Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer

Abstract

Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (n = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p<0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p<0.0001) and trastuzumab (62 vs. 67 %, p<0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients.

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

“…Do czynników ryzyka kardiotoksyczności spowodowanej lekami anty-HER2 należą: wcześniej-sza ekspozycja na antracykliny, krótki odstęp (3 tygodnie vs. 3 miesiące) między leczeniem antracyklinami a leczeniem anty-HER2, uprzednio występujące nadciśnienie tętnicze, niska LVEF i starszy wiek [3,55]. Jedną z najistotniejszych klinicznych implikacji kardiotoksyczności wywołanej przez trastuzumab jest przerwanie tego leczenia, które wiąże się ze wzrostem częstości występowania nawrotów nowotworu [56]. U chorych na raka piersi z nadekspresją receptora HER2 poddanych adiuwantowemu leczeniu trastuzumabem kardiotoksyczność była najczęstszym powodem przerwania tej terapii (u 13,5% chorych, w 30% przypadków z powodu HF, a w 70% przypadków z powodu bezobjawowego spadku LVEF).…”

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…Whether discontinuation of the HER2 targeted therapy is at all necessary is not known, but could have important implications on cancer related outcomes. In one study, interruption of trastuzumab treatment was common after diagnosis of asymptomatic cardiac dysfunction and resulted in lower cumulative doses of the medication 98. Tripathy et al reported that in the trastuzumab pivotal trial published in 2001,5 33 patients continued to receive trastuzumab therapy for a median of 26 weeks after development of cardiac dysfunction, and the cardiac status of 28 (85%) either improved or remained stable 99.…”

Cardiovascular toxic effects of targeted cancer therapy

“…One of the most relevant clinical implications of trastuzumab cardiotoxicity is treatment interruption, which is associated with increased cancer recurrence (29). The clinical benefit from HER2 inhibitors needs to be balanced against cardiotoxicity.…”