Abstract 3267
Background
Recently, the world of oncology has been revolutionized by immunotherapy which has shown considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiactoxicity has not been properly studied.
Methods
In human fetal cardiomyocytes exposed to Trastuzumab and Pembrolizumab alone or in combination, we studied: the cell viability (through MTS assay), the quantification of intracellular calcium, Interleukin 1β, 6 and 8; the expression of NF-kB and Leukotrienes. Preclinical studies were also performed in C57BL6 mice dividing them in 4 groups (6/group: untreated mice (control) ; mice treated with Pembrolizumab at 10 mg/Kg for the first dose, followed by 5 mg/Kg dose every 5 days until the study end point, according to literature; mice treated with Trastuzumab at 10 mg/kg/day; mice treated with both drugs in combination. After the administration period, we analyzed the fibrosis and inflammation in heart tissues.
Results
The combination of Pembrolizumab and Trastuzumab increases the intracellular calcium overload (of 3 times compared to untreated cells) and reduces the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively; p < 0.01 for both). Combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the cardiac fibrosis and Interleukins expression of 40-50 % compared to the single treatments; the expression of NF-kB and Leukotriene B4 were also significantly increased, compared to the single treatments.
Conclusions
The association of Pembrolizumab and Trastuzumab exerts pro-inflammatory and pro fibrotic effects in the heart; these effects are mainly mediated by overexpression of NF-kB and Leukotriene B4 related pathways and pro-inflamamtory cytokines.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work was funded by the “Ricerca Corrente” grant from the Italian Ministry of Health.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2344 - Lung Cancer in Europe: strengthening policy responses to address unmet needs
Presenter: Mary Bussell
Session: Poster Display session 3
Resources:
Abstract
1359 - Curative treatment timelines for breast, colorectal, lung and prostate cancer: Implications for medical leave coverage
Presenter: Selina Wong
Session: Poster Display session 3
Resources:
Abstract
4433 - Acute Diagnostic Oncology Clinic: A Unique Primary Care-Oncology Service
Presenter: Abhijit Gill
Session: Poster Display session 3
Resources:
Abstract
3506 - THE NEW MUTATIONAL MODEL IN ONCOLOGY. What changes in welfare, clinical practice, research, and regulatory procedures
Presenter: Nicola Normanno
Session: Poster Display session 3
Resources:
Abstract
3350 - Selection of a set of quality indicators (QI) for oncological clinical pathway
Presenter: Aude Fourcade
Session: Poster Display session 3
Resources:
Abstract
4400 - Sustainable drug prices at market launch: policy proposals and their empirical evidence
Presenter: Nora Fanzen
Session: Poster Display session 3
Resources:
Abstract
4118 - Impact of financial considerations on French physicians’ prescription choices for advanced non-small cell lung cancer (NSCLC)
Presenter: Nathalie Olympios
Session: Poster Display session 3
Resources:
Abstract
1340 - The direct medical cost of breast cancer in a Belgian hospital
Presenter: Hannan Lemhouer
Session: Poster Display session 3
Resources:
Abstract
1863 - Does the healthcare system approaches cancer patients for using private services during diagnostic process?
Presenter: Karolina Osowiecka
Session: Poster Display session 3
Resources:
Abstract
2637 - Measuring financial toxicity of cancer in the Italian health care system: initial results of the patient reported outcome for Fighting Financial Toxicity of cancer project (proFFiT).
Presenter: Silvia Riva
Session: Poster Display session 3
Resources:
Abstract