**4. Targeted therapy in TNBC**

Although chemotherapy can be effective in patients with TNBCs, molecular studies could still improve treatment outcomes by giving new treatment targets. The molecular heterogeneity of TNBCs means that patients with TNBCs need personalized treatment because currently 60–70% of patients with TNBC do not respond fully to chemotherapy. Genomic analyses of the TNBC revealed large-scale transcriptional, mutational, and copy number heterogeneity, without any frequently recurrent mutations, other than *TP53*. Consistent with this molecular heterogeneity, most targeted agents, so far, have a very low activity in unselected TNBC, but important "basket" trials are ongoing. Therefore, there are promising opportunities for studying targeted therapy in appropriately selected patients with residual disease after neoadjuvant chemotherapy. Several ongoing phase I/II studies are investigating phosphatidylinositol-3-kinase (PI3K) inhibitors in advanced TNBC, and early-phase studies are also assessing Janus kinase 2 and cyclin-dependent kinase inhibitors in hormone-negative breast cancer [29].

At least some important discoveries made in recent years seem to be worth emphasizing in this textbook. The molecular pathways and receptors mentioned below might become new treatment targets for patients with the TNBC.

## **4.1. Anti-angiogenic factors**

Blockage of angiogenesis has been one of the ways to treat patients with breast cancer. In patients with the TNBC, bevacizumab, among the drugs that interfere with angiogenesis, has been studied most extensively. In 2008, the Food and Drug Administration (FDA) approved bevacizumab in combination with a taxane (paclitaxel) as first-line therapy for metastatic HER2-negative breast cancer, including the TNBC [30]. A meta-analysis of phase III studies with bevacizumab showed an improvement in progression-free survival but not in overall survival in these patients. However, the addition of bevacizumab considerably increased treatment toxicity [31].

Based on these data, in 2011, the FDA withdrew bevacizumab as the treatment for metastatic breast cancer.
