CE: Swati; CCO/798; Total nos of Pages: 11; CCO 798 C URRENT O PINION Dual human epidermal growth factor receptor 2 blockade: another step forward in treating patients with human epidermal growth factor receptor 2-positive breast cancer AQ2 Dimitrios Zardavas, Ivana Bozovic-Spasojevic, and Evandro de Azambuja Purpose of review Many antihuman epidermal growth factor receptor (anti-HER2)-targeted agents, covering a broad spectrum of mechanisms of action, have been recently developed. The concept of dual anti-HER2 blockade has been preclinically and clinically assessed with positive results. In this article, the authors review the biologic rationale for dual HER2 blockade, along with the clinical findings. Recent findings Dual anti-HER2 blockade has been assessed in the metastatic setting, including with chemotherapy-free regimens, leading to impressive responses, even in heavily pretreated patients. In the neoadjuvant setting, dual anti-HER2 blockade combinations and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti-HER2 therapy. Similar strategies are now actively being pursued in the adjuvant setting and, it is hoped, will improve the outcome of many patients with HER2-positive breast cancer. Summary Combining different anti-HER2-targeted agents represents a promising therapeutic strategy, now reaching clinical practice. There are major clinical challenges yet to be resolved, rising from the increasing number of potential combinations and their mechanisms of resistance. Smartly designed clinical trials are required to address these challenges and perhaps to define a subset of patients that can be spared chemotherapy. Keywords breast cancer, dual antihuman epidermal growth factor receptor 2 blockade, human epidermal growth factor receptor 2 INTRODUCTION Epidermal growth factor receptor 2 [human epider- mal growth factor receptor (HER)2/neu, ErbB2], a type II transmembrane receptor, is a well studied oncogene, orchestrating a plethora of biologic effects, namely tumor cell proliferation, evasion of apoptosis, induction of angiogenesis and metastatic dissemination [1]. HER2 amplification and/or over- expression is reported in approximately 20% of breast cancer patients [2] and is clinically important because it confers an aggressive biologic behavior. Trastuzumab is a humanized monoclonal anti- body targeting domain IV of HER2 with a pleiotrop- ical mode of biologic actions, that is prevention of the shedding of the extracellular part of HER2, induction of antibody-dependent cellular cyto- toxicity (ADCC), activation of adaptive immunity mechanisms, prevention of homodimer formation and inhibition of apoptosis [3]. Its clinical efficacy has been proven in all settings of HER2-positive breast cancer, either as monotherapy or in combi- nation with cytotoxics or other molecularly targeted agents [4]. The success of trastuzumab is based on the dependence of HER2-positive breast cancer cells on HER2, a feature exemplifying oncogene addiction. Institut Jules Bordet, l’Universite ´ Libre de Bruxelles, Brussels, Belgium Correspondence to Evandro de Azambuja, MD, PhD, Medical Director, Br.E.A.S.T. Data Centre, Jules Bordet Institute, Boulevard de Waterloo, 121 (7th Floor), Brussels 1000, Belgium. Tel: +32 (0) 2 541 7244; fax: +32 (0) 2 541 3477; e-mail: Evandro.azambuja@bordet.be Curr Opin Oncol 2012, 24:000–000 DOI:10.1097/CCO.0b013e328358a29a 1040-8746 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-oncology.com REVIEW