Heart of darkness: the downside of trastuzumab.

The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Trastuzumab has been shown to be quite effective in reducing suffering and mortality from breast cancer in both the metastatic 1 and adjuvant settings. 2-5 With short follow-up, remarkably consistent results across five adjuvant, prospective, randomized clinical trials suggest that trastuzumab may decrease the odds of distant recurrence and mortality by approximately one half and one third, respectively. Dr George Sledge, who discussed the first presentations of the adjuvant trials at the 2005 Annual Meeting of the American Society of Clinical Oncology, proclaimed these results " astonishing, " and we agree (oral communication, May 2005). However, there is a dark side to trastuzumab that may limit its utility in some patients. Although in general, trastuzumab has been extremely well tolerated, a surprisingly high incidence of congestive heart failure (CHF) was observed in the early studies of metastatic disease, especially in patients who were treated concurrently with doxorubicin. 1,6 With this knowledge, most subsequent trial designs, particularly those in the adjuvant setting, avoided concurrent anthra-cycline and trastuzumab therapy, and included careful baseline and serial monitoring of cardiac function. Early results from these trials suggest that approximately 5% of all patients treated with adjuvant trastuzumab, either with nonanthracycline chemotherapy such as the taxanes or vinorelbine, or after all chemotherapy is complete, will develop some objective evidence of systolic cardiac dysfunction. Approximately 1% of patients will develop symptomatic CHF. These rates are approximately four to five times higher than in control patients who did not receive trastuzumab, and the absolute difference in echocardiogram or scintigram-detected cardiac dysfunction between trastuzumab-treated and control patients seems to be approximately 3% to 4%. These observations raise several questions. First, given the enormous benefit of trastuzumab, is pre-existing cardiac dysfunc-tion, especially if it is asymptomatic, sufficient reason to withhold the drug? Are the classic risk factors for cardiac disease, such as hypertension, diabetes, and family history, important predictors of trastuzumab-induced CHF? Is trastuzumab-related CHF reversible if the agent is discontinued, and is it safe to reinitiate this potentially life-saving agent if a patient has developed cardiac dysfunction while receiving it previously? Are there ways to avoid or minimize trastuzumab-related cardiac dysfunction? Will the incidence of this complication increase with longer follow-up of women who receive adjuvant trastuzumab? Finally, what is the mechanism of this perplexing toxicity? In the last …