Trastuzumab

Trastuzumab

File:Trastuzumab.gif
Legal status
Legal status	US: WARNING
Pharmacokinetic data
Elimination half-life	2-12 days
Identifiers
IUPAC name Humanized anti-HER2 antibody
CAS Number	180288-69-1
DrugBank	BTD00098
ECHA InfoCard	100.224.377
Chemical and physical data
Formula	C6470H10012N1726O2013S42
Molar mass	145531.5 g/mol

Trastuzumab (Herceptin®) is an anti-cancer therapy that acts on the HER2/neu (erbB2) receptor. Herceptin's principal use is in breast cancer in patients whose tumors overexpress (produce more than the usual amount of) this receptor. Trastuzumab is administered either once a week or once every three weeks intravenously for 30 to 90 minutes.

Mechanism of action

Amplification of ErbB2 occurs in 30% of early-stage breast cancers (Bange et al 2001). It encodes the transmembrane tyrosine kinase p185-erbB2 glycoprotein. Although the signaling pathways induced by the erbB2 receptor are incompletely characterized, it is thought that activation of the PI3K/Akt pathway is important. This pathway is normally associated with mitogenic signaling involving the MAPK pathway. However in cancer the growth promoting signals from erbB2 are constitutively transmitted---promoting invasion, survival and angiogenesis of cells (Ménard et al 2003). Furthermore overexpression can also confer therapeutic resistance to cancer therapies. Kute et al. (2004) suggest that the prime mechanism that causes increase in proliferation speed is due to induction of p27Kip1, an inhibitor of cdk2 and of cell proliferation, to remain in the cytoplasm instead of translocation in to the nucleus. This is caused by phosphorylation by Akt.

Herceptin is a monoclonal antibody which binds to the extracellular segment of the erbB2 receptor. Cells treated with Herceptin undergo arrest during the G1 phase of the cell cycle so there is reducted proliferation. It has been suggested that Herceptin induces some of its effect by downregulation of erbB2 leading to disruption of receptor dimerization and signaling through the downstream PI3K cascade. P27Kip1 is then not phosphorylated and is able to enter the nucleus and inhibit cdk2 activity, causing cell cycle arrest (Kute et al 2004). Also, Herceptin suppresses angiogenesis by both induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of erbB2 that results in the release of the extracellular domain. Herceptin has been shown to inhibit erbB2 ectodomain cleavage in breast cancer cells (Albenall et al 2003). There may be other undiscovered mechanisms by which Herceptin induces regression in cancer.

Impact

Herceptin has had a "major impact in the treatment of HER2-positive metastatic breast cancer" (Tan and Swain 2002). The combination of Herceptin with chemotherapy has been shown to increase both survival and response rate, in comparison to Herceptin alone (Nahta and Esteva 2003). It is possible to determine the 'erbB2 status' of a tumour, which can be used to predict efficacy of treatment with Herceptin. If it is determined that a tumour is overexpressing the erbB2 oncogene then a patient is eligible for treatment with Herceptin (Yu and Hung 2000). It is surprising that although erbB2 has great affinity for the receptor and the fact that such a high dose can be administered (due to its low toxicity) 70% of patients do not respond to treatment. In fact resistance is developed rapidly by treatment, in virtually all patients. It is suggested that a mechanism of resistance is the lack of p27Kip1 translocation to the nucleus in some strains, enabling cdk2 to induce cell proliferation (Kute et al., 2004).

Some recent clinical trials have found trastuzumab reduces the risk of relapse in breast cancer patients by 50% when given in the adjuvant setting (i.e. after breast cancer surgery, before the cancer has spread any further) for one year (Romond et al and Piccart-Gebhard et al 2005). In one British trial this translated as follows: 9.4% of those on the drug relapsed as opposed to the 17.2% of those not on Herceptin.

There has been some recent debate as to whether these benefits may have been over-stated (e.g., Littlejohn 2006).

Side effects

One of the significant complications of trastuzumab is its effect on the heart. Trastuzumab is associated with cardiac dysfunction in 2-7% of cases. The risk of cardiomyopathy is increased when trastuzumab is combined with anthracycline chemotherapy (which itself is associated with cardiac toxicity).

History

The biotech company Genentech gained FDA approval for trastuzumab in September 1998. The drug was jointly developed by that company, where the antibody was first discovered by scientists that included Dr Axel Ullrich, and the Jonsson Cancer Center at UCLA, where Dr Dennis Slamon subsequently worked further on trastuzumab's development.

In the clinical trials leading up to trastuzumab's approval 42% of patients taking trastuzumab in combination with the chemotherapy drug paclitaxel had significant responses. The comparable rate for the taxane alone was only 16%.

Costs

Recently there has been controversy in New Zealand and the UK about supplying this drug on the NHS due to its high cost and perceived limited benefit based on the complexity of screening requirements. The campaign waged by cancer victims to get the governments to pay for their treatment has gone to the highest levels in the courts and the cabinet [1] to get it licensed against the judgement of the regulator[2].

Few reporters have questioned the pricing of this drug, but when asked Genetech refuses to give details to explain the high costs[3].

References

• Albanell J, Codony J, Rovira A, Mellado B, Gascon P. (2003). "Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4". Advances in Experimental Medicine and Biology. 532: 253–268. PMID 12908564.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Bange J, Zwick E, Ullrich A. (2001). "Molecular targets for breast cancer therapy and prevention". Nature Medicine. 7: 548–552. PMID 11329054.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Kute T, Lack CM, Willingham M, Bishwokama B, Williams H, Barrett K, Mitchell T, Vaughn JP (2004). "Development of Herceptin resistance in breast cancer cells". Cytometry. 57A: 86–93. PMID 14750129.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Littlejohns P. (2006). "Trastuzumab for early breast cancer: evolution or revolution?". Lancet Oncology. 7 (1): 22–23. PMID: 16408378
• Ménard S, Pupa SM, Campiglio M, Tagliabue E (2003). "Biologic and therapeutic role of HER2 in cancer". Oncogene. 22: 6570–6578. PMID 14528282.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Nahta R, Esteva1 FJ (2003). "HER-2-Targeted Therapy – Lessons Learned and Future Directions". Clinical Cancer Research. 9: 5078–5048. PMID 14613984.{{cite journal}}: CS1 maint: numeric names: authors list (link)
• Piccart-Gebhart MJ, Procter M, Leyland-Jones B; et al. (2005). "Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer". New England Journal of Medicine. 353: 1659–1672. PMID 16236737. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Romond EH, Perez EA, Bryant J; et al. (2005). "Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer". New England Journal of Medicine. 353: 1673–1684. PMID 16236738. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Tan AR, Swain SM (2002). "Ongoing adjuvant trials with trastuzumab in breast cancer". Seminars in Oncology. 30 (5 Suppl 16): 54–64. PMID 14613027.
• Yu D, Hung M (2000). "Overexpression of ErbB2 in cancer and ErbB2-targeting strategies". Oncogene. 19: 6115–6121. PMID 11156524.

Further reading

• Bazell, Robert. Her-2: the making of Herceptin, a revolutionary treatment for breast cancer. Random House, 1998. 214 pages. ISBN 067945702X.
• The Guardian. The selling of a wonder drug. 29th March 2006

External links

• Herceptin (manufacturer's website)
• Trastuzumab (patient information)
• Reports of New Herceptin Risks