177Lu-trastuzumab radionuclide therapy: a promising strategy for trastuzumab-resistant brain metastases in HER2+ breast cancer.

Brain metastases (BrM) are a frequent and devastating complication of HER2-positive (HER2+) breast cancer (BC), affecting up to 30% of patients with metastatic disease. Although trastuzumab has transformed HER2+ BC treatment, its efficacy against BrM remains limited by brain-specific resistance mechanisms and heterogeneous blood-brain barrier (BBB) permeability. Here, we investigated whether HER2-targeted radionuclide therapy (TRT) using the β-emitting radioimmunoconjugate [177Lu]Lu-DOTA-trastuzumab could overcome trastuzumab resistance in HER2+ brain metastatic lesions. Brain-tropic cells retained HER2 expression but showed reduced sensitivity to trastuzumab, indicating the emergence of resistance mechanisms independent of target loss. By contrast, treatment with [177Lu]Lu-DOTA-trastuzumab produced robust DNA double-strand break-mediated cytotoxicity irrespective of trastuzumab sensitivity, demonstrating that resistance to antibody-mediated signaling inhibition does not confer cross-resistance to radiation-induced cell killing. In vivo, a single dose of [177Lu]Lu-DOTA-trastuzumab markedly reduced tumor progression and led to complete remission of established BrM in 40% of treated animals, whereas unconjugated trastuzumab showed minimal therapeutic benefit. Importantly, treatment was not associated with detectable neurotoxicity. While dynamic contrast-enhanced MRI demonstrated widespread BBB disruption across metastatic lesions, [89Zr]Zr-DFO-trastuzumab PET revealed marked heterogeneity in intracranial antibody delivery, with tracer uptake restricted to a subset of lesions. Collectively, these findings demonstrate that HER2-TRT can overcome trastuzumab resistance and eradicate brain metastatic lesions. Moreover, immuno-PET provides a non-invasive biomarker of intracranial antibody accessibility, supporting a theranostic strategy that combines patient stratification with TRT for HER2+ BrM.