Long-Term Complete Radiological Response in a Patient with Brain Metastases from HER2-Positive Breast Cancer Treated with Trastuzumab Deruxtecan: A Case Report and Literature Review.

Introduction: HER2-positive (HER2+) breast cancer (BC) is associated with a high incidence of brain metastases (BMs), which negatively affect prognosis and quality of life. Local therapies, such as whole-brain radiotherapy (WBRT), stereotactic radiotherapy, stereotactic radiosurgery, and neurosurgery, allow temporary control of metastatic spread. Systemic treatments are limited by the blood-brain barrier (BBB), which restricts the passage of many therapeutic molecules. Research initially focused on small molecule tyrosine kinase inhibitors due to their low molecular weight. Recent evidence suggests that tumor-induced disruption of the BBB may increase its permeability, potentially allowing larger molecules, including antibody-drug conjugates, to cross. Although trastuzumab deruxtecan (T-DXd) has demonstrated intracranial activity, evidence of durable complete responses in heavily pretreated patients with active BMs remains limited. Case Presentation: We report a case of a HER2+ BC patient with multiple (>20) active BMs, previously treated with WBRT and trastuzumab emtansine (T-DM1), who developed intracranial progression. Third-line treatment with T-DXd resulted in a complete radiological intracranial response, which has been maintained for more than 20 months under ongoing therapy, with associated improvement in neurological symptoms and quality of life. Conclusion: This case provides preliminary evidence that T-DXd may achieve deep and durable intracranial responses even in heavily pretreated patients with active BMs, including those previously treated with WBRT and T-DM1. The exceptional duration of response observed in this case appears to exceed historical expectations and warrants further investigation in this high-risk population.