Approximately 20%–25% of patients with breast cancer demonstrate amplification of the human epidermal receptor type 2 (HER2) gene, resulting in an overexpression of the HER2 receptor. This overexpression is associated with aggressive disease, relatively poor prognosis, and worse clinical outcomes. Neoadjuvant therapy is the standard treatment in patients with locally advanced, inflammatory, or inoperable primary breast cancer. It is generally used to downstage the tumors and therefore to improve surgical options including breast-conserving surgery rather than mastectomy. It has been confirmed that patients with pathological complete response (pCR) to neoadjuvant treatment have better disease-free survival (DFS) and overall survival (OS). Neoadjuvant treatment can also serve as in vivo test of sensitivity to the used therapeutic regimen. The preferred neoadjuvant approach to patients with HER2-positive breast cancer is a sequential anthracycline-taxane-based chemotherapy in combination with trastuzumab. Addition of other anti-HER2 agents has increased pCR rate up to 75% and will probably become a new therapeutic direction. In the first part of this paper, we summarize the information about HER2-positive breast cancer, the various treatment possibilities, and the results of the major neoadjuvant trials. The second part focuses on the data concerning the importance of pCR and the potential risk of cardiotoxicity associated with this treatment. 1. Introduction HER2 belongs to the epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases. This family consists of four receptors—HER1, HER2, HER3, and HER4—which are involved in regulating cell growth, survival, and differentiation. HER receptors are inactive monomers, and to activate signaling pathways, they have to undergo dimerization. Pairing among the molecules of the same HER receptor is called homodimerization; pairing of different HER receptor subtypes is called heterodimerization. HER dimerization leads to activation of two important signaling pathways—PI3K/Akt and Ras/Raf/MEK/MAPK [1]. HER2 is always in active conformation and it is a preffered partner for other HER receptors, especially HER3 and the HER2-HER3 dimer is an important oncogenic unit that signals constitutively to PI3K and Akt [2]. All breast cancers should be evaluated for HER2 overexpression. HER2 testing can be done by targeting protein and gene. The most widely used methods to detect HER2 amplification are immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH). Amplification or overexpression of
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