Approximately 30-50% of advanced HER2-positive breast cancer patients will 
develop central nervous system (CNS) metastases, with an annual risk of around 
10%, and a half of them will die from brain progression. An increased risk of 
brain metastases is also seen in patients with early HER2-positive breast cancer 
administered curative therapy. Brain metastases in HER2-positive breast cancer 
patients usually constitute the first site of recurrence. The administration of 
anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays 
the onset of symptomatic brain disease: however, the limited penetration of 
these compounds into the CNS hinders their efficacy. The small-molecule tyrosine 
kinase inhibitors of epidermal growth factor receptors family have established 
activity in HER2-positive breast cancer in both advanced disease and neoadjuvant 
setting. Favorable physico-chemical properties of these compounds allow them for 
a more efficient penetration through the blood-brain barrier, and hold the 
promise for more effective prevention and treatment of brain metastases. In this 
article we review the role of currently available or investigational HER2 
tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the 
treatment of brain metastases in HER2-positive breast cancer patients.