New molecular targets of breast cancer therapy

The development of new chemotherapeutic agents and concepts of radiation therapy, administered as primary, adjuvant and palliative therapy, has led to new perspectives in breast cancer therapy. Apart from conventional chemotherapy, recently developed novel agents interfere with molecular mechanisms that are altered in cancer cells. Those targets are not necessarily breast cancer-specific. In this review we will focus on novel agents with potential or already proved benefit to breast cancer patients. Promising strategies include inhibition of growth factor receptors, blocking of tumor angiogenesis and signal transduction pathways, modulation of apoptosis, cancer vaccination, and inhibition of invasion and metastasis.

Reports of relevant studies obtained from a search of MEDLINE and studies referenced in those reports were reviewed.

Apart from trastuzumab, other further developed compounds show promising results in clinical studies as a second generation of growth factor inhibitors. Different approaches in anti-angiogenetic therapy are under preclinical and clinical phase-II trials. Pro-apoptotic agents show synergistic effects with docetaxel in a clinical phase-I trial. Other compounds that target HSP 90, histone deacetylase and HMG-CoA reductase target atypical apoptotic pathways being lethal to tumor cells only but not to normal tissue, suggesting a tumor-specific way of action. MMP inhibitors have been demonstrating promising results in patients with refractory malignant pleural effusion in a phase-I trial. Several tyrosine kinase inhibitors currently under clinical investigation preliminarily show hopeful results in patients with advanced breast cancer. Furthermore, recent progress in defining the immunogenic epitopes of tumor antigens has rejuvenated the interest in cancer vaccines.

Typical dose escalation studies leading to the highest clinically still tolerated dose do not appear to be equally appropriate for the estimation of efficiency of those compounds as for conventional cytotoxic regimes. Rather, escalation up to an amount of therapeutic agent that is sufficient for maximum target inhibition should be promoted, where classical measures of cytoreduction such as complete or partial remission are replaced both by time to progression and treatment failure as an appropriate measure of the efficacy of an agent.