Abstract / Description: 

Importance Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. Objective To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. Design, Setting, and Participants In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. Interventions Treatment consisted of weekly 80-mg/m2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Main Outcomes and Measures Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. Results Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF at baseline was 65%; 12 weeks, 64%; 6 months, 64%; and 1 year, 64%. Conclusions and Relevance Cardiac toxic effects from paclitaxel with trastuzumab, manifesting as grade 3 or 4 LVSD or asymptomatic LVEF decline, were low. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year, and our findings suggest that LVEF monitoring during trastuzumab therapy without anthracyclines could be simplified for many individuals. Introduction In the United States, breast cancer is the most common female cancer and the second most common cause of cancer death in women.1 Amplification or overexpression of the human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu) oncogene is present in approximately 20% to 25% of primary invasive breast cancers.2 Trastuzumab has demonstrated a significant improvement in outcomes of women with early-stage breast cancer in key adjuvant trials, but most of these trials contained an anthracycline-based therapy followed by trastuzumab with or without a taxane in women with either node-positive or node-negative, high-risk breast cancer (usually defined as tumor size >1 cm or >2 cm).3-8 However, several studies from the pretrastuzumab era suggest a higher risk of recurrence for patients with ERBB2-positive, node-negative tumors compared with those with ERBB2-negative tumors of the same size.9-11 Recent retrospective studies have demonstrated a benefit from the combination of chemotherapy and trastuzumab in those with node-negative breast cancer and a time trend increase in the use of these agents.12-14 The most significant toxic effect of trastuzumab, especially following an anthracycline-based therapy, is symptomatic congestive heart failure (CHF) that has been reported from 0.9% to 4% and significant asymptomatic cardiac decline ranging from 4% to 19% in clinical trials.3-8,15-19 After the anthracycline phase, most symptomatic CHF and asymptomatic left ventricular ejection fraction (LVEF) decline occurred during the period of trastuzumab administration.3-8,15-19 Unlike cardiac toxic effects associated with anthracyclines, LVEF decline following trastuzumab therapy is not dose related and is considered to be mostly reversible.20 Most previous clinical trials involving trastuzumab included patients who were exposed to anthracyclines, but it is not clear how much the anthracyclines contributed to trastuzumab-mediated cardiac dysfunction. To reduce cardiac and noncardiac toxic effects with the hope of maintaining a high degree of effectiveness, we conducted a trial of weekly paclitaxel with trastuzumab in patients with early-stage ERBB2-positive breast cancer. The overall study results have been previously reported, and this article highlights the detailed cardiac data that have been collected.21

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Chau Dang, MD; Hao Guo, MS; Julie Najita, PhD; Denise Yardley, MD; Kelly Marcom, MD; Kathy Albain, MD; Hope Rugo, MD; Kathy Miller, MD; Matthew Ellis, MD, PhD; Iuliana Shapira, MD; Antonio C. Wolff, MD; Lisa A. Carey, MD; Beverly Moy, MD; John Groarke, MD; Javid Moslehi, MD; Ian Krop, MD, PhD; Harold J. Burstein, MD, PhD; Clifford Hudis, MD; Eric P. Winer, MD; Sara M. Tolaney, MD