Predictive markers of tubulin-targeting agents in breast cancer

Microtubules are formed by an equal amount of alpha- and beta-tubulins through a dynamic process of polymerization and depolymerization that reaches equilibrium. Tubulin-targeting agents affect the microtubule function to disrupt cell shape, microvesicle transportation, and spindle formation. The use of tubulin-targeting agents, especially the newer agents such as taxanes, has significantly increased the response and even survival in patients with many cancers, including breast cancer. However, not all patients respond to these agents. Also, most patients develop recurrent or progressive disease, especially in the metastatic setting. The use of predictive markers of tubulin-targeting agents is therefore needed to increase the therapeutic ratio in the selected patient population. However, many clinical studies have failed to identify reliable and reproducible clinical or biologic markers that serve this purpose. Of the various markers examined, beta-tubulin III and its related proteins, such as tau, seem to predict the response to taxanes in preliminary clinical studies. However, most of these studies are limited by many factors such as small sample size, heterogeneous patient population, disease stages, and different methods in marker detection. None of these markers have been validated by large prospective clinical trials. Since tumor cells are driven by many signal transduction pathways, the study of the gene expression signature rather than a single gene is more likely to identify the ultimate predictive markers of response to tubulin-targeting agents. Gene expression profiling and proteomics are in preclinical development and in early clinical trials. They will eventually enable us to offer patients tailored chemotherapy with the tubulin-targeting agents. Before such predictive markers are available, these agents may be considered in patients with good performance status and aggressive tumors.