Pertuzumab-induced cardiotoxicity: safety compared with trastuzumab

Yildirim Beyazit University, Faculty of Medicine, Department of Medical Oncology, 06800, Ankara, Turkey Hacettepe University Cancer Institute, Department of Medical Oncology, Ankara, Turkey *Author for correspondence: Tel.: +90 312 2912525; masendur@yahoo.com.tr Trastuzumab is the first humanized monoclonal antibody that binds to the extracellular domain of HER2 [1,2]. Adding trastuzumab to standard chemotherapy significantly improves response rates, progression-free survival and overall survival in patients with HER2-positive metastatic breast cancer (MBC) [3,4]. Although trastuzumab is the major cornerstone of the treatment of HER2-positive MBC, the majority of patients with MBC who initially respond to trastuzumab demonstrate disease progression within 1 year of trastuzumab treatment [3]. The lack of response to trastuzumab of HER2positive MBC in some patients challenges clinicians to find new therapies directed at HER2. Pertuzumab, a new recombinant humanized monoclonal antibody, prevents the dimerization of HER2 with other HER receptors (HER3, HER1 and HER4), especially with HER3, by binding to the HER2 dimerization domain [5]. The randomized, double-blind, placebo-controlled, Phase III CLEOPATRA study showed that adding pertuzumab to a trastuzumab plus docetaxel combination was associated with significantly improved progression-free survival and overall survival in patients with treatmentnaive HER2-positive MBC [6,7]. Both of the randomized NEOSPHERE and TRYPHAENA trials showed significantly improved pathological complete response rates when adding pertuzumab to trastuzumab arms compared with trastuzumab-alone arms in the neoadjuvant setting [8,9]. Due to the combination of dual antibodies against HER2 being more active compared with single anti-HER2 treatment, the US FDA approved pertuzumab in combination with trastuzumab in the neoadjuvant setting and in treatment-naive MBC. Trastuzumab-induced cardiotoxicity (TIC) is the main dose-limiting adverse event in HER2positive breast cancer patients treated with trastuzumab [10]. In a pivotal trial, the risks of TIC were 27 and 13% in patients treated with anthracycline plus cyclophosphamide with trastuzumab concomitantly and trastuzumab plus paclitaxel, respectively [10]. In a meta-analyses of ten randomized controlled trials, the incidence of TIC was reported to be 7.5%, with a 1.9% incidence of congestive heart failure among 11,882 patients receiving trastuzumab [11]. The combination of pertuzumab with trastuzumab demonstrated signif icant tumor regression compared with trastuzumab or pertuzumab alone in xenograft tumor model