177Lu-Trastuzumab Radionuclide Therapy: an Effective Approach for Resistant Brain Metastases in HER2+ Breast Cancer

Purpose Breast cancer (BC) is the most common malignancy in women, with HER2 amplification present in 25–30% of metastatic cases. Although HER2-targeted therapies like trastuzumab have significantly improved patient outcomes, their efficacy in HER2 + brain metastases (BrM) is hindered by the emergence of resistance mechanisms. This study explores the therapeutic potential of trastuzumab radiolabeled with the β⁻-emitting radionuclide ¹⁷⁷Lu as a strategy to overcome resistance in HER2 + BrM. Material and methods HER2 + BC cell lines and their brain-tropic derivatives were assessed for HER2 expression and sensitivity to trastuzumab and [ ¹⁷⁷ Lu]Lu-DOTA-Trastuzumab. In vivo models were established by orthotopic implantation of HER2 + BC cells for primary tumor formation or intracardiac injection to induce BrM. Once tumors were established, the therapeutic efficacy of trastuzumab and [¹⁷⁷Lu]Lu-DOTA-Trastuzumab was evaluated by monitoring tumor progression via magnetic resonance imaging (MRI). [⁸⁹Zr]Zr-DFO-Trastuzumab PET imaging was performed to assess HER2 expression, while blood-brain barrier (BBB) permeability was evaluated using dynamic contrast-enhanced MRI. Results Brain-tropic HER2 + cells exhibited trastuzumab resistance despite maintaining HER2 expression. In contrast, [ ¹⁷⁷ Lu]Lu-DOTA-trastuzumab induced significant DNA damage and cytotoxicity. PET imaging confirmed specific radiotracer uptake in HER2 + primary tumors and BrM. A single dose of [ ¹⁷⁷ Lu]Lu-DOTA-trastuzumab effectively suppressed primary tumor growth and achieved complete BrM remission in 40% of treated animals. Heterogeneous BBB permeability was observed across metastatic lesions, potentially influencing radiotracer uptake and therapeutic efficacy. Conclusion These findings underscore [¹⁷⁷Lu]Lu-DOTA-trastuzumab as a novel therapeutic strategy to overcome trastuzumab resistance in HER2 + BrM, offering a promising approach to improve outcomes in metastatic BC.