Trastuzumab

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Trastuzumab
Mass / length primary structure 145.5  kDa
Identifier
External IDs
Drug information
ATC code L01 XC03
DrugBank DB00072
Drug class Cytostatic , monoclonal antibody

Trastuzumab ( trade name Herceptin ® , manufacturer Roche ) is a humanized monoclonal antibody that is used as a drug in certain forms of breast cancer and gastric cancer .

Trastuzumab binds to the epidermal growth factor receptor HER2 / neu (Human Epidermal Growth Factor Receptor) on the cell surface of cancer cells , which inhibits their growth.

history

Trastuzumab was founded in 1998 in the United States and 2000 in the European Union for patients with metastatic breast cancer with a overexpression of ERBB2 (HER2 / neu) admitted. Such an increased formation of HER2 / neu occurs in about every fourth breast cancer patient. Dennis J. Slamon and Axel Ullrich , who at the time were basic researchers at the biotech company Genentech , played a key role in the development of trastuzumab . Several studies have shown that trastuzumab significantly reduces the risk of relapse even when given as an adjuvant, ie in women with HER2-positive breast cancer who do not have metastases. Use for this indication has been approved in Europe since May 2006.

In January 2010, approval was extended to the treatment of metastatic HER2-positive gastric cancer , with trastuzumab being administered in combination with capecitabine or 5-fluorouracil and cisplatin . The survival advantage with trastuzumab therapy only existed in a few weeks. Given the cost of the drug, its use in gastric cancer is viewed critically.

Slamon's life and his efforts to research the HER2 / neu receptor and the possibility of treatment with Herceptin were filmed in the 2008 television film Living proof with Harry Connick junior in the lead role.

therapy

Before initiating trastuzumab therapy, the HER2 status is determined from a tissue sample in the laboratory. Evidence of HER2 overexpression is mandatory. The therapy usually takes place in combination with other drugs.

Mechanism of action

Trastuzumab binds to the growth factor receptor HER2 from the outside of the cell. This leads to the inhibition of tumor cell proliferation as a result of apoptosis or antibody-dependent destruction of the tumor cells by the immune system . As mechanisms of action primarily four mechanisms are discussed: the recruitment of immune cells , inhibition of intracellular signal transduction, inhibition of proteolytic cleavage of HER2 and anti- angiogenic effect.

In addition to this desirable effect on cancer cells, reversible damage to the heart muscle can occur in less than 4% of cases , the mechanism of which is still unclear. Therefore, the cardiac function in patients who are eligible for trastuzumab therapy is constantly monitored both before the start of treatment and during treatment. Treatment of patients with heart failure must be carefully considered.

administration

Trastuzumab is usually given as an infusion over 30 to 90 minutes once a week . Trastuzumab has also been approved for three-week therapy since 2006. The duration of therapy with adjuvant administration is twelve months; In patients with metastases, the therapy is continued at least until the tumor recurs.

However, trastuzumab can also be used in combination with pertuzumab and docetaxel in the treatment of HER2-positive breast cancer .

Trastuzumab emtansine

Trastuzumab emtansine: The maytansinoid DM1, bound to the monoclonal antibody trastuzumab (mab). The part in which DM1 differs from its parent compound maytansine is shown in red and the linker SMCC is shown in blue.

The antibody-drug conjugate trastuzumab-emtansine (T-DM1, trade name Kadcyla ) has been approved for the treatment of patients with HER2-positive (overexpressing human epidermal growth factor receptor 2), inoperable, locally advanced or metastatic breast cancer since November 2013 . It contains the maytansinoid DM1, a microtubule inhibitor that is linked to the antibody via a linker. In April 2014, the Institute for Quality and Efficiency in Health Care (IQWiG) certified that the antibody-drug conjugate had significant additional benefits . The KATHERINE study examined whether trastuzumab emtansine improves the prognosis of Her2-positive breast cancer if tumor residues remained after neoadjuvant (treatment before surgery) treatment with a taxane and trastuzumab. It is known that breast cancer patients whose tumor does not regress adequately through neoadjuvant treatment have a poor prognosis. In this phase III study, the postoperative administration of 14 cycles of T-DM1 was able to reduce the risk of tumor recurrence or death by 50% compared to therapy with trastuzumab. However, the rate of side effects, especially thrombopenia and hypertension , was higher with T-DM1 than with trastuzumab.

See also

Individual evidence

  1. ↑ YJ Bang, E. Van Cutsem, A. Feyereislova, HC Chung, L. Shen: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. In: The Lancet . Aug 19, 2010. PMID 20728210 .
  2. ↑ Living Proof in the Internet Movie Database (English)
  3. ↑ Kadcyla - trastuzumab emtansine , European Public Assessment Report (EPAR) and product information for Kadcyla on the website of the European Medicines Agency (EMA) , accessed on April 1, 2014.
  4. ↑ ado-trastuzumab emtansine. Retrieved March 21, 2015 .
  5. ↑ Trastuzumab emtansine: Indication of considerable additional benefit in metastatic breast cancer with anthracycline pretreatment , PM of IQWiG dated April 1, 2014, accessed on April 1, 2014.
  6. ↑ Gunter von Minckwitz, Chiun-Sheng Huang, Max S Mano, Sibylle Loibl, Eleftherios P ​​Mamounas: Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer . In: The New England Journal of Medicine . tape 380 , no. 7 , 2019, pp. 617-628 , doi : 10.1056 / NEJMoa1814017 , PMID 30516102 .
  7. ↑ Michael Untch, Peter A Fasching, Gottfried E Konecny, Stephan Hasmüller, Annette Lebeau: Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups . In: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology . tape 29 , no. 25 , September 1, 2011, p. 3351-3357 , doi : 10.1200 / JCO.2010.31.4930 , PMID 21788566 .

literature

  • M. Untch et al.: Adjuvant therapy with trastuzumab in breast cancer patients . In: Dtsch Arztebl. 103 (50), 2006, pp. A-3406 / B-2961 / C-2841
  • GA Viani, SL Afonso, EJ Stefano, LI De Fendi, FV Soares: Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. Review. In: BMC Cancer . 7, 8 Aug 2007, p. 153. PMID 17686164 , PMC 1959236 (free full text)
  • Robert Bazell: Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer , Random House 1998

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