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Antiangiogenic therapy for breast cancer first burst onto the scene in 2005 with the reporting of results from the US Intergroup trial E2100, which demonstrated highly statistical improvement (in both relative and absolute terms) in progression-free survival (PFS) for front-line metastatic breast cancer. Subsequent phase III trials with bevacizumab reported statistically significant (but inferior to E2100's) PFS, and analysis of all three trials (both individually and collectively) showed no overall survival benefit for bevacizumab. This failure to demonstrate a survival benefit, combined with the variable PFS results and real toxicity of bevacizumab, led to the US Food and Drug Administration's withdrawal of bevacizumab's indication in metastatic breast cancer.

The withdrawal of bevacizumab's indication in metastatic breast cancer suggests that it is time to re-evaluate the role, not just of bevacizumab, but also of antiangiogenic therapy as a whole, as targeted therapy for breast cancer. Several questions are worth addressing:

  1. What is the biologic rationale for antiangiogenic therapy in metastatic breast cancer?

  2. What data suggest clinical benefit (or lack thereof) of antiangiogenic therapy for breast cancer?

  3. Does antiangiogenic therapy represent targeted therapy for breast cancer, and if not can it evolve towards targeted therapy?

  4. What are the future prospects for antiangiogenic therapy in breast cancer?


There are several reasons to believe that antiangiogenic therapy might prove beneficial in breast cancer. First, data from as long ago as the early 1990s suggested that the prognosis of patients with early stage breast cancer is related to measures of blood vessel formation in general (e.g. microvessel density in human breast cancers [1]) and to specific proangiogenic growth factors in particular. The most robust datasets exist for vascular endothelial growth factor (VEGF) (reviewed in [2]). Increased VEGF content is associated with impaired clinical outcome (i.e. VEGF is prognostic in early breast cancer) as well as resistance to both hormonal therapy and chemotherapy (i.e. VEGF is predictive of therapeutic response to standard breast cancer therapies) [2].

Angiogenesis is a hallmark of breast carcinogenesis, with both increased microvessel density and increased VEGF production occurring at the transition from atypical hyperplasia to in situ carcinoma [3, 4]. In invasive breast cancer, angiogenesis and VEGF production are most prominent in the most inherently aggressive breast cancers, correlating with aggressive intrinsic subtypes (HER2-positive and triple negative breast cancers) and poor histologic differentiation [5, 6].

In multiple preclinical models of breast cancer, antiangiogenic therapy attacking multiple points of the angiogenic cascade results in diminished tumor growth, and the combination of anti-VEGF therapy with other breast cancer therapies (including both chemotherapy and HER2-targeted therapy) results in additive or synergistic antitumor effects [5-7].

Antiangiogenic therapy therefore represented a biologically rational approach to breast cancer therapy. In retrospect, preclinical model ...

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