Since 2005, major progresses have been made in the neoadjuvant treatment of HER2-positive breast cancer. Trastuzumab introduction associated with chemotherapy has been the first major step leading to the improvement of the complete pathological response rate and, like in the adjuvant studies, better survivals. Dual HER2 blockade has been the next step and trastuzumab is associated now with other anti-HER2 therapies like lapatinib or pertuzumab, the latter being much more easy to use in combination with chemotherapy. Additional knowledge is necessary to better define within the HER2 tumor subgroup which patients could benefit more from targeted therapies. Different biomarkers have been studied to predict the response after anti-HER2 neoadjuvant therapies but until now none has been validated. 1. Introduction Neoadjuvant chemotherapy in breast cancer treatment is now recognized as a standard care to increase conservative surgery [1, 2]. Its utility is also documented in inflammatory or locally advanced tumors [3]. Long-term results of neoadjuvant chemotherapy are equivalent to those obtained with adjuvant chemotherapy if locoregional treatments are fully applied [1, 2]. In HER2-positive breast cancer, randomized studies with and without anthracyclines have demonstrated the essential role of anti-HER2 therapies in obtaining increased pathological complete response rates and good long-term results. 2. Neoadjuvant Anti-HER2 Therapies and Their Impact on the Pathological Complete Response Rate 2.1. Trastuzumab Several randomized trials have evaluated, in the neoadjuvant setting, the role of trastuzumab (Herceptin, Roche laboratory), a recombinant humanized monoclonal antibody that targets HER2 receptor. The first randomized trial in patients with operable noninflammatory disease was stopped early when the pathological complete response (pCR) rate in the trastuzumab group was more than twice as high as that of the control group (65% versus 26%) [4, 5]. The pCR rates in the following studies varied between 26% and 40% in the trastuzumab arms [6–9]. These differences can be explained by various inclusion criteria, different type, and different duration of the regimens. Nonetheless, all the studies showed a higher pCR rate when trastuzumab was combined with chemotherapy compared to chemotherapy alone (Table 1). In the ABCSG-24 study, 536 patients were randomized to receive either 6 cycles of EDC (epirubicin, docetaxel, and capecitabine) or 6 cycles of ED (epirubicin, Docetaxel) [7]. Patients with HER2-positive tumors were also randomized to receive trastuzumab or
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