HER2 in Breast Cancer - Anti-HER2 Therapy

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HER2 in Breast Cancer--What Does it Mean?
[Nursing Treatment Updates - © 2000 Medscape, Inc.]

Targeting the HER2 Antibody With Anti-HER2 Therapy

Dennis Slamon,^[1] MD, chief of the Division of Hematology-Oncology at UCLA's Jonsson Comprehensive Cancer Center, is a central figure in the study of HER2 and anti-HER2 therapies. In multiple presentations at the 1999 ECCO conference, he provided a brief historical summary of early studies and the course taken by researchers over the last several years. Once HER2 overexpression was identified as a factor in breast cancer, subsequent studies demonstrated that this alteration was found to play a direct role in causing the aggressive phenotype.^[10,21-23] Consequently, studies designed to evaluate therapeutic targets to HER2 amplification/ overexpression followed.^[21-25]

Monoclonal antibodies studied in mice were found to have positive antitumor activity but showed limited results when administered in humans due to immune response to the nonhuman protein. Trastuzumab humanized monoclonal anti-HER2 antibody (rhuMAb HER2, Herceptin) was produced. Phase I and II trials demonstrated that trastuzumab is well tolerated and produced responses both alone and in combination with cisplatin.^[26,27].

The mechanism of action for trastuzumab remains unknown but is believed to be multidimensional. Possible effects include down-regulation of HER2 overexpression, accelerated receptor degradation, disruption of receptor heterodimer formation, altered signal transduction, and induction of antibody-dependent cell-mediated cytotoxicity.

Early trial results provided the rationale to study trastuzumab as a single agent and in combination with chemotherapy in pivotal phase II and III clinical trials conducted by Slamon and his colleagues.^[28-30] The first of these was an open-label multinational trial of single agent trastuzumab given to 222 HER2-overexpressing metastatic breast cancer patients.^[28] The overall response rate in the trastuzumab-treated patients was 15%, with 6 confirmed with a complete response and 25 confirmed with partial responses. Median duration of responses was 8.4 months and median survival was 13 months.

The second and more definitive study evaluated 469 women who were treated with first-line therapy for metastatic disease with either chemotherapy alone (6 cycles of anthracyline plus cyclophosphamide or, if they had received prior adjuvant anthracyclines, paclitaxel) or trastuzumab plus chemotherapy.^[29,30] An important note is that women who received chemotherapy alone and failed the treatment had the option to cross over to receive trastuzumab at the end of the study. Despite this potential bias, Dr. Slamon was pleased with the results. At 29 months of follow-up, the following results were demonstrated:

Time to disease progression and median response duration were significantly longer in the trastuzumab plus chemotherapy group than in the group receiving chemotherapy alone.
Overall response rate (50% vs 32%) and overall survival duration (25.4 vs 20.3 months) were significantly greater in the trastuzumab plus chemotherapy group.
One-year survival rates differed significantly between the 2 groups: 78% in the trastuzumab plus chemotherapy group versus 67% in the chemotherapy alone group.
Responders in the trastuzumab plus chemotherapy group survived a median of 10 months longer.

It should be noted that cardiotoxic effects have been reported in regard to trastuzumab. The cardiotoxicity was most severe when trastuzumab was administered with anthracyclines. The evidence suggests that trastuzumab alone is not cardiotoxic, but it may be when used with, or proximal to, an anthracycline.

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