MECHANISM OF ACTION OF HERCEPTIN R IN BREAST CANCER

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DESCRIPTION: (Applicant's Abstract) The HER-2 neu proto-oncogene product is over-expressed in 20 percent to 30 percent of breast cancers and is associated with a worse clinical outcome. Clinical evidence in patients with metastatic breast cancer demonstrates that interference with HER-2 by a new recombinant DNA-derived humanized monoclonal antibody, rhumMabHer-2 (Herceptin) can lead to clinical responses. To further develop the clinical use of Herceptin, it would be important to define its efficacy in earlier stage disease, where cure is still possible. Although the cellular mechanisms of action are not fully understood, this targeted biologic therapy directed at a molecular determinant of breast cancer represents a promising prototype for improving the efficacy of anti-cancer treatment. The applicant expects that greater understanding of the cellular response to Herceptin will provide insight on the optimal clinical use of this receptor-targeted strategy, and on the mechanisms of cellular resistance to HER-2 blockade. The understanding of the mechanism could also lead to the development of small molecules targeting the critical portion of the pathway important for therapeutic effect. This project has two specific aims. The first is to demonstrate the clinical efficacy of Herceptin when given with docetaxel as neoadjuvant therapy. The second is to define the mechanisms of the cellular response to Herceptin. For Specific Aim 1, the applicant proposes to perform a neoadjuvant clinical trial in patients with locally advanced HER-2 over-expressing breast cancers with weekly Herceptin given initially as a single agent for the first three weeks, followed by combination of weekly Herceptin and three-weekly docetaxel for 12 weeks before primary surgery. The final surgical specimen would be examined for histological complete response, and the rate of this response would serve as a validated surrogate marker of long-term efficacy. An increase in histological complete remission with this regimen when compared to historical controls would provide encouraging evidence of the greater potential of cure with Herceptin and docetaxel, especially in the adjuvant setting. For Specific Aim 2, sequential core biopsies of the primary breast tumors will be taken in patients enrolled in this clinical study. These patients will have biopsies taken at time of diagnosis, 24 hours after the first dose of Herceptin, and just prior to subsequent doses of Herceptin on days 8, 15, and 22. These core biopsies and the tumor specimens obtained at surgery will then be assessed for the effects of Herceptin by immunohistochemical analysis in the following areas: proliferation and cell cycle regulatory molecules (Ki67, p27, cyclin D1), apoptosis and its regulation (TUNEL assay, p53, bcl-2, bax), components of antibody-dependent cell mediated cytotoxicity (lymphocytic infiltrate, NK cells, macrophages), angiogenesis (VEGF and microvessel density), HER-2 levels and its phosphorylation status, and breast cell differentiation into a milk-producing phenotype (expression of casein and milk lipids).