Systemic management of brain metastases in HER2+ breast cancer in 2022

Up to half of all patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer will eventually acquire brain metastases (BrMs), which are associated with reduced overall survival and decreased quality of life. Although the median overall survival was previously less than a year, novel systemic treatments have significantly extended life expectancy in patients with HER2+ breast cancer BrMs. The current first-line standard of care for all patients with HER2+ metastatic breast cancer, regardless of BrMs status, is dual HER2 antibody therapy with pertuzumab/trastuzumab plus a taxane. Second-line systemic therapy has recently evolved, with the option of trastuzumab deruxtecan (T-DXd) or tucatinib in combination with trastuzumab and capecitabine. T-DXd has shown dramatically superior progression-free survival in comparison with trastuzumab emtansine (T-DM1) in patients with stable BrMs in the second-line setting. Patients who have untreated or locally treated/progressive BrMs may benefit from a regimen with robust intracranial response rates, such as tucatinib in combination with trastuzumab and capecitabine. Third-line therapy and beyond includes multiple options that require careful selection, with the patient's BrMs status, comorbidities, and performance status taken into account. In this review, we focus on current management and evolving strategies for the treatment of patients with HER2+ breast cancer BrMs.