A major class of targeted therapies inhibits angiogenesis, yet anti-angiogenic therapies have failed to improve overall survival (OS) in both early-stage and metastatic breast cancer. According to a recent review published in Cancer Treatment Reviews, predictive biomarkers may be the key to unlock the success of anti-angiogenic agents for a subset of patients with breast cancer.1

Targeting Angiogenesis

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Angiogenesis is a key factor for tumor growth and metastasis, and studies link angiogenic factors to the development of cancer. A major pathway involved in angiogenesis is the release of vascular endothelial growth factor (VEGF) from hypoxic tumor cells and its binding to the VEGF receptor (VEGFR), located on endothelial cells.

Activation of VEGFR promotes a signaling cascade that induces the transcription of pro-angiogenic genes within the nucleus of the endothelial cell. This initiates new endothelial cell growth and causes new blood vessel formation.

VEGF also promotes vascular permeability and vasodilation, inhibits apoptosis, and can recruit endothelial progenitor cells from the bone marrow.

“The VEGF family and their relevant receptors represent the most important angiogenic factors and were found to be expressed in the majority of human cancers,” wrote the authors. In breast cancer, the level of angiogenesis is associated with survival, and high levels of VEGF and other angiogenic factors indicate high-risk disease correlating with poor prognosis.

Recognition of the importance of angiogenesis for tumor growth and metastasis led to the development of agents that target this pathway. The first anti-angiogenic therapy approved by the U.S. Food and Drug Administration (FDA) was bevacizumab, a humanized monoclonal antibody that binds to all isoforms of VEGF-A.

Since then, tyrosine kinase inhibitors targeting angiogenic factors such as VEGFR, platelet-derived growth factor receptor, and others, were developed and are primarily used to treat renal cell carcinoma. An antibody targeted to the VEGFR2, ramucirumab, was also developed and is approved for use in advanced gastric cancer, metastatic colorectal cancer, and advanced non-small cell lung cancer.

The Overall Survival and Progression-free Survival Paradox

Bevacizumab was approved for the treatment of metastatic, HER2-negative breast cancer in 2008, based on the E2100 trial and the surrogate endpoint of progression-free survival (PFS). In the trial, PFS was significantly prolonged from 5.9 months to 11.8 months (hazard ratio, 0.60; P < .001).

The improved PFS did not, however, translate into prolonged OS and, in 2011, the FDA withdrew the approval of bevacizumab for breast cancer.

This paradox—improved PFS but not OS—was the result of multiple trials investigating bevacizumab in various settings of breast cancer, including first-line treatment in combination with chemotherapy or hormonal therapy. Although the response rate increased with the addition of bevacizumab to chemotherapy in the second- and third-line setting, there was no difference in PFS or OS.

Bevacizumab has also been evaluated in early-stage breast cancer, but the data in this setting are mixed and largely disappointing. Several trials failed to demonstrate a difference in disease-free survival (DFS) or OS with bevacizumab in the neoadjuvant and adjuvant settings. Disappointing results were also reported with tyrosine kinase inhibitors that target angiogenic factors, such as sunitinib, sorafenib, and pazopanib.

“The scientific rational for anti-angiogenics appears to be well-supported, but the clinical benefit demonstrated so far is not outweighed by the toxicity and costs of the agents,” said Kim C. Aalders, MD, of the medical department of the European Organization of Research and Treatment of Cancer (EORTC) in Brussels, Belgium.

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Dr Aalders suggested that this is likely because “angiogenesis is a complex process that involves multiple mediators and therefore possible compensatory mechanisms when blocking the process at one point.” She also noted that it can be difficult to show an OS benefit in breast cancer due to the therapies a patient may receive after progression on the study drug.