Long-Term Cardiac Tolerability of Herceptin (Trastuzumab)

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herceptinTrastuzumab (Herceptin), a humanized anti-HER2 monoclonal antibody, is highly effective for treating HER2-overexpressing invasive breast cancer. In patients with HER2-positive metastatic breast cancer, trastuzumab plus chemotherapy improved objective response rate, time-to-disease progression, and overall survival, compared with chemotherapy alone.

In the pivotal randomized trial, 28% of patients who received trastuzumab plus chemotherapy (predominantly those who received concurrent trastuzumab and anthracycline-based chemotherapy) experienced adverse cardiac events. More recently, in several large randomized clinical trials, trastuzumab in combination with adjuvant chemotherapy has significantly lowered risk for recurrence in patients with early-stage breast cancer; however, the collective experience from adjuvant therapy trials suggests that ~5% of patients who receive trastuzumab will show some evidence of systolic cardiac dysfunction.

Follow-up reports suggest that most patients who develop trastuzumab-induced cardiac dysfunction will recover normal cardiac function when trastuzumab is discontinued, with or without subsequent medical management.

Researchers from M.D. Anderson report on the long-term cardiac status of 173 patients with HER2-positive metastatic breast cancer who were treated with trastuzumab for at least 1 year(median cumulative time of trastuzumab administration, 21.3 months; median follow-up, 33.6 months). Standard clinical practice at this center includes cardiac evaluations; left ventricularejection fraction (LVEF) and cardiac toxicity were assessed. A total of 49 patients (28%) experienced adverse cardiac events: 3 patients showed asymptomatic decreases (>50%) in LVEF,27 patients experienced grade 2 cardiac toxicity (LVEF range, 40%–50%), and 19 patients experienced grade 3 cardiac toxicity (symptoms of CHF or LVEF range, 20%–40%). Only 15 patients were symptomatic at diagnosis; one patient with CHF died.

In patients who developed either CHF or large asymptomatic decreases in LVEF, trastuzumab was discontinued. For other patients, decisions to stop or continue therapy were made on a case-by-case basis. Fourteen symptomatic patients discontinued trastuzumab and 11 recovered, with or without cardiac therapy. Among the asymptomatic patients, 17 discontinued trastuzumab, and 15 recovered; 17 continued trastuzumab, and 15 recovered. In 26 patients (symptomatic or asymptomatic) who discontinued therapy, trastuzumab therapy was resumed after complete cardiac recovery: 16 patients experienced no further adverse cardiac events, whereas 10 experienced additional adverse events. Of these 10, 5 recovered completely after trastuzumab was discontinued again, and 5 maintained a slightly lowered LVEF (asymptomatic) while continuing trastuzumab.

Comment: This report, although retrospective, reflects "real world" clinical practice, without the rigid guidelines stipulated by a clinical trial. As such, it offers several important observations and lessons. First, the study includes only patients who received trastuzumab for at least 1 year. Second, most patients with trastuzumab-associated cardiac toxicity recovered completely, and many were re-treated with trastuzumab, without additional cardiac toxicity. A substantial number of patients did not discontinue trastuzumab, despite cardiac dysfunction. Patients who experiencetrastuzumab-induced cardiac toxicity should be managed in concert with cardiologists, and decisions to continue or resume trastuzumab must be made only after careful discussion of potential benefits and risks associated with further therapy.

— William J. Gradishar, MD

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