Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology-College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER-1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.
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PMID:The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. 2696 27

The approval of trastuzumab for use in metastatic breast cancer marked a breakthrough in the understanding of the biology of the disease. However, like most cancer therapies, the disease finds a way to advance despite the treatments developed to eradicate it. Although trastuzumab has had a large effect on the treatment of early and advanced-stage disease, a substantial proportion of patients with HER2-positive breast cancer still progress after receiving the drug. Potential mechanisms of resistance to trastuzumab include bypass mechanisms, mutations of the HER2 target, masking of HER2 proteins, inhibition of insulin-like growth factor, and phosphatase and tensin homologue (PTEN) deficiency. Many therapies are being developed to target these mechanisms in patients with HER2-positive, trastuzumab-resistant breast cancer. Additionally, treatment strategies other than trastuzumab with unique mechanisms of action are being assessed in this specific group of patients. In this review, we discuss the emerging data assessing therapeutic approaches in the management of trastuzumab-resistant HER2-positive disease.
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PMID:Evolving novel anti-HER2 strategies. 2020 10

Human epidermal growth factor receptor 2-positive (HER2+) breast cancers, which account for 25%-30% of breast cancers, are characterized by an aggressive course and a high propensity for recurrence in the 4 years following diagnosis. The use of trastuzumab-based chemotherapy in the adjuvant setting has markedly improved the outcome for patients with early stage HER2+ breast cancer. Likewise the use of trastuzumab in combination with chemotherapy in patients with metastatic HER2+ breast cancers has prolonged survival, with current expected median survival of about 3 years. Despite these major improvements in outcome, approximately 10% of patients develop a distant recurrence following adjuvant trastuzumab-based chemotherapy, and all patients with metastatic disease eventually develop disease progression. Known mechanisms of resistance to trastuzumab include increased signaling through upstream growth factors, phosphatase and tensin (PTEN) deficiency and alterations of the HER2 receptor. Many of these mechanisms are being targeted in the clinic in an attempt to improve outcome for patients with HER2+ breast cancers. The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in trastuzumab-resistance, through these and other mechanisms, and represents a logical target for drug development for trastuzumab-resistant breast cancers. The use of mammalian target of rapamycin (mTOR) inhibition has been demonstrated to potentially reverse resistance to trastuzumab in patients with HER2+, metastatic breast cancers. Phase I and II trials have produced encouraging results when the mTOR inhibitor, everolimus, was combined with trastuzumab with or without chemotherapy, in patients with trastuzumab-resistant HER2+ metastatic breast cancer. These results are being confirmed in ongoing phase III trials in the first-line and trastuzumab-resistant settings. The mechanism of how mTOR inhibitors reverse resistance to trastuzumab remains largely unexplained. Other agents targeting the PI3K pathway in trastuzumab-resistant breast cancers are in early phase clinical trials.
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PMID:Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. 2111 25