Long-term trastuzumab safety in tailored dose-dense anthracycline containing adjuvant chemotherapy in the PANTHER phase III trial.

Abstract

12024 Background: Cardiotoxicity is a known side effect of trastuzumab and combination with anthracyclines increases the risk for cardiotoxicity. Adjuvant dose-dense (DD) chemotherapy has demonstrated beneficial breast cancer (BC) outcomes in patients with high risk for relapse, but data on long-term cardiac toxicity when combined with trastuzumab is scarce. We have previously reported on the safety of trastuzumab at six years follow-up, in a subset of patients treated with dose-dense chemotherapy in the Pan-European Tailored Chemotherapy (PANTHER) phase III trial. We hereby present long-term safety data from 10-year follow-up from the same subset. Methods: This is a protocol-predefined cardiac safety study, among Swedish sites included in the PANTHER trial, including patients with HER2-positive (HER2+) and HER2-negative (HER2-) BC matched for age, treatment group and institution. Enrolled patients were up to 65 years old with node-positive or high-risk, node-negative BC were randomized 1:1 to either dose tailored (according to hematologic nadirs) and biweekly DD epirubicin and cyclophosphamide followed by docetaxel or standard 5-fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. They underwent echocardiography (ECHO) or multigated acquisition scanning and electrocardiography at baseline, at 4, 6 and 10 years of follow-up. Data on cardiac medication NT-proBNP, lipid profile and ECG were also collected. Results: ECHO at 10-years follow-up was available for 94 patients; 48 HER2+ (19 DD, 29 control) and 46 HER2- (21 DD, 25 control). Overall, incidence of cardiotoxicity was low. Mean LVEF was 58 % (range 49-68%) and 60.65% (range 50-76%) in HER2+ and HER2- respectively. Only one patient had LVEF < 50% (DD HER2+) and additional 12 patients had LVEF 50-54%, equally distributed between the treatment groups. In total, 27 patients were treated with cardiac medications at this point; 15 (56%) of which had been treated with trastuzumab and 10 of them (n = 7 HER2+), not reporting cardiac medication at previous timepoints. The majority of the patients did not report any symptoms related to heart disease, per NYHA-classification (41 patients in both groups report NYHA class 0). Overall, no significant changes were seen in the biomarkers. Conclusions: Cardiotoxicity of trastuzumab in DD anthracycline chemotherapy, examined in the context of a randomized trial sub-study, was very low. Our results underline the safety of trastuzumab in this context, providing support to offer the patients best treatment options for improving breast cancer survival. Clinical trial information: NCT00798070 .