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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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Trastuzumab for Metastatic Breast Cancer - Herceptin
From American Family Physician, 10/15/01 by Bill Zepf

Trastuzumab is not the first monoclonal antibody to be used as an anti-tumor agent, but it may be the most publicized. In about one third of breast cancers, the human epidermal growth factor receptor (HER2) gene is overexpressed, which encodes the growth factor receptor that is targeted by trastuzumab. Given the current modest beneficial effects of standard chemotherapy in patients with metastatic breast cancer, any agent that can improve survival in even a small portion of patients is eagerly anticipated. Phase I and II trials of trastuzumab have already shown some benefits. Slamon and colleagues report the results of a larger, randomized phase III trial of usual chemotherapy versus chemotherapy plus trastuzumab in patients with metastatic breast cancer.

Women with overexpression of the HER2 receptor were identified by immunohistochemical staining of tumor specimens. A total of 469 women were enrolled in the study. The trastuzumab group was followed for a median length of 40 weeks. Because of their decreased survival, follow-up was shorter in the usual chemotherapy group (median length: 25 weeks).

The usual chemotherapy consisted of an anthracycline (e.g., doxorubicin) plus cyclophosphamide, or paclitaxel alone in patients who had already received an anthracycline earlier in the course of their breast cancer treatment. Patients who were randomly assigned to the trastuzumab group received an intravenous loading dose and then smaller infusions until there was evidence of disease progression. In any patient with disease progression during the study, an option to enter an open-label study of trastuzumab was offered; two thirds of such patients elected to transfer.

Several benefits were noted in patients who received trastuzumab in addition to usual chemotherapy. Median survival increased from 20.3 to 25.1 months, there was a higher rate of overall response and a longer duration of response. Trastuzumab use was also associated with a longer time to disease progression, a significantly lower death rate at one year and a 20 percent reduction in the risk of death. Patients with a higher degree of HER2 overexpression benefited more from the addition of trastuzumab.

The most significant adverse effect identified in patients who received trastuzumab was an increased incidence of cardiotoxicity. The highest rate of cardiac dysfunction (27 percent) occurred in the subgroup that received trastuzumab, cyclophosphamide and an anthracycline. Although cardiotoxicity could be severe and possibly life-threatening, symptoms generally improved with standard medical care. The possibility of this side effect should be weighed against trastuzumab's potential clinical benefit.

The authors concluded that, when added to conventional chemotherapy, trastuzumab improved survival for the subset of metastatic breast cancer patients that overexpresses the HER2 gene.

COPYRIGHT 2001 American Academy of Family Physicians
COPYRIGHT 2001 Gale Group

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