The cardiac (myocyte) effects of trastuzumab differ fundamentally from those of anthracyclines; in particular, trastuzumab does not cause myocyte loss. In patients with trastuzumab-related cardiac dysfunction, myocytes appear histologically normal; changes may be seen only by using electron microscopy, in keeping with a reversible cardiomyopathy (Guarneri et al, 2006
), and this has led to the classification of trastuzumab-related CRCDs as Type II () (Ewer and Lippman, 2005
; Guarneri et al, 2006
), as opposed to the irreversible changes associated with anthracyclines (Type I CRCD).
There is evidence that trastuzumab-related left ventricular systolic dysfunction (LVSD) is mediated through the binding of trastuzumab to the extracellular domain of the HER2 protein present on cardiac myocytes, blocking ErbB2-ErbB4 signalling. This results in the disabling of an important cell-protective, growth-promoting pathway within the myocardium. The pathway is required for cell survival and continuing function, and seems to be stimulated when the myocardium encounters adverse haemodynamic or other stress, such as that associated with anthracyline therapy. Withdrawal of trastuzumab allows return of function of the pathway and reversal of LVEF decline, in contrast to the permanent myocyte dysfunction and loss caused by anthracyclines. This proposed mechanism is consistent with the increase in cardiac effects when trastuzumab is used concomitantly with anthracyclines.
The incidence of serious adverse events during trastuzumab monotherapy is low and the most frequently reported acute adverse effect of trastuzumab therapy is a hypersensitivity-like infusion reaction (Adamo et al, 2007
; Herceptin PI, 2007). The antiproliferative side effects commonly associated with cytotoxic chemotherapy have not been reported. However, when trastuzumab was added to chemotherapy in the pivotal registration trial, CHF was reported in an unexpectedly high number of patients, prompting a detailed retrospective cardiac evaluation (Slamon et al, 2001
). Anthracycline-naive patients received doxorubicin, and anthracycline-pretreated patients received paclitaxel, to avoid an excessive cumulative anthracycline dose. Paclitaxel monotherapy was associated with a 1% incidence of CHF; concurrent use of trastuzumab increased this to 13%. Patients receiving concurrent anthracycline and trastuzumab had a 27% incidence of symptomatic heart failure (16% NYHA Grade III/IV). Trastuzumab-associated LVSD was not dose-related, and appeared to improve with standard medical management including angiotensin-converting enzyme (ACE) inhibitors.
In adjuvant trials, there were stringent cardiac eligibility criteria, and trastuzumab was interrupted or discontinued in response to the development of CHF or following protocol-defined changes in LVEF. In a large North American study (NSABP B-31) (Rastogi et al, 2007
), patients with HER2-positive, node-positive early breast cancer, and an LVEF >50% received 4 cycles of anthracycline-containing chemotherapy followed by 4 cycles of paclitaxel. Patients were randomised to receive trastuzumab for a total of 1 year, starting concurrently with paclitaxel. In the control arm (no trastuzumab), 10 of 872 (1.3%) patients with a normal post-anthracycline LVEF had confirmed cardiac events (9 CHF, 1 death), compared with 35 of 932 (3.9%) patients in the trastuzumab-treated arm (35 CHF, no deaths). Trastuzumab was discontinued because of cardiac dysfunction in 15.6% of patients. Age >50 years, prescription of antihypertensive medication, and post-anthracycline LVEF values of 50–54% (0.50–0.54) were all associated with an increased risk of CHF.
The European HERA trial evaluated the effects of using trastuzumab after completion of all chemotherapy; 94% of patients received anthracyclines. A post-chemotherapy LVEF of 55% was required in HERA, compared with 50% in the US study, and there was an in-built delay of several months between the completion of (cytotoxic) chemotherapy and initiation of trastuzumab (for either 1 or 2 years). No cardiac deaths occurred, the rate of severe heart failure was <1% (Smith et al, 2007
; Suter et al, 2007
), and only 4.3% of patients discontinued trastuzumab because of cardiac dysfunction (Suter et al, 2007
). The reduction in cardiac event rate has been attributed to the higher baseline LVEF requirement and the protocol-driven delay between the end of cytotoxic therapy and start of trastuzumab (Smith et al, 2007
). Experience from one US cancer centre showed a median time to decline in LVEF during trastuzumab therapy of 4.5 months (Ewer et al, 2005
). After cessation of trastuzumab (37 of 38 patients), and commencement of standard treatment for LVSD (31 patients), the mean time to recovery of LVEF was 1.5 months.