Antibody therapy for breast cancer.

Targeted therapies against tumor biological properties are an essential part of individualized therapy concepts in breast cancer. Next to risk-adapted strategies using conventional chemo- and/or endocrine therapies, antibody therapy has become an additional option. The humanized monoclonal antibody trastuzumab (Herceptin) is the first novel targeted therapy approved for routine clinical application in advanced breast cancer. Patients with HER2/neu protein overexpression as assessed by immunohistochemistry (IHC) and/or gene amplification as assessed by fluorescence in-situ hybridization (FISH) in their tumors respond well to palliative trastuzumab therapy, either as single agent or in combination with chemotherapy. New combinations with endocrine therapy are currently being evaluated in clinical trials. Trastuzumab therapy is generally well-tolerated. So far, considerable cardiotoxicity was seen only in combination with doxorubicin. Thus, extensive cardiomonitoring is now performed in trials assessing further chemotherapeutic partners. Clinical trials looking at early trastuzumab therapy in the adjuvant (e.g. HERA, BOND 006) or neoadjuvant (e.g. TECHNO) setting are still open for recruitment in Germany. Since only about those 25 % of breast cancers which are HER2/neu-positive are eligible for trastuzumab, novel targeted therapeutics for the remaining HER2/neu-negative tumors are needed. Another therapeutic antibody, 2C4 (Pertuzumab, Omnitarg), is currently under clinical evaluation. It binds to a different epitope on HER2/neu than trastuzumab and inhibits heterodimerization with other HER receptors. Phase I data showed that 2C4 is well tolerated and clinically active.

Invasion factors uPA/PAI-1 and HER2 status provide independent and complementary information on patient outcome in node-negative breast cancer.

PURPOSE: The independent clinical relevance of invasion factors urokinase-type plasminogen activator (uPA)/PAI-1 and HER2 status was evaluated in lymph node-negative breast cancer patients (N = 118) without adjuvant systemic therapy after long-term follow-up of more than 10 years (median, 126 months). PATIENTS AND METHODS: Levels of uPA and its inhibitor PAI-1 were prospectively measured by enzyme-linked immunosorbent assay in primary tumor tissue extracts. HER2 gene amplification (HER2_AMP) was evaluated by fluorescence in situ hybridization (FISH; Ventana Medical Systems HER-2/neu probe; Tucson, AZ), and HER2 protein overexpression (HER2_EXP) was evaluated by immunohistochemistry (IHC; Oncogene Science antibody Ab-3; Cambridge, MA) on parallel-cut formalin-fixed paraffin-embedded tissue sections. RESULTS: uPA/PAI-1 was high (either one or both factors were high) in 44% of the tumors. HER2_AMP was detected by FISH in 33% of the patients, and HER2_EXP was found by IHC in 44% of the patients. In a multivariate analysis of established and tumor-biologic prognostic factors, uPA/PAI-1 was the only independent prognostic factor for disease-free survival ([DFS]; P <.001; relative risk [RR], 8.3; 95% confidence interval [CI], 3.4 to 20.4). Although HER2_AMP and HER2_EXP did not reach significance for DFS, they were significant for overall survival (OS), even in multivariate analysis (HER2_AMP: P =.004; RR, 3.7; 95% CI, 1.5 to 9.2; HER2_EXP: P =.009; RR, 3.4; 95% CI, 1.4 to 8.7). CONCLUSION: After long-term follow-up, uPA/PAI-1 levels in primary tumor tissue reliably and strongly indicate an aggressive course of disease in lymph node-negative breast cancer independent of HER2 status. The particular prognostic effect of HER2 status on OS may reflect its ability to predict resistance to systemic therapy.