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\begin{document}

\title{Reoccurence of Takotsubo Cardiomyopathy Induced by Osimertinib: Case
Report}



\author[1]{Yuko Fukuda}%
\author[1]{Yoshitaka Kawa}%
\author[1]{Akiko Nonaka}%
\author[2]{Hideyuki Shiotani}%
\affil[1]{Hyogo Cancer Center}%
\affil[2]{Kobe Tokiwa University}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
A patient with lung cancer was administrated osimertinib. She developed
symptomatic heart failure due to Takotsubo-cardiomyopathy (TC). As her
condition improved after discontinuing osimertinib, TC was thought to be
caused by osimertinib. Re-occurrence of TC was seen after
re-administraing half dose of osimernitib.%
\end{abstract}%



\sloppy


\textbf{Reoccurence of Takotsubo Cardiomyopathy Induced by Osimertinib:
Case Report}

\textsuperscript{1}Yuko Fukuda, MD, PhD, \textsuperscript{2}Yoshitaka
Kawa, MD, PhD, \textsuperscript{1}Akiko Nonaka, MD,
PhD,\textsuperscript{3}Hideyuki Shiotani, MD, PhD

\textsuperscript{1}Division of Onco-cardiology, Hyogo cancer
center,\textsuperscript{2}Division of Respiratory Medicine, Hyogo cancer
center, \textsuperscript{3}Division of Health Sciences,Department of
Nursing, Kobe Tokiwa University

\textbf{Corresponding Author}

Yuko Fukuda, MD, PhD

Division of Onco-cardiology, Hyogo cancer center, Akashi, Japan

13-70, Kitaoji-cho, Akashi, 673-8558, Japan

Tel; +81-78-929-1151, Fax; +81-78-929-2380

E-mail; yukoishikawa3825@yahoo.co.jp

ORCID iD: 0000-0001-9199-0246

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.

\textbf{Word count for the manuscript} : 1272 words

\textbf{Number of table: 1}

\textbf{Number of figures: 2}

\textbf{Keywords:} osimertinib, heart failure, Takotsubo cardiomyopathy,
stress cardiomyopathy

\begin{CJK}{UTF8}{gbsn}\textbf{Introduction　}

\end{CJK}\selectlanguage{english}Chemotherapy-induced Takotsubo (stress) cardiomyopathy (TC) have been
reported for several anticancer agents including antimetabolites,
fluoropyrimidines, and molecularly targeted agents(1). Some molecularly
targeted agents reportedly cause cardiovascular side effects, including
heart failure, arrhythmia (QT prolongation), and myocardial infarction
(2). The epidermal growth factor receptor (EGFR) inhibitors except
trastuzumab are known to cause less cardiotoxicity than BCR-ABL
inhibitors and vascular endothelial growth factor (VEGFR) inhibitors
(3). However, osimertinib has been reported more adverse cardiac events
than other EGFR inhibitors, including heart failure (4-6). While there
exist a few reports of osimertinib-induced heart failure in detail, none
have so far reported TC induced by osimertinib. Herein, we report a case
of TC caused by osimertinib.

\textbf{Case History}

A 73-year-old woman with no history of smoking underwent a thoracoscopic
right upper-middle lobectomy in 2016 for non-small cell lung cancer
(NSCLC). Her clinical stage was T2N0M0, and she did not receive adjuvant
chemotherapy. One year later, a chest computed tomography (CT) scan
showed pleural dissemination, and brain metastasis was suspected based
on brain magnetic resonance imaging (MRI). She was admitted to our
institution for targeted therapy. One year and 10 months after
administering erlotinib and bevacizumab as first-line therapy (a total
of 26 courses), pleural dissemination was found to be a progressive
disease. Pleural biopsy revealed a T790M mutation.

