HER2 / new

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HER2 / new

Existing structural data : 2A91 , 1N8Y , 1N8Z , 1S78 , 1IIJ , 2J1H , 2JWA

Properties of human protein
Mass / length primary structure 1233 amino acids (monomer)
Secondary to quaternary structure Heterodimer; single pass membrane receptor
Identifier
Gene name ERBB2
External IDs
Enzyme classification
EC, category 2.7.10.1 ,  tyrosine kinase
Response type Phosphorylation
Substrate ATP + protein L-tyrosine
Products ADP + protein L-tyrosine phosphate
Orthologue
human House mouse
Entrez 2064 13866
Ensemble ENSG00000141736 ENSMUSG00000062312
UniProt P04626 P70424
Refseq (mRNA) NM_001005862 NM_001003817
Refseq (protein) NP_001005862 NP_001003817
Gene locus Chr 17: 39.69 - 39.73 Mb Chr 11: 98.41 - 98.44 Mb
PubMed search 2064 13866

HER2 / neu ( human epidermal growth factor receptor 2 , official name: ERBB2 , erb-b2 receptor tyrosine kinase 2 ) belongs to the family of epidermal growth factor receptors ( EGF receptors ). HER2 / neu stimulates cell proliferation via the RAS - MAP kinase pathway and inhibits programmed cell death (apoptosis) via the mTOR signal path. In addition to its well-known use in breast cancer, HER2 / neu is also used in the diagnosis and treatment of gastro-oesophageal adenocarcinomas (e.g. gastric carcinoma ).

Therapeutic importance in breast cancer

HER2 / neu plays an important role in the treatment and diagnosis of breast cancer ( breast cancer ). The receptor is highly overexpressed in around 15-30% of all invasive breast cancers . This means that its effect is multiplied, which, up until the development and approval of special antibody therapies in 2000, was expressed in a poor prognosis, that is, with faster tumor growth and faster tumor spread. Immunohistochemical methods can be used to determine whether the course of the disease is influenced by HER2 / neu overexpression. The determination of the detected overexpression is referred to as "HER2-positive". The result is usually expressed in the following scale:

0 = negative, no overexpression
1+ = weak response, no overexpression
2+ = moderately strong reaction, weak overexpression
3+ = strong reaction, strong overexpression

A therapeutic approach resulted from the following consideration: If it were possible to block these receptors with an antibody directed against the HER2 / neu protein, thus keeping the growth-promoting signals away from the cancer cells, then the growth of the cancer cells should be slowed down and stopped.

Trastuzumab

"HER2-positive" patients can therefore benefit from therapy with a humanized antibody trastuzumab (trade name: Herceptin , manufacturer: Roche ) because it is directed against the extracellular part of the HER2 receptor. It blocks it and thus interrupts its intracellular effectiveness. Trastuzumab can also be given in combination with the monoclonal antibody pertuzumab and docetaxel .

Because therapy with the antibody is very expensive, it must be ensured before therapy that an effect can be expected. Before treatment with trastuzumab, immunohistochemistry is used to test whether the HER2 gene is amplified and overexpressed. Only a triple positive result in the immunohistochemical examination of the tumor tissue, in the sense of a particularly clear overexpression, is considered sufficient to establish the indication for therapy with the antibody. In cases of doubt, in-situ hybridization , or more precisely the FISH test, is available as a confirmatory test . Therapy with trastuzumab is carried out according to various protocols, for example over a year with three-weekly dosing, and is generally well tolerated. However, there is the possibility of toxic effects on the heart, which is why regular cardiac ultrasound examinations are carried out to accompany therapy.

Neratinib

The tyrosine kinase inhibitor neratinib (trade name: Nerlynx , manufacturer: Pierre Fabre ) has been approved for the treatment of "HER2-positive" breast cancer in the early stages after an operation in order to reduce the risk of the disease occurring again ( relapse ) since August 2018 . Neratinib is used after treatment with trastuzumab.

Individual evidence

  1. ↑ Symbol report for ERBB2. genenames.org, accessed on April 15, 2019 (english).
  2. ↑ Hudis CA. Trastuzumab - mechanism of action and use in clinical practice. N Engl J Med . 2007 Jul 5; 357 (1): 39-51. PMID 17611206
  3. ↑ Olayioye MA. Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2 / HER-2 and family members. Breast Cancer Res . 2001; 3 (6): 385-9. PMID 11737890 , PMC 138705 (free full text)
  4. Jump up ↑ Y. Bang, H. Chung, J. Xu, F. Lordick, A. Sawaki: Pathological features of advanced gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening program of the ToGA trial . In: Journal of Clinical Oncology . tape 27 , 15_suppl, May 20, 2009, ISSN  0732-183X , p. 4556–4556 , doi : 10.1200 / jco.2009.27.15_suppl.4556 ( ascopubs.org [accessed June 20, 2020]).
  5. ↑ Luca Albarello, Lorenza Pecciarini, Claudio Doglioni: HER2 Testing in Gastric Cancer . In: Advances in Anatomic Pathology . tape 18 , no. 1 , January 2011, ISSN  1072-4109 , p. 53-59 , doi : 10.1097 / PAP.0b013e3182026d72 ( lww.com [accessed June 20, 2020]).
  6. ↑ Hee Eun Lee, Kyoung Un Park, Seol Bong Yoo, Soo Kyung Nam, Do Joong Park: Clinical significance of intratumoral HER2 heterogeneity in gastric cancer . In: European Journal of Cancer . tape 49 , no. 6 , April 1, 2013, ISSN  0959-8049 , p. 1448–1457 , doi : 10.1016 / j.ejca.2012.10.018 ( sciencedirect.com [accessed June 20, 2020]).
  7. ↑ M. Untch et al .: Adjuvant therapy with trastuzumab in breast cancer patients Dtsch Arztebl 2006; 103 (50): A-3406 / B-2961 / C-2841
  8. ↑ Data From Omnitarg Clinical Program Presented at the American Society of Clinical Oncology Meeting. Genentech, accessed August 16, 2014 .
  9. ↑ Penault-Llorca F, Bilous M, Dowsett M, et al. : Emerging technologies for assessing HER2 amplification . In: Am. J. Clin. Pathol. . 132, No. 4, October 2009, pp. 539-48. doi : 10.1309 / AJCPV2I0HGPMGBSQ . PMID 19762531 .
  10. ↑ Stortecky S, Suter TM: Insights into cardiovascular side-effects of modern anticancer therapeutics . In: Curr Opin Oncol . 22, No. 4, July 2010, pp. 312-7. doi : 10.1097 / CCO.0b013e32833ab6f1 . PMID 20535072 .
  11. ↑ Summary of Product Characteristics , EMA EPAR, accessed on October 29, 2019