Trastuzumab

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Compound Name:TrastuzumabMolecular Target:c-erbB2/HER2Molecular Structure:humanized receptor antagonistLicensed Indication:HER2 overexpressing breast cancerManufacturer and/or Distributor:GenentechInitial FDA Approval:1998Summary:Trastuzumab (Herceptin) is a humanized recombinant IgG1k monoclonal antibody targeted at the extracellular domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2, also known as Neu, c-erbB2, CD340 or p185). HER2 is a transmembrane receptor protein, which is overexpressed in some malignancies, including about 25% of breast cancers and perhaps a somewhat smaller percentage of gastric carcinomas. Trastuzumab is administered by intravenous infusion every 1 or 3 weeks, depending on the indication. Herceptin was FDA approved for the treatment of HER2-positive breast cancer in 1998. In combination with chemotherapy for treatment of metastatic disease, trastuzumab has been reported to prolong survival. Adding trastuzumab to chemotherapy significantly improved the overall and disease-free survival of a combined 4046 patients with early HER2-positive breast cancer. It can also be used as adjuvant treatment, where it has been shown to prolong disease-free survival. In 2010, an indication was added for HER2-positive, metastatic, gastric or gastroesophageal junction adenocarcinoma, where an improvement in survival was found. Significant safety concerns are cardiac and pulmonary toxicity, infusion reactions, neutropenia, and embryo-fetal toxicity. Trastuzumab is being studied for possible use in other cancers, including lung, other GI, and genitourinary.References

Package Insert: http://www.gene.com/gene/products/information/pdf/herceptin-prescribing.pdf  

1. Pegram M, Slamon D. Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. Semin Oncol. 2000 Oct;27(5 Suppl 9):13-19.  http://www.ncbi.nlm.nih.gov/pubmed/11049052 

2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-792.  http://www.ncbi.nlm.nih.gov/pubmed/11248153

3. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-1672. http://www.ncbi.nlm.nih.gov/pubmed/16236737

4. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012 Jan;9(1):16-32.  http://www.ncbi.nlm.nih.gov/pubmed/22124364 

5. Sengupta PP, Northfelt DW, Gentile F, Zamorano JL, Khandheria BK. Trastuzumab-induced cardiotoxicity: heart failure at the crossroads. Mayo Clin Proc. 2008 Feb;83(2):197-203.  http://www.ncbi.nlm.nih.gov/pubmed/18241629  

6. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer. 2007;7:153.  http://www.ncbi.nlm.nih.gov/pubmed/17686164 

7. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. 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, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-697.  http://www.ncbi.nlm.nih.gov/pubmed/20728210   

8. Funakoshi T, Suzuki M, Muss HB. Infection risk in breast cancer patients treated with trastuzumab: a systematic review and meta-analysis. Breast Cancer Res Treat. 2014 Nov 11. http://www.ncbi.nlm.nih.gov/pubmed/25385179

9. Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annual review of medicine. 2015;66:111-128. http://www.ncbi.nlm.nih.gov/pubmed/25587647

10. Perez EA, Barrios C, Eiermann W, Toi M, Im YH et al. Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol. 2017 Jan 10;35(2):141-148. https://www.ncbi.nlm.nih.gov/pubmed/28155054

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