Abstract
The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for women with early-stage and advanced HER2-positive breast cancer (BC).HER-2 targeted therapies represent a major step forward in achieving the goal of delivering individualized targeted therapy for BC, and trastuzumab was the first anti-HER-2 strategy to be approved for treatment of HER-2 positive BC.This review discusses the treatment of metastatic HER2-positive BC and describes efficacy and safety of novel anti-HER2 target therapies in first-line metastatic settings and the future challenges include refining such treatments, reducing toxicity and simultaneously developing innovative therapies. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.In the next future will be possible to use an ample armamentarium of combination therapies directed against HER2 and key signaling components integrated in the HER network. This approach will allow clinicians to tailor the management of the individual patient on the basis of tumor- specific biomarker profiles.There is an urgent need for prospective biomarker-driven trials to identify patients for whom targeting is cost-effective.
Highlights
About 20 % of invasive breast cancers (BC) are HER2positive and characterized by amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2), a transmembrane receptor with tyrosine kinase (TK) activity, resulting in HER2 gene amplification on chromosome 17
Trastuzumab, a humanized monoclonal antibody that selectively binds to the HER2 on the surface of tumour cells, when added to chemotherapy in the first-line advanced treatment of HER2-positive BC is associated with a significantly reduced risk of progression and death compared to chemotherapy alone [12,13,14,15,16]
With regard to the management of advanced HER2positive BC, trastuzumab, pertuzumab, trastuzumab emtansine and lapatinib are approved as standard care for inhibiting HER2 activity in the treatment of HER2 positive metastatic BC (MBC) and for increasing the incidence of progression free survival (PFS), overall survival (OS) and overall response rate (ORr) when compared with chemotherapy alone or standard anti-HER2 molecule [26,27,28, 29,30,31]
Summary
About 20 % of invasive breast cancers (BC) are HER2positive and characterized by amplification and/or overexpression of HER2, a transmembrane receptor with tyrosine kinase (TK) activity, resulting in HER2 gene amplification on chromosome 17. With regard to the management of advanced HER2positive BC, trastuzumab, pertuzumab, trastuzumab emtansine (formerly known as T-DM1) and lapatinib are approved as standard care for inhibiting HER2 activity in the treatment of HER2 positive MBC and for increasing the incidence of PFS, OS and overall response rate (ORr) when compared with chemotherapy alone or standard anti-HER2 molecule [26,27,28, 29,30,31]. In the intent-to-treat population who received a median of three prior trastuzumabcontaining regimens, the combination of lapatinib with trastuzumab versus lapatinib alone significantly improved PFS (HR: 0.73; 95 % CI: 0.57-0.93; P =0.008) and clinical benefit rate (25 % in the combination arm versus 12 % in the monotherapy arm; p = 0.01), offering a chemotherapy-free option with an acceptable safety profile to patients with HER2positive MBC. An important challenge is the prevention of CNS metastases in HER2 positive metastatic disease For the first time, in the recent CEREBEL study [58] patients with HER2- positive MBC without brain metastases were randomized to compare trastuzumab-capecitabine versus lapatinib-capecitabine in order to evaluate the incidence of CNS metastases as first site of relapse
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