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Etanercept Has Potential For Treating Metastatic Breast Cancer: Presented at AACR-NCI-EORTC

By Paula Moyer

BOSTON, MA -- November 24, 2003 -- The recombinant tumour necrosis factor-alpha (TNF-alpha) inhibitor etanercept (Enbrel) is showing feasibility in treating metastatic breast cancer, according to British researchers presenting here on November 19^th at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

"Targeting TNF-alpha is an ongoing project in our institution to see if this is a clinically valid approach," said Srinivasan Madhusudan, MBBS, Imperial Cancer Research Fund, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, United Kingdom. "We saw favourable toxicity and a biological response against interleukin-6 and CD-8."

Etanercept is approved for the treatment of several autoimmune disorders, such as rheumatoid arthritis.

The investigators were interested in etanercept's potential as a breast-cancer therapy because of its role against TNF-alpha. TNF-alpha is important in the pathogenesis of breast cancer for several reasons, particularly its production of the cytokine monocyte chemoattractant protein (MCP-1) and its role in stimulating the production of pro-angiogenic factors such as vascular endothelial growth factor, interleukin-6 (IL-6), and thymidine phosphorylase. By binding to TNF-alpha, etanercept renders it biologically unavailable, Mr. Madhusudan explained.

In this phase II, consecutive, open-labelled study, Mr. Madhusudan and co-investigators recruited 16 patients with progressive metastatic breast cancer that had not responded to conventional therapy. The investigative team wanted to determine etanercept's toxicity, tumour response, and biological activity in this patient population. At the time of their cancer diagnosis, the patients were a median of 53 years old, with a range of 34 to 74 years. At the time of enrolment, the Eastern Cooperative Oncology Group performance status was 0 for 3 patients and 1 for 13 patients.

Patients received the treatment by subcutaneous injection at a dose of 25 mg twice weekly until the investigators documented a progression in their disease. The patients received a total of 141.6 weeks of therapy with a median treatment duration of 8.1 weeks. For 7 patients, the duration of treatment was 12 weeks; for 9 patients, the treatment lasted less than 12 weeks.

Mr. Madhusudan said that the patients tolerated treatment well, and that the investigators documented no treatment-related deaths or serious infections. The most commonly reported adverse effects consisted of injection-site reactions in 6 patients, fatigue in 5, and loss of appetite in 2. One patient each experienced nausea, headache, and dizziness.

The laboratory assessments showed that patients developed an elevated immunoreactive TNF-alpha within 24 hours after therapy was initiated. This response persisted throughout the treatment period. A cytokine-release assay also assessed the level of phytohaemagglutinnin, which stimulates the production of IL-6 and MCP-1 in the peripheral blood. This assessment showed a statistically significant decrease in MCP-1 at days 56 and 84 (P = .01). The investigators also saw a consistent decrease in IL-6.

The investigators documented a brief period of disease stabilisation lasting 16.4 weeks in 1 patient. The patient, who had liver metastasis, also experienced minor regression of her disease.

As a result of these findings, Mr. Madhusudan said that he and his co-investigators will test the treatment either on patients with less advanced disease or in combination with chemotherapy.


[Study Title: A phase II trial of etanercept, a recombinant human soluble tumour necrosis factor receptor (p75) fusion protein in patients with metastatic breast cancer. Abstract B228]

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