7.1 Anti-HER-2 Targeted Therapy
According to the latest National Cancer Report of 2019 released by the National Cancer Center in January 2019，lung cancer，colorectal cancer and female breast cancer are still the main malignant tumors in China，and breast cancer accounts for the first place in women's disease whose incidence has about 30.4 million people.Her-2 positive breast cancer in breast cancer accounts for 20%to 30%of the total number of breast cancers.It has always been called“the most dangerous”breast cancer.Especially her-2+breast cancer progresses fast and relapses easily.Metastasis and poor prognosis can be combined with triple-negative breast cancer.
In recent years，there have been many milestones in the systematic treatment of breast cancer，especially the use of anti-HER-2 targeted drugs has significantly improved the prognosis of HER-2 positive breast cancer patients.The main reason for rapid treatment progress is the biological behavior of breast cancer.The targeting of HER-2 drugs has made great achievements in the treatment of advanced and early breast cancer.This chapter mainly discusses anti-HER-2 adjuvant therapy for HER-2 positive early breast cancer..
Since 1984，American scholars first discovered the HER2 gene of breast cancer，the importance of HER2 pathway in the occurrence and development of breast cancer has gradually been recognized.Blocking the HER2 signaling pathway has become the main strategy for targeted therapy research.Her2 is a family of tyrosine.The acid kinase-active transmembrane receptor glycoprotein is widely present in tissues such as the stomach，breast，intestine，and respiratory tract.Its overexpression promotes cell proliferation，which is closely related to the occurrence and development of tumors，and plays a role in the formation of tumors.
The human ErbB receptor belongs to the type I receptor tyrosine kinase（TK）family.These include ErbB1（EGFR），ErbB2（HER2），ErbB3（HER3），and ErbB4（HER4）.The structure of HER-2 includes the binding region of extracellular growth factors，the transmembrane region of light lipids，and the intracellular region with regulatory hydroxyl-terminal fragments.Cancer patients'ErbB-1（EGFR）and ErbB-2（HER-2）receptors are often overexpressed or otherwise altered.It is known that human epidermal growth factor receptor-2（ErbB-2，HER-2）is a well-understood human oncogene closely related to breast cancer，and its high expression in breast cancer often indicates easy lymph node.Metastasis and poor tumor differentiation，poor prognosis.(https://www.daowen.com)
The HER-2 mediated signaling pathway is a complex network system that includes an input layer，an information processing layer，and an output layer.At present，there are four major HER-2 intracellular signaling pathways，namely Ras/MAPK（mitogen-activated protein kinase），PI3K/PKB（phosphatidylinositol-3-kinase/protein kinase B），PLC-PKC（phospholipase C-protein kinase C）and STAT（signal transduction and transcriptional activator）pathways.Under the influence of various factors，HER-2 overexpression or amplification can promote the occurrence，development and malignant transformation of tumors.The intracellular domain of the HER-2 receptor has protein tyrosine kinase（PTK）activity and itself has a phosphorylation site for the tyrosine（Tyr）residue.When the growth factor binds to HER-1，HER-3 or HER-4，it induces a conformational change in the outer membrane region of the protein，and forms a heterodimer with the HER-2 molecule，resulting in a significant increase in the PTK activity inside the cell membrane and a receptor molecule.Tyr catalyzes autophosphorylation with each other；at the same time，p185 itself Tyr phosphorylates，which is recognized and specifically bound by a series of downstream signaling proteins，which in turn triggers a cascade-like chain reaction signal.Signal transduction through the cell membrane and interstitial cells，nucleus，and activators，and finally increase the transcription levels of early nuclear reaction genes such as c-fos and c-jun，promote mitosis，etc.，cause cell proliferation，differentiation，migration，and thus induce tumors.
A number of studies have shown that HER-2 is an important prognostic factor for breast cancer.Patients with HER-2 gene amplification or overexpression have poor prognosis，short disease-free survival and overall survival，and HER-2 is predictable.The biological indicators of certain therapeutic responses，HER-2 gene amplification or overexpression suggest that tumors have lower response to endocrine therapy and cmf regimen，but are more sensitive to anthracycline chemotherapy.Of course，HER-2 status，For the anti-HER-2 targeted therapy has direct guiding significance，the presence of HER-2 gene amplification or overexpression is the adaptation of anti-HER-2 targeted therapy.
According to the molecular mechanism，the drugs targeting HER2 are mainly divided into three categories：the first category is monoclonal antibodies，including trastuzumab and pertuzumab，which are specific to the extracellular region Ⅳ or Ⅱ of the HER2 receptor，respectively.Binding，inhibits HER2 receptor activation；Class 2 is a small molecule tyrosine kinase inhibitor，representing the drug lapatinib，which reversibly interacts with the epidermal growth factor receptor（EGFR）and HER2 receptor tyrosine kinase regions.The adenosine triphosphate（ATP）site binds to inhibit its tyrosine kinase activity；the third class of drugs is a conjugate of a monoclonal antibody and a chemotherapeutic drug，and the drug is an antibody-conjugated drug trastuzumab-emtansine（T-DM1）which is a combination of trastuzumab and anti-tubulin chemotherapeutic drugs through disulfide bonds.It has both a targeting effect and a chemotherapy effect.It can selectively bring chemotherapeutic drugs into cancer cells and enhance cancer cell death.Induction of death.