Gene expression profiling studies have suggested that mTNBC might be preferentially sensitive to the inhibition of the protooncogene Src. Although combination therapy trials are currently ongoing, dasatinib, a potent orally available inhibitor of the Src family kinase, was tested in an early phase study of mTNBC and yielded a CBR of 9.2%.78 Due to its activity in the setting of ER/PR-positive tumors that have developed hormone resistance, there is a developing interest in DNA methyltransferase and histone deacetylase (HDAC) inhibitors in mTNBC as preclinical studies have suggested that the inhibition of these mechanisms could result in re-expression of a functional ER mRNA and protein. Currently, clinical trials evaluating the HDAC inhibitor vorinostat in combination with chemotherapy are underway to test the drug’s efficacy among patients with mTNBC.79

Several preclinical and early phase studies have implicated other possible chemotherapeutic strategies and targetable pathways in mTNBC, for which clinical trials are currently underway (Table 2 and Fig. 3).72,80–97 One of these targets is the androgen receptor, for which there have been some data on its ability to predict chemotherapy sensitivity and prognosticate patient outcomes.98–100 Although there have only been preclinical and early phase studies looking at androgen receptor blockers as a targeted agent in mTNBC, larger clinical trials are currently ongoing.72 Despite the widespread use and success among patients with other tumor types, there is limited data to suggest a therapeutic benefit from immune checkpoint inhibitors, vaccines, or chimeric antigen receptor T-cell therapy in mBC.101


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(To view a larger version of Figure 3, click here.)

CONCLUSION

The management of patients with mTNBC can be quite complex and often requires consideration of many different patient-, tumor-, and therapy-related factors in order to tailor the treatment and optimize the care. Although there have been many new agents approved for mBC over the past 20 years, the treatment options for the subset of patients with mTNBC remain somewhat limited. It is unclear how much the difference in survival among these patients is secondary to the inherent aggressive biology of mTNBC, rather than the availability of effective treatment. Nonetheless, more research is needed to further understand this complex disease and its involved genomic signatures and signaling pathways, with the ultimate goal of improving the long-term outcomes of this subset of patients compared to that of other patients with mBC.