Targeting HER2 in breast cancer with brain metastases: A pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments

Giorgio Guglielmi; Claudio Zamagni; Marzia Del Re; Romano Danesi; Stefano Fogli

doi:10.1016/j.ejphar.2024.177076

Targeting HER2 in breast cancer with brain metastases: A pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments

Eur J Pharmacol. 2024 Oct 30:985:177076. doi: 10.1016/j.ejphar.2024.177076. Online ahead of print.

Authors

Giorgio Guglielmi¹, Claudio Zamagni², Marzia Del Re³, Romano Danesi⁴, Stefano Fogli⁵

Affiliations

¹ Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
² IRCCS Azienda Ospedaliero-universitaria di Bologna, Italy.
³ Saint Camillus International University of Medical and Health Sciences, Rome, Italy; Direzione Scientifica, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.
⁴ Department of Oncology and Hemato-Oncology, University of Milano, Italy.
⁵ Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy. Electronic address: stefano.fogli@unipi.it.

PMID: 39486766
DOI: 10.1016/j.ejphar.2024.177076

Abstract

Understanding the capability of a drug to penetrate the blood-brain barrier (BBB) is an unmet medical need in patients with positive human epidermal growth factor receptor 2 (HER2 positive) and brain metastases. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. Predicting the BBB permeability of these therapeutic agents is a pharmacological challenge due to the various factors involved in the barrier functions. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain, and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

Keywords: ADCs; Brain metastases; HER2 positive breast cancer; TKIs.

Publication types

Review