The experience from concurrent anthracycline and trastuzumab therapy in metastatic breast cancer has triggered further research into the molecular mechanism of anthracycline-induced cardiotoxicity. Gene targeting studies in mice show that HER2, a proto-oncogene and a member of the erbB family of transmembrane tyrosine kinases, is essential for cardiac development,[16] and conditional deletion of HER2 leads to the development of a dilated cardiomyopathy.[17] In mice that are deficient in HER2 protein or its associated ligand, neuregulin (NRG), a paracrine peptide messenger that activates HER2, the induction of cardiac stress pathways by an anthracycline promotes the onset of left-ventricular dysfunction.[17]

These results have provided an explanation for the increased cardiotoxicity observed with concurrent administration of an anthracycline and trastuzumab, an anti-HER2 monoclonal antibody. In response to acute stress such as exposure to anthracycline, the cardiomyocytes-survival pathway is activated by neuregulins binding to the HER2:HER4 heterodimer, preventing death of cardiomyocytes.[18] Trastuzumab, by inhibiting the HER2 receptor, interferes with this survival signaling pathway and thus promotes the cardiotoxic effects of anthracycline.

Risk Factors
A number of risk factors for the development of anthracycline-induced cardiotoxicity have been identified (Table 1). The strongest risk factor is cumulative dose. Other potential risk factors include age, preexisting cardiac risk factors, radiation therapy, and other chemotherapy agents. However, while some of these are known risk factors for the development of CHF in the general population, it is unclear from most studies whether they potentiate the effects of anthracyclines or whether their effects are simply additive.

Cumulative Dose
A high cumulative anthracycline dose is the most recognized risk factor for cardiac damage and remains the best predictor of subsequent cardiac dysfunction. This association was first observed by Von Hoff et al in a retrospective analysis showing that anthracycline toxicity and heart failure were dose-related, with the incidence of complications rising sharply as cumulative doses of doxorubicin increase.[10] The estimated percentage of patients who developed CHF at a dose of 400 mg/m² was 3%, increasing to 7% at 550 mg/m² and to 18% at 700 mg/m².[10] This led to a recommended limit on lifetime cumulative doxorubicin dose of 450 to 550 mg/m².

Subsequent studies have confirmed this observation, but most did not control for competing causes of mortality or take into account the effect of time on the risk of cardiotoxicity.[19] This was addressed by Ryberg et al in a recent retrospective study of 1,097 patients with metastatic breast cancer treated with epirubicin over a 20-year period.[20] They first identified independent predictive factors for the development of cardiotoxicity and other causes of mortality, respectively. Using competing risk analysis, they were able to determine the maximum dose resulting in no more than a 5% rate of CHF for patients with different sets of risk factors. For a patient aged 40 years with no other risk factors for CHF, the recommended dose yielding a 5% risk of CHF at 2.5 years of treatment would be 806 mg/m². If the same woman were 70 years old, the maximum cumulative dose drops to 609 mg/m².[20] This analysis showed that maximum cumulative dosage of anthracycline would differ among patients depending on preexisting cardiac risk factors and other competing factors for mortality.

Age
An early study by Von Hoff has suggested that anthracycline-induced cardiotoxicity may be more pronounced with advancing age.[10] In a retrospective analysis of three clinical trials involving 630 patients who were treated with doxorubicin, Swain et al showed that patients more than 65 years old are 2.25 times more likely to experience anthracycline-induced CHF compared with patients less than 65 years old, but the effect is only pronounced after a cumulative dose of 400 mg/m².[19] In addition, the number of CHF events that occurred in the subgroup analysis was small, and a non–anthracycline-treated comparison group was not included. Therefore, the interpretation of the findings is difficult.

Several studies have used the Surveillance, Epidemiology and End Results (SEER)-Medicare database to evaluate the risk of CHF following anthracycline administration in women with early-stage breast cancer,[21] finding over a twofold increase in the risk of cardiomyopathy and a 40% increase in CHF. These studies found that CHF was associated with advanced age, black race, increased number of comorbid conditions, and a prior history of cardiac conditions and cardiac risk factors.[21] The risk of CHF after anthracycline treatment in these studies appeared to be higher than the rate of CHF observed by other adjuvant breast cancer trials, where patients were generally younger.[7] While these studies were strengthened by large numbers of subjects and up to 10 years of follow-up, they were limited by a lack of anthracycline dose information in the database, and the outcomes of CHF being determined only through billing claims.