Trastuzumab associated with increased reversible cardiac changes

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1. At 8 years median follow-up, trastuzumab treatment for HER2-positive breast cancer is associated with slightly increased rates of CHF (Congestive heart failure) and LVEF (Left ventricular ejection fraction) decrease but not cardiac death.

2. The associated increases occurred mostly during the treatment interval and were almost all reversible.

Evidence rating: 1 (Excellent)

Study Rundown: Trastuzumab, or Herceptin, is a humanized monocolonal antibody against the human epidermal growth factor receptor 2 (HER2) that has been shown to increase survival in patients with breast cancer that expresses the receptor. Initial data from the Herceptin Adjuvant (HERA) trial as well as data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial both showed a trend towards increased cardiac events in the Herceptin treatment arms. In this modified amendment to the HERA protocol, patients randomized to observation, 1 year of trastuzumab, or 2 years of trastuzumab after receiving standard, primary treatment for breast cancer, were followed up for cardiac events. The authors show that there were minimal, yet statistically significant, increases in severe CHF and LVEF decrease in patients treated with trastuzumab. Furthermore, the increases were higher in the 2 year treatment arm. Rates of cardiac death were not significantly increased in either the 1 year or 2 year treatment intervals. This analysis of the HERA data also showed that the majority of these adverse cardiac events took place during the treatment interval and were mostly reversible. A serious limitation of this study is that only patients with LVEF of at least 55% after primary treatment were included. This would have underestimated the rates of adverse cardiac events due to exclusion of patients with more tenuous initial cardiac function, who would have realistically been given HER-2 targeted therapy in clinical practice.

Click to read the study in Journal of Clinical Oncology

Relevant reading: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

In-Depth [randomized controlled trial]: Patients with HER-2 positive invasive breast cancer who were treated with a subset of adjuvant or neoadjuvant chemotherapy, radiation, and surgery were randomly assigned to observation (n=1,698), 1 year of trastuzumab (n=1,703), or 2 years of trastuzumab (n=1,701). Of note, only patients with LVEF of at least 55% after primary treatment were included. The rates of cardiac death in the observation, 1 year Herceptin, and 2 year Herceptin arms were 0.1%, 0%, and 0.2 %, respectively. 95% confidence intervals for rate difference between 1 year versus observation was -0.3 to 0.0 and for 2 year versus observation was -0.2 to 0.3. The rates of severe CHF were 0.0%, 0.8%, and 0.8%, respectively. 95% CI: 0.4 to 1.3 and 0.4 to 1.2, respectively. The rates of significantly decreased LVEF were 0.0%, 4.1%, and 7.2 %, respectively. 95% CI: 2.2 to 4.3 and 5.0 to 7.6, respectively. In the 1 year treatment arm, the cardiac endpoint occurred within the treatment period 78.3% of the time while 93.4% occurred within this scheduled time in the 2 year arm. Of all patients who had any cardiac events, 79.5% of those in the 1 year arm acutely recovered, while 87.2% acutely recovered in the 2 year arm.

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