Approximately 50% of patients with advanced human epidermal growth factor 2 
(HER2)-positive breast cancer and triple-negative breast cancer (TNBC) 
ultimately develop breast cancer brain metastases (BCBM), which are associated 
with significant morbidity and mortality. The advent of HER2-directed therapy 
resulted in greatly improved survival outcomes, but unfortunately at the price 
of an increased cumulative incidence of BCBM. We review challenges in the 
management of BCBM, and potential treatment strategies, including novel agents 
such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors 
(olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors 
(palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287). 
The utility of human epidermal growth factor 2 (HER2)-directed 
therapies-lapatinib, ado-trastuzumab emtansine (T-DM1), neratinib and 
tucatinib-is also being studied in this setting. We address the need for 
improved imaging techniques and innovation in clinical trial design. For 
example, the current practice is to initially administer whole-brain 
radiotherapy (WBRT) as treatment for patients with multiple BCBM. However, in 
selected circumstances, first-line systemic treatment may be more appropriate in 
order to avoid neurocognitive toxicities, and potential options should be 
evaluated in window of opportunity trials. Other strategies that may aid 
development of more effective clinical trials and expedite the development of 
promising agents include the use of different clinical endpoints and different 
imaging tools.