Antiangiogenic therapy for metastatic breast cancer: current status and future directions.

The use of chemotherapy and endocrine therapy have led to objective tumour shrinkage and improved survival in women with metastatic breast cancer. Despite the availability of many chemotherapeutic drugs, these agents do not act specifically on the various growth signalling pathways that drive tumour growth and progression. This lack of specificity is likely to explain the inconsistent responses seen across the population of breast cancer patients and contributes to the undesirable adverse effects. The expanding knowledge of the important molecular pathways involved in tumourogenesis and tumour progression has led to the exciting development of several classes of targeted agents. The potential advantage of such treatment is to improve cancer cell kill with less damage to healthy tissues. Hormonal agents were the first to utilize the specific estrogen receptor-related growth pathways for therapeutic efficacy. Agents directed to the human epidermal growth factor receptor (HER)-2/neu growth signalling pathway exemplify the effectiveness of the new generation of targeted biological agents, but are limited to the 20-25% of breast cancers that overexpress the receptor. However, angiogenesis is a critical component of tumour development that is necessary for all tumour growth and is not limited to a subset of breast cancers. Therefore, agents that can diminish or prevent tumour angiogenesis are likely to have a far broader application and benefit to women with breast cancer. Several anti-angiogenic agents have been evaluated in phase I, II and III trials for patients with metastatic breast cancer. These trials have demonstrated efficacy of anti-angiogenic agents when used in combination with chemotherapy and the toxicity profile has been better defined. Issues regarding the mechanisms of resistance, identifying combination regimens that result in the greatest clinical benefits and minimizing the adverse effects are areas that require further research.