Heart of Darkness: The Downside of Trastuzumab

Trastuzumab has been shown to be quite effective in reducing suffering and mortality from breast cancer in both the metastatic and adjuvant settings. 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. With this knowledge, most subsequent trial designs, particularly those in the adjuvant setting, avoided concurrent anthracycline 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 dysfunction, 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 few years, a substantial number of publications have addressed the cardiac toxicity of trastuzumab in both prospective clinical trials and from individual institutional experiences. In this issue of the Journal of Clinical Oncology, Guarneri et al report their results from a retrospective analysis of 218 metastatic breast cancer patients who received trastuzumab for at least 1 year from 1998 to 2003. In this series, 28% of patients had some type of cardiac event (CE), and 10.9% had grade 3 cardiotoxicity, with one cardiac death. Therefore, coupled with the larger, prospective trials, the results from this study provide additional insight into our questions. Given that all of the clinical trials of trastuzumab have excluded women with obvious pre-existing heart failure, we cannot determine if this condition should preclude a patient’s receiving it; however, until data to the contrary are reported, we believe it should. What about those who apparently have healthy hearts but have received pretrastuzumab anthracyclines, which are incorporated into most adjuvant regimens? In the adjuvant, prospective, randomized clinical trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP B-31) and the Breast Cancer Intergroup of North America, 6.7% of women who had completed four cycles of doxorubicin and cyclophosphamide (AC) were deemed ineligible to proceed to trastuzumab because of left ventricular dysfunction. We agree that this condition of eligibility was prudent. One might wonder if these patients could have been treated with trastuzumab and monitored closely with discontinuation of the drug on evidence of additional decline in cardiac function. In this regard, a cautionary note comes from the NSABP, which has reported that patients in NSABP B-31 with marginal post-AC left ventricular ejection fractions (LVEF) but who were still eligible for trastuzumab had higher rates of subsequent cardiac dysfunction than those who started trastuzumab with normal cardiac parameters. So for now, the presence of LV dysfunction or heart failure symptoms should exclude the addition of trastuzumab. The study by Guarneri et al may provide additional clues to our questions. Although the study was retrospective and limited by a small number of events, careful analysis of Table 1 suggests that several pre-existing factors may predict trastuzumab CEs. For example, it seems that although only 7% of women who received radiation to the right side developed a CE, 26% of those who received radiation to the left side were affected, although these differences did not reach statistical significance. Again considering the limited power, pre-existing diabetes, coronary artery disease, and valvular dysfunction were all associated with apparent higher rates of trastuzumab-related CEs. Curiously, hypertension and older age were not. In the NSABP/Intergroup analysis of adjuvant patients, age and hypertension were risk factors for cardiac dysfunction. Additional analysis of the NSABP trial data suggest that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 25 SEPTEMBER 1 2006