Osimertinib (80 mg/day, taken orally) was chosen as the second-line
therapy. Within one month of starting osimertinib, she was admitted to
our institution with progressive shortness of breath, fatigue, and edema
in the body and extremities. Chest radiography revealed pulmonary
congestion, pleural effusion, and cardiac dilation. An echocardiogram
revealed left ventricular akinesis from the apical to the midventricular
portion, which did not match with coronary arterial perfusion (Fig 1(A,
B)). The left ventricular dimension increased from 34 mm pre-osimertinib
treatment to 46 mm, and left ventricular ejection fraction (LVEF) was
reduced from 75\% to 58\%. The eletrcocardiogram changed from normal to
a right bundle branch block (Fig 2(A, B). She was diagnosed as
symptomatic acute heart failure.

\textbf{Differential Diagnosis}

The differential diagnosis of cause of heart failure included coronary
artery disease, arrhythmia, and valvular disease. Cardiac MRI showed no
significant stenosis of the coronary arteries, and a monitored
electrocardiogram showed no bradycardia nor tachycardiac arrhythmia.
Echocardiography revealed no significant left-side valvular disease.

\textbf{Outcome and Follow-up}

She was diagnosed with osimertinib-induced acute heart failure due to
TC. She was admitted to our institution on the same day for treatment of
cardiac failure. Her condition improved after discontinuing osimertinib
and adding treatment for heart failure.

Thirty-five days after admission, left ventricular wall motion
abnormality improved to almost normal kinesis (Fig 1(C, D)), and
electrocardiogram showed ST changes normalized after extensive negative
T waves (Fig 2(C, D)). She improved from class IV to class II as per the
New York Heart Association classification.

Since osimertinib was highly effective against lung cancer, the
treatment was restarted at a reduced dose of 40 mg/day. After 63 days of
restarted osimertinib therapy, an echocardiogram showed hypokinesis on
the left ventricular apical portion (Fig 1(E, F)). Electrocardiogram
showed reappearance of extensive negative T waves (Fig 2(E)). She was
diagnosed with asymptomatic TC, and osimertinib treatment was
subsequently stopped. Two weeks after stopping osimertinib, left
ventricular wall motion improved to normal. She was started on
3\textsuperscript{rd}-line chemotherapy.

\textbf{Discussion}

Osimertinib is a third-generation oral EGFR tyrosine kinase inhibitor
(TKI) used for the treatment of advanced EGFR-mutant NSCLC with acquired
T790M mutations. It has also been shown to improve progression-free
survival compared to platinum therapy (7). Although cardiotoxicity from
EGFR-TKI (human EGFR1: HER1) has been reported to be less than that of
HER2, BCR-ABL, and VEGFR inhibitors (3), osimertinib is likely to cause
cardiac side effects (4-6).

TC is a transient systolic left ventricular dysfunction with a variety
of wall motion abnormalities (8). Elderly women and emotional or
physical triggers were considered to be the cause of TC, but conditions
without an evident trigger have also been reported (8,9). In a previous
study, EGFR was found to be expressed in the central nervous system, and
infusion of EGFR into the midbrain had increased dopamine precursor
levels in an experimental rat model. One of the mechanisms of
osimertinib-induced TC might be that osimertinib, may cross the
blood-brain barrier, increasing the dopamine release in the central
nervous system (10).

Osimertinib may cause TC, which has the possibility of cause of heart
failure. The findings of our case study suggest that osimertinib therapy
should not be resumed in patients diagnosed with symptomatic heart
failure due to TC induced by osimertinib.

\textbf{Authorship Contributions:}

All authors made substantial contributions to prepare and writing the
manuscript, and were involved in revising it critically for important
intellectual content, and gave final approval of the version for
submission.

\textbf{Conflict of Interest}

None declared.

\textbf{References}

1. Smith SA, Auseon AJ. Chemotherapy-induced takotsubo cardiomyopathy.
Heart Fail Clin 2013;9:233-42, x.

2. Orphanos GS, Ioannidis GN, Ardavanis AG. Cardiotoxicity induced by
tyrosine kinase inhibitors. Acta Oncol 2009;48:964-70.

3. Force T, Krause DS, Van Etten RA. Molecular mechanisms of
cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer
2007;7:332-44.

