Karina Gadkari

Background: HER2-positive breast cancer, comprising approximately 15–20% of all breast cancers, is associated with aggressive tumor biology and a heightened risk of brain metastases.¹ Improvements in systemic therapy have extended patient survival, paradoxically increasing the incidence of central nervous system (CNS) metastases as micrometastases have more time to develop.¹ Treatment of brain metastases is complicated by the blood–brain barrier (BBB) and blood–tumor barrier (BTB), which restrict penetration of systemic therapies, including traditional HER2-targeted monoclonal antibodies such as trastuzumab.^1,2 The BBB consists of tight junction endothelial cells, astrocytes, and pericytes that limit entry of large molecules into the CNS, and the BTB is further characterized by heterogeneous permeability across metastatic lesions.^2,3 Antibody drug conjugates (ADCs) have emerged as a promising therapeutic strategy capable of overcoming these barriers through receptor-mediated uptake and intracellular drug delivery, necessitating investigation of their mechanistic basis for intracranial efficacy.^2,5

Objective: This narrative review examined the mechanistic basis by which HER2-targeted ADCs achieve intracranial efficacy and described their translational development from preclinical models to clinical application in patients with HER2-positive breast cancer brain metastases.

Search Methods: A literature search was conducted using the PubMed database from 2017 to 2026 using the following MeSH terms and keywords: “HER2”, “breast cancer”, “brain metastases”, “antibody drug conjugate”, “trastuzumab deruxtecan”, “blood–brain barrier”, “FcRn”, and “blood–tumor barrier”.

Results: HER2-targeted ADCs consist of a monoclonal antibody, a cytotoxic payload, and a cleavable linker; upon binding to HER2 receptors on tumor cells, receptor-mediated endocytosis is triggered, and lysosomal enzymes release the cytotoxic payload intracellularly.⁵ Trastuzumab deruxtecan (T-DXd) carries a topoisomerase I inhibitor with a high drug-to-antibody ratio and a membrane-permeable payload capable of producing a bystander effect on neighboring tumor cells with low HER2 expression.⁵ Mechanistic studies identified the neonatal Fc receptor (FcRn) as a key transporter facilitating antibody transcytosis across BTB endothelial cells; blocking FcRn significantly reduced intracranial drug concentration and tumor growth inhibition in mouse brain metastasis models.² Studies of BTB heterogeneity demonstrated that ADC uptake and tumor growth suppression were not correlated with passive permeability markers, indicating that receptor-mediated internalization is the dominant mechanism of intracranial ADC delivery rather than passive diffusion.³ Clinically, trastuzumab emtansine (T-DM1) improved invasive disease-free survival and overall survival in HER2-positive patients with residual disease, establishing the ADC platform as therapeutically effective.⁴ The phase II TUXEDO-1 trial of T-DXd in patients with active brain metastases demonstrated high intracranial response rates, durable disease control, and manageable toxicity, providing strong clinical validation of the mechanistic findings.¹

Conclusion: HER2-targeted ADCs achieve intracranial efficacy through three complementary mechanisms: HER2 receptor-mediated internalization, FcRn-facilitated transcytosis across the BTB, and membrane-permeable payload diffusion producing a bystander effect.^1,2,5 These mechanistic properties enable tumor control despite the pharmacologic sanctuary of the CNS and the heterogeneous permeability of the BTB.³ Successful translation from preclinical models to clinical trials demonstrates how mechanistic laboratory research can guide development of effective CNS therapies.^1,4 Future research should focus on optimizing ADC design for improved CNS penetration, identifying biomarkers predictive of response, and investigating resistance mechanisms and combination strategies to further improve outcomes in patients with HER2-positive breast cancer brain metastases.^1,5

Works Cited:

1. Bartsch R, Berghoff AS, Furtner J, et al. Final outcome analysis from the phase II TUXEDO-1 trial of trastuzumab-deruxtecan in HER2-positive breast cancer patients with active brain metastases. Neuro Oncol. 2024;26(12):2305-2315. doi:10.1093/neuonc/noae123
2. Khan I, Kumar D, Zhang W, et al. Trastuzumab deruxtecan efficacy, FcRn-facilitated penetration of the blood-tumor barrier and distribution to tumor cells in HER2+ brain metastasis model systems. Neuro Oncol. Published online January 7, 2026. doi:10.1093/neuonc/noag002 3. Gril B, Wei D, Zimmer AS, et al. HER2 antibody-drug conjugate controls growth of breast cancer brain metastases in hematogenous xenograft models, with heterogeneous blood-tumor barrier penetration unlinked to a passive marker. Neuro Oncol. 2020;22(11):1625-1636. doi:10.1093/neuonc/noaa118
3. Geyer CE Jr, Untch M, Huang CS, et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med. 2025;392(3):249-257. doi:10.1056/NEJMoa2406070
4. Kabraji S, Ni J, Sammons S, et al. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases. Clin Cancer Res. 2023;29(1):174-182. doi:10.1158/1078-0432.CCR-22-2066