Trastuzamab (Herceptin^®)-related cardiotoxicity in pregnancy

Introduction

Trastuzamab (Herceptin®) is a humanized monoclonal antibody that binds to the extracellular juxtamembrane domain of Human Epidermal Growth Factor Receptor type 2 (HER2) and prevents the activation of its intracellular tyrosine kinase.¹ HER2 occurs in 20–30% of invasive breast cancers and Trastuzamab inhibits the proliferation and survival of HER2 dependent tumours thereby improving disease-free survival when used in combination with chemotherapy.¹ An increasing number of women diagnosed with HER2 positive breast cancer are becoming pregnant while receiving treatment with Trastuzamab. The fetal effects such as anhydramnios² have been reported in the literature but as yet no maternal side-effects from the drug have been published. Although in general Trastuzamab is well-tolerated by patients, there is a 5% risk of cardiotoxicity.³ We report such a case in pregnancy.

Case report

A 36-year-old woman was diagnosed with Grade 3, HER2 positive multifocal (T2, N1) invasiveductal carcinoma of her right breast. Oestrogen and progesterone receptor status was negative. She underwent a mastectomy and axillary clearance. Adjuvant chemotherapy with epirubicin followed by radiotherapy to the chest wall was then given. Following the radiotherapy, Trastuzamab was started. She discovered that she was pregnant at approximately 17 weeks gestation and based on ultrasound dating, conception probably occurred 4–5 weeks prior to the start of treatment with Trastuzamab.

Detailed fetal scans showed no abnormality and after a discussion on the risks and benefits of continuing versus stopping Trastuzamab treatment, she decided to continue with the drug.

Her cardiac ejection fraction at the start of treatment with Trastuzamab was 61%. Three months later (at 17 weeks gestation) there had been a decline to 52% and then a month after that (21 weeks gestation) it had dropped further to 48%. Trastuzamab was stopped when she was 21 weeks pregnant in accordance with the US Food and Drug Administration (FDA) recommendations on development of cardiotoxicity with Trastuzamab. Exposure to Trastuzamab was therefore in the first and second trimesters.

Digoxin 250 mcg daily was commenced. Her ECG showed a sinus tachycardia. Repeat echocardiography continued to show a decline in left ventricular function to 40% at 36 weeks. She had developed symptoms of worsening left ventricular function such as breathlessness on minimal exertion (New York Heart Association classification 3). Labour was induced at 37 weeks and an epidural was sited. She had a spontaneous vaginal delivery of a boy weighing 3.2 kg. The baby developed mild transient tachypnoea of the newborn requiring CPAP for 24 hours.

Postdelivery the mother was started on Frusemide, Bisoprolol and Ramipril. An echocardiogram 4 months postdelivery has shown a persistent systolic impairment with the ejection fraction remaining at 50% and we await further echocardiography to see if her ejection fraction recovers to pre-treatment levels.

Discussion

There are many theories emerging as to the mechanism of cardiotoxicity with Trastuzamab.³ It is thought that the drug has a direct adverse effect on the contractility of cardiomyocytes leading to the development of ventricular dysfunction and congestive cardiac failure that is reversible after stopping the drug. Approximately 14% of patients treated with Trastuzamab will develop some asymptomatic deterioration in left ventricular function but 4% of patients will develop symptomatic congestive cardiac failure.⁴ Pregnancy, as well as pre-existing cardiac disease and concurrent use of doxorubicin, must be considered a risk factor for developing cardiotoxicity.

The key elements of the cardiovascular adaptation in a healthy pregnancy are changes in peripheral resistance, cardiac output and blood volume with an overall increase in ventricular performance. Peripheral resistance falls rapidly in the first trimester associated with an increase in plasma volume of 40–45% of the pre-pregnancy volume. Cardiac output rises early and reaches a peak in the third trimester. Mean arterial blood pressure falls during pregnancy, beginning in the first trimester when cardiac output is already rising and reaching a nadir in mid-pregnancy. These changes lead to an increase in left ventricular end-diastolic volume which with end-systolic volume remaining unchanged results in an overall increase in left ventricular ejection fraction and myocardial hypertrophy in pregnancy.⁵

Any factor that compromises contractility of the heart causes these physiological adaptations to be poorly tolerated. The risk with severe ventricular impairment (LVEF <40%) is that of decompensation as a result of the increased intravascular volume and cardiac output. Administering Trastuzamab in pregnancy when the heart is already physiologically stressed may increase the risk of developing drug-induced myocardial dysfunction. In the current literature of Trastuzamab exposure in pregnancy, only two cases have had cardiac function specifically commented on. In one patient there was no change in ejection fraction during pregnancy,² and in the other there was an asymptomatic decline in LVEF leading to discontinuation of the drug at 24 weeks gestation.⁶ Because our patient is the first reported case of Trastuzamab-related cardiotoxicity in pregnancy, it is difficult to make recommendations regarding the saftey profile of Trastuzamab cardiotoxicity in pregnancy, however the potential incrased risk of this complication occurring needs to be explained to women during counselling.

To our knowledge there have been seven cases of Trastuzamab use in pregnancy reported. These have concentrated on the fetal effects; there were three cases of anhydramnios^2,7,8 and three cases of neonatal respiratory distress.^6,9,10 Out of these seven cases there has been one infant death due to multi-organ failure¹⁰ and one pregnancy with no fetal or maternal complications.¹¹ Trastuzamab does cross the placenta and it is known that the epidermal growth factor receptor group which includes HER2 does play a crucial role in fetal renal and pulmonary development. Blocking the HER2 receptor with Trastuzamab may adversely affect fetal development.

The inicidence of breast cancer in pregnancy is set to increase as women delay childbearing. This in turn will mean that more women will be exposed to Trastuzamab in pregnancy making the side-effect of cardiotoxicity clinically relevant. The US FDA have categorized Trastuzamab as a category B drug⁴ (animal reproduction studies have failed to demonstrate a risk to the fetus but there are no adequate well-controlled studies in pregnant women). This case report, as well as the other published cases, highlights the potential maternal and fetal concerns regarding safety of Trastuzamab exposure in pregnancy. The overall safety and efficacy of Trastuzamab in pregnancy has yet to be established and in the absence of data from large well-designed studies, anecdotal evidence has to be used to guide management. We could emphasize that Trastuzamab should be used in pregnancy with extreme caution and only after careful counselling weighing up the risks and benefits. If it is to be continued in pregnancy, careful monitoring of the mother with regular echocardiography to detect cardiotoxicity and regular fetal scanning to detect changes in liquor volume and growth problems should be in place as well as a multidisciplinary approach from obstetricians, cardiologists and paediatricians.

Footnotes

DECLARATIONS —

Competing interests None declared

Funding None

Ethical approval Patient consent obtained

Guarantor Jamal Zaidi, Clinical Director, ESHT

Contributorship Both authors contributed equally

Reviewer Robin Ferner