Targeting HER2+ Breast Cancer Brain Metastases: A Review of Brain-Directed HER2-Directed Therapies

• Published in: CNS drugs 2022-02, Vol.36 (2), p.167-179
• Main Authors: Chiec, Lauren, Kumthekar, Priya
• Format: Article
• Language: English
• Subjects: Brain cancer; Breast cancer; Cancer therapies; Central nervous system; Chemotherapy; Clinical trials; Cytotoxicity; ErbB-2 protein; Medicine; Medicine & Public Health; Meninges; Metastases; Metastasis; Monoclonal antibodies; Nervous system; Neurology; Neurosciences; Patients; Pharmacotherapy; Psychiatry; Psychopharmacology; Radiation therapy; Review Article; Trastuzumab
• ISSN: 1172-7047; 1179-1934
• DOI: 10.1007/s40263-021-00894-x

Despite advances in the treatment of metastatic, HER2+ breast cancer, the development of central nervous system metastases remains a therapeutic challenge. The challenge is amplified by the exclusion of patients with active brain metastases from many clinical trials. Initial HER2-targeted therapies, such as trastuzumab and pertuzumab, have shown limited efficacy for patients with brain metastases. In addition, the landscape of systemic therapy for HER2+ metastatic breast cancer is changing rapidly. In recent years, the development of small-molecule inhibitors in combination with chemotherapy has shown promise, though the efficacy is often balanced by key toxicities. Other HER2-targeted therapies, including antibody-drug conjugates, have presented new therapeutic options for this patient population; however, additional data for both small-molecule inhibitors and antibody-drug conjugates with respect to patients with central nervous system metastases is needed. Here, we specifically review the data for the management of HER2+ parenchymal brain metastases. A limited discussion of leptomeningeal disease is included; a more detailed review of this specific subgroup is outside the scope of this article. Key clinical trial data supporting the use of HER2-targeted and non-targeted therapies, including monoclonal antibodies and antibody-drug conjugates, are reviewed, with a specific focus on the use of HER2-targeted small-molecule inhibitors. We also review future directions and provide an overview of ongoing clinical trials which include patients with HER2+ brain metastases. With future focus on inclusive clinical trial design, particularly inclusion of patients with brain metastases, optimal strategies for management will be better elucidated.