Drug Treatment Direction Based on the Molecular Mechanism of Breast Cancer Brain Metastasis

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2025 Feb 26

PMID 40006075

Authors

Yumin Zhang

Haotian Shang

Jiaxuan Zhang

Yizhi Jiang

Jiahao Li

Huihua Xiong

Tengfei Chao

Affiliations

Soon will be listed here.

Abstract

Today, breast cancer (BC) is the most frequently diagnosed malignancy and a leading cause of cancer-related deaths among women worldwide. Brain metastases (BMs) are a common complication among individuals with advanced breast cancer, significantly impacting both survival rates and the overall condition of life of patients. This review systematically analyzes the innovative approaches to drug treatment for breast cancer brain metastases (BCBMs), with particular emphasis placed on treatments targeting molecular mechanisms and signaling pathways and drug delivery strategies targeting the blood brain barrier (BBB). The article discusses various drugs that have demonstrated effectiveness against BCBM, featuring a mix of monoclonal antibodies, nimble small-molecule tyrosine kinase inhibitors (TKIs), and innovative antibody-drug conjugates (ADCs). This study of various drugs and techniques designed to boost the permeability of the BBB sheds light on how these innovations can improve the treatment of brain metastases. This review highlights the need to develop new therapies for BCBM and to optimize existing treatment strategies. With a deeper comprehension of the intricate molecular mechanisms and advances in drug delivery technology, it is expected that more effective personalized treatment options will become available in the future for patients with BCBM.

References

Winkler E, Bell R, Zlokovic B . Central nervous system pericytes in health and disease. Nat Neurosci. 2011; 14(11):1398-1405. PMC: 4020628. DOI: 10.1038/nn.2946. View

Lajoie J, Shusta E . Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. Annu Rev Pharmacol Toxicol. 2014; 55:613-31. PMC: 5051266. DOI: 10.1146/annurev-pharmtox-010814-124852. View

Leone J, Emblem K, Weitz M, Gelman R, Schneider B, Freedman R . Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases. Breast Cancer Res. 2020; 22(1):131. PMC: 7706261. DOI: 10.1186/s13058-020-01372-w. View

Brastianos P, Kim A, Giobbie-Hurder A, Lee E, Lin N, Overmoyer B . Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results. Nat Med. 2023; 29(7):1728-1737. PMC: 10644912. DOI: 10.1038/s41591-023-02392-7. View

Gaedcke J, Traub F, Milde S, Wilkens L, Stan A, Ostertag H . Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer. Mod Pathol. 2007; 20(8):864-70. DOI: 10.1038/modpathol.3800830. View

Klocker E, Egle D, Bartsch R, Rinnerthaler G, Gnant M . Efficacy and Safety of CDK4/6 Inhibitors: A Focus on HR+/HER2- Early Breast Cancer. Drugs. 2025; 85(2):149-169. PMC: 11802638. DOI: 10.1007/s40265-024-02144-y. View

Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y . Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006; 9(1):23-32. DOI: 10.1016/j.ccr.2005.12.012. View

Pena Q, Wang A, Zaremba O, Shi Y, Scheeren H, Metselaar J . Metallodrugs in cancer nanomedicine. Chem Soc Rev. 2022; 51(7):2544-2582. DOI: 10.1039/d1cs00468a. View

Zhao X, Qu J, Sun Y, Wang J, Liu X, Wang F . Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget. 2017; 8(18):30576-30586. PMC: 5444766. DOI: 10.18632/oncotarget.15736. View

10.

Nam D, Jeon H, Kim S, Kim M, Lee Y, Lee M . Activation of notch signaling in a xenograft model of brain metastasis. Clin Cancer Res. 2008; 14(13):4059-66. DOI: 10.1158/1078-0432.CCR-07-4039. View

11.

Kumthekar P, Tang S, Brenner A, Kesari S, Piccioni D, Anders C . ANG1005, a Brain-Penetrating Peptide-Drug Conjugate, Shows Activity in Patients with Breast Cancer with Leptomeningeal Carcinomatosis and Recurrent Brain Metastases. Clin Cancer Res. 2020; 26(12):2789-2799. DOI: 10.1158/1078-0432.CCR-19-3258. View

12.

Steeg P . The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol. 2021; 18(11):696-714. DOI: 10.1038/s41571-021-00529-6. View

13.

Lorger M, Felding-Habermann B . Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol. 2010; 176(6):2958-71. PMC: 2877856. DOI: 10.2353/ajpath.2010.090838. View

14.

Hurvitz S, Hegg R, Chung W, Im S, Jacot W, Ganju V . Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2022; 401(10371):105-117. DOI: 10.1016/S0140-6736(22)02420-5. View

15.

Klemm F, Bleckmann A, Siam L, Chuang H, Rietkotter E, Behme D . β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis. Carcinogenesis. 2010; 32(3):434-42. DOI: 10.1093/carcin/bgq269. View

16.

Chen W, Hoffmann A, Liu H, Liu X . Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis Oncol. 2018; 2(1):4. PMC: 5871901. DOI: 10.1038/s41698-018-0047-0. View

17.

Gray R, Bhattacharya S, Bowden C, Miller K, Comis R . Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2009; 27(30):4966-72. PMC: 2799052. DOI: 10.1200/JCO.2008.21.6630. View

18.

Trudeau M, Crump M, Charpentier D, Yelle L, Bordeleau L, Matthews S . Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada - Clinical Trials Group (NCIC-CTG). Ann Oncol. 2006; 17(6):952-6. DOI: 10.1093/annonc/mdl056. View

19.

Zhang J, Stevens M, Bradshaw T . Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2011; 5(1):102-14. DOI: 10.2174/1874467211205010102. View

20.

Zhou Q, Guo P, Kruh G, Vicini P, Wang X, Gallo J . Predicting human tumor drug concentrations from a preclinical pharmacokinetic model of temozolomide brain disposition. Clin Cancer Res. 2007; 13(14):4271-9. DOI: 10.1158/1078-0432.CCR-07-0658. View