Strategies for improving the clinical benefit of antiangiogenic drug based therapies for breast cancer.

Viewed as a whole, the aggregate outcomes of a number of positive randomized phase III clinical trial results evaluating the VEGF-pathway targeting antiangiogenic drug bevacizumab, with or without concurrent chemotherapy, in metastatic breast cancer patients have been disappointingly modest. In the case of antiangiogenic tyrosine kinase inhibitors (TKIs) the results have been negative. Nevertheless, several findings indicate antiangiogenic drugs, especially bevacizumab, are active and can lead to demonstrable clinical benefit in some patients, thus stimulating research into developing strategies to significantly improve their efficacy and reduce toxicity. Some of these initiatives include: 1) discovery and validation of predictive markers that can prospectively identify patients more likely to benefit from antiangiogenic therapy; 2) recognition that the nature of the chemotherapy partner or backbone can strongly impact outcomes when combined with antiangiogenic drugs such as bevacizumab, and thus developing what may be improved combination chemotherapy partner regimens, e.g. metronomic chemotherapy; 3) evaluating prospectively in more depth whether subtypes of the disease-especially triple negative or inflammatory breast cancer-are more responsive to antiangiogenic therapy than other subtypes; 4) evaluating new agents that inhibit angiogenesis in a VEGF-independent manner and other types of drug that can be effectively combined with antiangiogenics, e.g. c-met inhibitors; 5) uncovering the basis of resistance or relapse/progression on the therapy with antiangiogenic drugs; 6) development of improved predictive preclinical breast cancer models for therapy testing, e.g. treatment of mice with established multi-organ breast cancer metastatic disease or genetically engineered mouse models of breast cancer, or mice bearing patient derived breast cancer tissue xenografts.