4. Anand K, Ensor J, Trachtenberg B, Bernicker EH. Osimertinib-Induced
Cardiotoxicity. JACC: CardioOncology 2019;1:172-178.

5. Kunimasa K, Oka T, Hara S et al. Osimertinib is associated with
reversible and dose-independent cancer therapy-related cardiac
dysfunction. Lung Cancer 2021;153:186-192.

6. Kunimasa K, Kamada R, Oka T et al. Cardiac Adverse Events in
EGFR-Mutated Non-Small Cell Lung Cancer Treated With Osimertinib. JACC
CardioOncol 2020;2:1-10.

7. Hirashima T, Satouchi M, Hida T et al. Osimertinib for Japanese
patients with T790M-positive advanced non-small-cell lung cancer: A
pooled subgroup analysis. Cancer Sci 2019;110:2884-2893.

8. Medina de Chazal H, Del Buono MG, Keyser-Marcus L et al. Stress
Cardiomyopathy Diagnosis and Treatment: JACC State-of-the-Art Review. J
Am Coll Cardiol 2018;72:1955-1971.

9. Templin C, Ghadri JR, Diekmann J et al. Clinical Features and
Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med
2015;373:929-38.

10. Iwakura Y, Nawa H. ErbB1-4-dependent EGF/neuregulin signals and
their cross talk in the central nervous system: pathological
implications in schizophrenia and Parkinson's disease. Front Cell
Neurosci 2013;7:4.

\textbf{Table Legend}

Echocardiographic parameters, BNP values and Number of Figure of
echocardiogram and electrocardiogram from baseline to TC treatment.

AHF: acute heart failure, TC: takotsubo (stress) cardiomyopathy, LVDd:
left ventricular diastolic dimension, LVDs: left ventricular systolic
dimension, FS: fractional shortening, LVEF: left ventricular ejection
fraction, TR: tricuspid regurgitation, PG: pressure gradient, GLS:
global longitudinal strain using speckle tracking method

\textbf{Figure Legends}

\emph{Figure 1} : Echocardiography on acute heart failure due to TC (A:
diastole, B: systole), after treatment of heart failure (C: diastole, D:
systole), and on reoccurrence of TC (E: diastole, F: systole)

\emph{Fig 1(A, B).} Akinetic left ventricle wall motion is seen from the
apical to mid portion (yellow arrows on Fig(B)), which does not match
with the coronary arterial perfusion. Basal wall motion is hyperkinetic
instead.

\emph{Fig 1(C, D).} Thirty-five days after treatment of heart failure.
Left ventricle wall motion improved to almost normal kinesis.

\emph{Fig 1(E, F).} Sixty-three days after restarting osimertinib,
akinetic left ventricle wall motion on apical portion was seen (yellow
arrows on Fig(F)).

\emph{Figure 2:} Electrocardiogram on baseline (A), on acute heart
failure (B), after heart failure treatment (C, D), and on reoccurrence
of TC (E).

\emph{Fig 2(A).} Baseline electrocardiogram was normal sinus rhythm with
heart rate of 71bpm.

\emph{Fig 2(B).} On acute heart failure due to TC, an electrocardiogram
showed complete right bundle branch block with heart rate of 92bpm.

\emph{Fig 2(C).} Eleven days after treatment of heart failure. Negative
T-wave with broad induction was observed.

\emph{Fig 2(D).} Nine weeks after treatment of heart failure. ST changes
has normalized.

\emph{Fig 2(E).} Sixty-three days after restarting osimertinib. Negative
T-wave with broad induction was observed.

\textbf{Hosted file}

\verb`Figure TC 20220506.docx`  available at \url{https://authorea.com/users/482268/articles/568873-reoccurence-of-takotsubo-cardiomyopathy-induced-by-osimertinib-case-report}

\textbf{Hosted file}

\verb`Table 20220502.docx`  available at \url{https://authorea.com/users/482268/articles/568873-reoccurence-of-takotsubo-cardiomyopathy-induced-by-osimertinib-case-report}

\selectlanguage{english}
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