![]() This drug has European approval for use in combination with docetaxel and trastuzumab for the treatment of patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. Pertuzumab is monoclonal antibody that binds to extracellular domain of HER2 inhibiting its activation. 12-14 Lapatinib has European approval for the treatment of HER2-positive breast cancer, used in combination with capecitabine for patients with advanced or metastatic disease that have progressed on prior chemotherapy or trastuzumab, in combination with trastuzumab for patients with hormone receptor-negative metastatic disease that have progressed on prior trastuzumab therapies in combination with chemotherapy, or in combination with an aromatase inhibitor for postmenopausal women with hormone receptor-positive metastatic disease. Lapatinib is a small molecule inhibitor of the kinase activity of HER2 and EGFR that has demonstrated clinical benefit as monotherapy or in combination with chemotherapy or trastuzumab in patients with HER2-positive metastatic breast cancer. ![]() 8-10 Long-term follow-up of two randomised trials demonstrated that adjuvant trastuzumab sustains both a significant disease free and overall survival benefit compared with chemotherapy alone. Trastuzumab has European approval for the treatment of early-stage and metastatic HER2-positive breast cancer based on clinical trials that have demonstrated improved response rates, and reduced risk of recurrence and mortality when this drug is used as monotherapy or in combination with chemotherapy in early stage and metastatic breast cancer expressing HER2. Trastuzumab is a humanized monoclonal antibody that targets the extracellular domain of HER2, blocking its activation, and has demonstrated significant survival benefit when used first line or in an adjuvant setting in patients with HER2-positive tumours. HER2-positivity is also associated with greater response to chemotherapeutic agents including anthracyclines and taxanes and with poorer response to endocrine therapies. HER2 is an important predictive biomarker of response to HER2-targeted therapies, including trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). 7 HER2 as a Predictive Biomarker in Breast Cancer 6 HER2 overexpression/amplification has also been associated with poorer outcomes in node-negative breast cancer patients. 5 Many subsequent studies have confirmed this link with poor prognosis and demonstrated an association of HER2-positivity with high grade tumours, lymph node involvement, and a higher rate of disease recurrence and mortality. The potential of HER2 as a prognostic biomarker in breast cancer was first reported in 1987, with its amplification associated with reduced time to progression and reduced overall survival. HER2 as a Prognostic Biomarker in Breast Cancer ![]() 1ĭiscovery of the HER2 oncogene led to the development of one of the first approved humanised monoclonal antibody-based targeted therapy, trastuzumab, revolutionising breast cancer management. 4,5 Amplification of the gene leads to high-level expression driving the basal level of HER2 activity above a threshold that can stimulate tumour growth. 3 Overexpression of HER2 in breast cancer occurs predominantly through amplification of the HER2 gene and is associated with a more aggressive phenotype. Oncogenic HER2 is overexpressed in 15-20% of primary breast cancers 2 and in approximately 10% of ER-positive breast cancers. 1 This constitutive activation of HER2 leads to un-regulated activation of the PI3K/AKT/mTOR and MAPK pathways, which promotes uncontrolled cell proliferation, evasion of apoptosis, angiogenesis, and invasion, leading to tumour growth and progression. HER2 acts as an oncogene in breast cancer, its overexpression resulting in ligand-independent dimerisation which leads to constitutive activation of its cytoplasmic kinase domain. In normal cells, activation of HER2 via homo- or hetero-dimerisation mediates cell signalling pathways including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways, which regulate cellular processes of proliferation, motility and survival. It is a member of the epidermal growth factor receptor (EGFR) family, which includes also EGFR (HER1), HER3, and HER4. The human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor tyrosine kinase located on chromosome 17q21.
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