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Herceptin

Trastuzumab (Herceptin®) is an anti-cancer therapy that acts on the HER2/neu (erbB2) receptor. "Receptors" are usually protein molecules on the surface of a cell which allow the cell to respond to hormones and other signals from other cells. 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. more...

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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. In cancer growth producing 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 its extracellular segment of the erbB2 receptor. Cells treated with Herceptin undergo arrest during the G1 phase of the cell cycle and experience a reduction in 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 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). In combination with chemotherapy Herceptin 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 on treatment of virtually all patients. It is suggested that a mechanism of resistance is the lack p27Kip1 translocation to the nucleus in some strains, enabling cdk2 to induce cell proliferation (Kute et al., 2004).

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Herceptin Linked to Serious Side Effects, Deaths - Brief Article - Statistical Data Included
From Family Pratice News, 6/15/00 by Elizabeth Mechcatie

Genentech has issued a warning about serious side effects that have been reported in women who have been treated with Herceptin, the monoclonal antibody approved for treating women with metastatic breast cancer.

In a "Dear Doctor" letter, the biotechnology firm said that since Herceptin was marketed in the fall of 1998, there have been 62 reports of serious adverse events related to Herceptin, including 15 fatalities. "These serious adverse events are characterized by one or more of the following categories: hypersensitivity, infusion, and pulmonary reactions," the letter said.

Of these patients, 15 had pulmonary and other side effects and died, including 9 women who developed the symptoms within 24 hours of the Herceptin infusion. Most of the fatalities were in patients with significant preexisting pulmonary compromise. The pulmonary events have included adult respiratory distress syndrome, which had not been previously reported with Herceptin. A boxed warning has been added to Herceptin labeling to reflect these reports.

Most of the adverse events were associated with the first Herceptin dose and usually occurred within 12 hours of the infusion, although some occurred more than 24 hours later, according to Genentech. Since approval, an estimated 25,000 women have received Herceptin worldwide, the letter said.

Herceptin, which is administered in a weekly infusion, was approved in the fall of 1998, for the treatment of women with breast tumors that overexpress the HER-2/neu gene. Herceptin binds to a protein encoded by the HER-2/neu gene, which is over-expressed by the tumors of 25%-30% of women with breast cancer and is associated with more aggressive disease and a poor prognosis. Herceptin's generic name is trastuzumab.

A copy of the Genentech letter can be found at: www.fda.gov/medwatch/safety/2000/safety00.htm#hercep. Adverse reactions to any drug, biologic, or device can be reported directly to the manufacturer or to the FDA' s Medwatch program by contacting the FDA at 800-FDA-1088 (phone), 800-FDA-0178 (fax), or online at wwwfda.gov/medwatch.

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