Abstract
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.
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PK has received research and grant support from Genentech, Novocure, DNAtrix, and Orbus Therapeutics. PK has served on medical advisory boards for Biocept, Sintetica, Novocure, Janssen, Affinia, Celularity, and SDP Oncology. PK has provided consulting to Bliss Bio, Biocept, Enclear Therapies, Angiochem, and Affinia Therapeutics. LC has no conflicts of interest relevant to this article.
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Chiec, L., Kumthekar, P. Targeting HER2+ Breast Cancer Brain Metastases: A Review of Brain-Directed HER2-Directed Therapies. CNS Drugs 36, 167–179 (2022). https://doi.org/10.1007/s40263-021-00894-x
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DOI: https://doi.org/10.1007/s40263-021-00894-x