3964/© 2015 The Authors. Published by Elsevier B.V. This is an open access article underthe population were all healthy, with no comorbidities and had never
been exposed to chemotherapy. In fact, many patients with HER2 posi-
tive breast cancer receive anthracyclines, which are also associatedwith
a risk of cardiotoxicity. Hence the interpretation of themechanisms un-
derlying cardiotoxicity in this population is more challenging, and the
current study represents a relatively homogeneous cohort, without the
confounding effects of potentially cardiotoxic chemotherapy. The most
interesting observation in this study was that trastuzumab was associat-
ed with an immediate, transient increase in body weight. The authors
suggested that there was haemodilution caused by ﬂuid retention post
trastuzumab administration, and that this observation might provide
some insight into the cardiovascular effect of trastuzumab. Furthermore,
it was postulated that this might have been a direct consequence of car-
diac myocyte stress induced by exposure to trastuzumab. However, the
small placebo group (as comparator) limits this study and cautious inter-
pretation of the ﬁndings is recommended. Although the authors conclud-
ed that monitoring of biomarkers and measuring body weight as used in
the studymight contribute to establishing a patient's risk of trastuzumab-
induced haemodynamic alterations, the lack of a signiﬁcant change in
LVEF and the lack of correlation between haemodynamic alterations
and cardiotoxicity, argues against the routine use of thesemeasurements
in clinical practice.
As noted, many patients with HER2 positive breast cancer receive
anthracyclines, which can cause oxidative damage to cardiac myocytes.
Those cells sustaining sufﬁcient damage undergo apoptosis leading to
cardiotoxicity, while other cells can repair the damage from these pro-
cesses. If trastuzumab is then introduced, it binds to the damaged
myocytes and inhibits cell repair thereby resulting in an even higher
incidence of cardiac dysfunction Ewer and Ewer, 2010. Trastuzumab
also can cause cardiotoxicity when administered as a single agent or
with a non-anthracycline chemotherapeutic agent, albeit at a much
lower incidence. The mechanism differs to that of anthracycline-related
cardiotoxicity, evidenced by the evaluation of cardiac biopsy specimens
after trastuzumab exposure, which do not show typical anthracycline
ultrastructural changes Ewer et al., 2005. In addition, withdrawal of
trastuzumab can reverse the cardiac effects, with LVEF improving in
most patients and trastuzumab rechallenge often possible Guarneri
et al., 2006. However, LVEF recovery is not universal and some patients
will be left with signiﬁcant cardiac dysfunction. Therefore, a major focus
of ongoing research is the development of biomarkers to identify those
patients at most risk.the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
803T.G. Lyons, P.G. Morris / EBioMedicine 2 (2015) 802–803Research into potential biomarkers to predict risk of cardiotoxicity
in patients treated with trastuzumab, including the study by Reijers
et al., has focused on cTns, which are relatively speciﬁc for myocardial
damage. However, results from clinical studies have been conﬂicting.
Cardinale et al. identiﬁed a subgroup of patients treated with
trastuzumab and elevated cTnI, who were more likely to develop
trastuzumab-induced cardiotoxicity, less likely to recover fully and
who had a 25-fold increase in risk for major adverse cardiac event
Cardinale et al., 2010. In contrast, in a prospective study investigating
cTnI in patients treated with chemotherapy, trastuzumab and the oral
anti-HER2 agent lapatinib, therewas no association between elevations
in cTnI and LVEF decline Morris et al., 2011. Similarly, in the present
study by Reijers et al., there was no increase in NT-proBNP and
troponin-T post exposure to trastuzumab and no link to cardiotoxicity.
In short, the clinical utility of these cardiac biomarkers in predicting
trastuzumab-related toxicity is currently unclear.
Trastuzumab-induced cardiotoxicity remains an important clinical
concern for all patients undergoing therapy for HER2 positive breast
cancer. As evidence accumulates we are developing a clearer under-
standing of the pathophysiology of this important clinical problem.
However, further research is needed to discover potential biomarkers,
which will allow identiﬁcation of those people at risk of developing
cardiotoxicity and thereby, tailoring therapy (both anticancer and
cardioprotective) to ensure that our patients achieve the optimal bene-
ﬁt of trastuzumab without the potential long term toxicity.Disclosure
The authors declare no conﬂicts of interest.
References
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Ewer, M.S., Ewer, S.M., 2010. Troponin I provides insight into cardiotoxicity and the
anthracycline–trastuzumab interaction. J. Clin. Oncol. 28, 3901–3904.
Ewer, M.S., Vooletich, M.T., Durand, J.B., et al., 2005. Reversibility of trastuzumab-related
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How can clinical research help our understanding of trastuzumab-related cardiotoxicity? 

Tomás G. Lyons

Patrick G. Morris

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How can clinical research help our understanding of trastuzumab-related cardiotoxicity?

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