Trastuzumab cardiotoxicity: biological hypotheses and clinical open issues.
BACKGROUND
Trastuzumab has significantly improved the prognosis of breast cancer patients overexpressing the human epidermal growth factor receptor 2 (HER2). This result has been achieved in all disease settings, by increasing overall survival in early stage and advanced disease and by increasing pathological complete responses in neoadjuvant disease.


OBJECTIVE
Although the greatest impact of this monoclonal antibody has been seen in the adjuvant setting, by increasing disease-free survival and overall survival rates an increased rate of both symptomatic and non-symptomatic cardiac toxicity has also been observed.


METHODS
In the following review, the different mechanisms of trastuzumab cardiac toxicity are described and, in addition, the clinical data coming from both trials and meta-analyses is discussed.


RESULTS
While there is strong evidence for the incidence of trastuzumab-related cardiac toxicity, there is still little known on the exact pathogenesis of this toxicity. Interestingly, both experimental and clinical data suggest that trastuzumab may sensitize cardiomyocytes to injuries and stress from administration of anthracyclines. This has led to a proposed novel mechanism of cardiotoxicity that appears to be quite different from the anthracycline-associated cardiotoxicity. Trastuzumab does not seem to cause any overt ultrastructural abnormality; it does, however, lead to myocardial dysfunction.


CONCLUSIONS
Most of the proposed hypotheses seems to be related to the activity of trastuzumab in interfering with the ERBB-2 receptor. Indeed, data from clinical trials in the adjuvant setting report increased cardiac toxicity in those patients who previously received anthracyclines.
Bria
Emilio
E
Regina Elena National Cancer Institute, Department of Medical Oncology, Via Elio Chianesi 53, 00144, Rome, Italy. emiliobria@yahoo.it
Cuppone
Federica
F
Milella
Michele
M
Verma
Sunil
S
Carlini
Paolo
P
Nisticò
Cecilia
C
Vaccaro
Vanja
V
Rossi
Antonio
A
Tonini
Giuseppe
G
Cognetti
Francesco
F
Terzoli
Edmondo
E
D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002986:Clinical Trials as Topic; D006321:Heart / Q000187:drug effects*; D006801:Humans; D011379:Prognosis; D015996:Survival Rate; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab