Long term cardiac tolerability of trastuzumab in HER-2-overexpressing metastatic breast cancer (MBC).

Background: The use of trastuzumab is associated with an increased risk of cardiotoxic events such as congestive hearth failure (CHF) and decline in the left ventricular ejection fraction (LVEF). Our objectives were to evaluate the incidence of cardiac dysfunction, to identify risk factors and to evaluate the outcome of patients with MBC treated with trastuzumab for one year or longer. Methods: Among 218 MBC patients treated with trastuzumab-based therapy for at least one year, 173 patients were evaluable for cardiac toxicity. Cardiac events (CE) were defined as follows: 1) asymptomatic drop of LVEF below 50%; 2) drop of 20 percentage points in LVEF compared to the baseline; 3) signs or symptoms of CHF. The cardiac toxicity was graded according the NCI-CTCAE, version 3.0. Results: Median age at the start of trastuzumab therapy was 50 years (range, 26-79), median cumulative time on trastuzumab was 21.3 months (range, 11.6-77.6), and median follow-up was 32.2 months (range, 9.7-79.0). Eighty-five percent of patients received prior anthracyclines (median cumulative doxorubicin dose: 300 mg/m2). Forty-nine patients (28%) experienced a CE: 3 patients (1.7%) had an asymptomatic drop in the LVEF of 20 percentage points; 27 patients (15.6%) experienced grade 2 cardiac toxicity; and 18 patients (10.4%) experienced grade 3 cardiac toxicity. There was one cardiac related death (0.5%). Cardiac event-free survival was 87.3% at 1 year. All but four patients had improved LVEF or symptoms of CHF after stopping trastuzumab or with appropriate therapy. After complete recovery, 26 patients were re treated with trastuzumab; 16 patients did not experience further CE. Concomitant taxane use was the only factor significantly associated with a CE (HR: 4.37, 95%CI 1.06-17.98, p:0.04).Prior anthracycline exposure was not associated with increased risk of CE. Conclusions: The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function. The increased risk of cardiotoxicity associated with taxane administration needs to be further investigated.