Trastuzumab Emtansine

Trastuzumab-emtansine induced pleural and pericardial effusions

Jeffrey Lombardi1 , Pauline Lory2, Nils Martin3,
Didier Mayeur3, Sandrine Combret2, Aure´lie Grandvuillemin2, Charle`ne Boulay4 and Antonin Schmitt1,5
J Oncol Pharm Practice
0(0) 1–4

A The Author(s) 2021 Article reuse guidelines: DOI: 10.1177/10781552211015772

Introduction: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combine trastuzumab (T), a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), and a cytotoxic molecule derived from maytansine (DM1).
Case report: We report the first case of T-DM1-associated pleural and pericardial effusions three weeks after the second course of T-DM1 in a patient with breast cancer. Drug-induced pleural and pericardial effusions was implicated in the absence of other etiologies. The Naranjo Scale indicated a probable drug-induced adverse reaction.
Management & outcome: The patient fully recovered after thoracentesis and discontinuation of T-DM1. The patient has reported no side effect after the sixth course of trastuzumab.

Discussion: To our knowledge, this is the first case in the literature of bilateral pleural and pericardial effusions in a patient treated with T-DM1. The successful initiation of treatment with trastuzumab following withdrawal of T-DM1 suggests that emtansine played a role in the development of bilateral pleural and pericardial effusions. We hypothesize that the patient’s condition was a result of a local inflammatory reaction to emtansine by direct toxicity.

Pleural effusions, pericardial effusion, adverse drug reaction, trastuzumab-emtansine, oncology
Date received: 29 March 2021; revised: 19 April 2021; accepted: 19 April 2021

Trastuzumab emtansine (T-DM1) is a combination of a humanized monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2), trastuzu- mab (T), and a maytansine-derived cytotoxic chemo- therapy (DM1). Approximately three molecules of DM1 are linked to one molecule of trastuzumab bybreast. The patient provided informed consent before publication. The tumor was positive for estrogen recep- tors, negative for progesterone receptors, and positive for HER2. It should be noted that during the initial assessment, an infiltrating lobular adenocarcinoma of the left breast was discovered and was found to bestable covalent thioether bonds, giving them high selectivity for tumor cells that overexpress HER21. T-DM1 is indicated as monotherapy in the treatment of adult patients with unresectable HER2-positive or locally advanced metastatic breast cancer who have previously received at least one treatment with taxane and trastuzumab.2

Case report
We report the case of a 75-year-old female patient diag- nosed with grade 2 invasive carcinoma of the right
1Pharmacy Department, Centre Georges-Franc¸ois Leclerc, Dijon, France 2Regional Pharmacovigilance Centre of Burgundy, University Hospital of Dijon, Dijon, France
3Medical Oncology Department, Centre Georges-Franc¸ois Leclerc, Dijon, France
4Pharmacovigilance Centre of Rouen, University Hospital of Rouen, Rouen, France
5INSERM U1231, University of Burgundy Franche-Comt´e, Dijon, France

Corresponding author:
Jeffrey Lombardi, Pharmacy Department, Centre Georges-Franc¸ois Leclerc, 1 rue Pr. Marion, 21000 Dijon, France.
Email: [email protected]

positive for estrogen and progesterone receptors, but negative for HER2. The patient’s main medical history was hypercholesterolemia treated with rosuvastatin and high blood pressure treated with irbesartan. She underwent a hysterectomy with bilateral anexectomy nearly 30 years ago, was treated 12 years ago for poly- radiculoneuritis and had a cholecystectomy 8 years ago. She received neoadjuvant chemotherapy with three courses of epirubicin in combination with cyclophos- phamide, followed by nine courses of weekly paclitaxel in combination with trastuzumab. Mammography, ultrasound and MRI showed only a partial therapeutic response. A bilateral segmentectomy with a sentinel node was done thereafter. Anatomopathological anal- ysis of the right segmentectomy found the persistence of a tumor and lymph node metastasis. Treatment with adjuvant T-DM1 followed by radiotherapy and hor- mone therapy was indicated. The patient then received two courses of T-DM1 (3.6 mg/kg every three weeks). Only ondansetron was administered as premedication. Metoclopramide was used as an antiemetic during intercourse. One week after the second course of T- DM1, she presented with a significant deterioration of overall health, including anorexia, nausea and vom- iting, and an episode of left chest pain and dizziness. Eight days after this episode, the patient presented with grade II mucositis with probable oral mycosis, anorex- ia, nausea, and persistent chest pain associated with dyspnea. She was hospitalized on the 22nd day after the second course of T-DM1. We performed a CT scan, which showed bilateral pleural and pericardial effu- sions, and excluded a detectable infectious focus,pulmonary embolism or metastatic development. An ultrasound-guided thoracentesis was performed three days after admission. Laboratory analysis of the pleu- ral fluid confirmed a sterile exudate without cancer cells. A cardiac origin was suspected due to the decrease in left ventricular ejection function (LVEF) to 54%, estimated by cardiac scintigraphy (compared with 68% five months earlier), and transient increase of NT-proBNP after the second administration of T- DM1 (Figure 1). However, CT scan imaging was normal. LVEF is considered normal at 54%, and mon- itoring of ventricular function on cardiac scintigraphy at 3 weeks post-admission showed a LVEF of 61%. Diagnosis of heart failure was exluded in view of the normalization of NT-proBNP five days after thora- centesis and the absence of consistent signs on CT and cardiac scintigraphy imaging.

Given that no other etiology was found for the
patient’s pleural and pericardial effusions, T-DM1 was suspected. No drug interaction between T-DM1 and others concomitant treatments have been found. T-DM1 was withdrawn and the patient totally recov- ered after thoracentesis. The regional pharmacovigi- lance center was consulted and concluded that, in view of the timeline of the symptoms and the absence of any other aetiology, T-DM1 may have caused the effusions.
Two weeks after the thoracentesis, the patient’s car- diac function was tested by cardiac scintigraphy (LVEF ¼ 61%), and the care team decided to restart
monotherapy with trastuzumab every three weeks.
After six courses of trastuzumab and monitoring of

2. Table 1. Naranjo adverse drug reaction probability scale.
Question Yes No Do not know Score
1. Are there previous conclusive reports on this reaction? þ1 0 0 0

2. Did the adverse event appear after the suspected drug was administered?
3. Did the adverse event improve when the drug was discontinued or a specific antagonist was administered?
4. Did the adverse event reappear when the drug was readministered?
5. Are there alternative causes that could on their own have caused the reaction?
þ2 —1 0 þ2
þ1 0 0 þ1
þ2 —1 0 0
—1 þ2 0 þ2

6. 7. Was the drug detected in blood or other fluids in concentra-
tions known to be toxic? þ1 0 0 0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? þ1 0 0 0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? þ1 0 0 0
10. Was the adverse event confirmed by any objective evidence? þ1 0 0 0
core: 15

2. Did the reaction reappear when a placebo was given? —1 þ1 0 0

Total S
Note: Adverse Drug Reaction Probability Scale is as follows: Certain,>9; Probable, 5–8; Possible, 1–4; Unlikely, 0.

NT-proBNP every three weeks, there has been no recurrence and NT-proBNP has remained within the normal range. The patient has reported no side effect after the sixth course of trastuzumab. Considering these factors, we hypothesize that emtan- sine had a role in the occurrence of pleural and peri- cardial effusions in this patient. The Naranjo Algorithm (Table 1) indicate a probable drug-induced adverse reaction.3

The most common side effects reported in individuals treated with T-DM1 are hematological, neurological, hepatic, pulmonary and cardiac side effects, with an increased risk of heart failure, particularly symptomat- ic congestive heart failure in patients with impaired LVEF.4 Concerning trastuzumab, some studies report that cardiac toxicity occurs in nearly 7% of patients treated with monotherapy.5,6 The mechanism poten- tially implicated here was reversible myocardial injury without structural damage.7 It is thought that this com- plex mechanism involves the combination of oxidative stress and inhibition of the antiapoptotic mechanism, leading to the formation of free radicals.8,9 Interstitial lung disease has also been reported in association with T-DM1, sometimes leading to acute respiratory distress syndrome or death.10 We were unable to find a case similar to ours in the literature, but another case is reported in the French pharmacovigilance database. This case involved a 64-year-old patient treated for metastatic breast cancer (pre-pectoral, pleural and lymph node metastases) with three courses of T-
DM1. Eight days after her third course, the patient presented with dyspnea and chest pain, and bilateral pleural effusion was identified. Nine days later, trans- thoracic echocardiogram showed pericardial effusion. The patient received treatment with furosemide, T- DM1 was discontinued, and the patient fully recovered. In the present case report, the increase in NT-proBNP levels occurred two days after the patient was admitted to hospital, after the onset of dyspnea and chest pain. One hypothesis is that the pericardial and pleural effusions may have caused the transient increase in NT-pro-BNP. The level of NT-proBNP returned to normal within five days of the thoracent- esis. To date, we have not found this type of side effect in the literature with trastuzumab, although it has been
more widely used than T-DM1 for many years.

To our knowledge, this is the first case in the literature of bilateral pleural and pericardial effusions in a patient treated with T-DM1. Clinical, imaging and bio- logical investigations failed to detect the origin of the bilateral and pericardial pleural effusions. However, the chronology of the patient’s treatment schedule and symptom onset, and the conclusions of our region- al pharmacovigilance center are in favor of an etiology related to the patient’s treatment regimen. The success- ful initiation of treatment with trastuzumab following withdrawal of T-DM1 suggests that emtansine played a role in the development of bilateral pleural and peri- cardial effusions. While the mechanism remains unclear, we hypothesize that the patient’s conditionwas a result of a local inflammatory reaction to emtan- sine by direct toxicity.

Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Jeffrey Lombardi Antonin Schmitt

1. Barok M, Joensuu H and Isola J. Trastuzumab emtan- sine: mechanisms of action and drug resistance. Breast Cancer Res 2014; 16: 1–12.
2. Has-sant´ [website], 2. 2. fr/kadcyla-trastuzumab-emtansine-anticorps-ciblant-le- 2. recepteur-her-2-couple-a-un-cytotoxique (accessed 13 November 2020).
3. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–245.
4. Product Information: KADCYLAVR intravenous injec- tion, ado-trastuzumab emtansine intravenous injection. South San Francisco, CA: Genentech Inc (per FDA), 2019.
5. Seidman A, Hudis C, Pierri M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215–1221.
6. Perez EA and Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol 2004; 22: 322–329.
7. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. Jco 2005; 23: 7820–7826.
8. . Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhi- bition. Circulation 2006; 114: 2474–2481.
9. Nakagami H, Takemoto M and Liao JK. NADPH oxidase-derived superoxide anion mediates Trastuzumab Emtansine angiotensin II-induced cardiac hypertrophy. J Mol Cell Cardiol 2003; 35: 851–859.
10. Alkan A. Interstitial pneumonitis associated with trastu- zumab emtansine. J Oncol Pharm Pract 2019; 25: 1798–1800.