Complete Response to First-Line Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Extra-axial Central Nervous System Metastases

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate approved for the treatment of unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in patients who have received a prior anti-HER2-based regimen.HER2-positive breast cancer has a high propensity for central nervous system (CNS) spread, which confers significant morbidity and a poor prognosis.We report the case of a 47-year-old woman with metastatic HER2-positive breast cancer who developed debilitating symptomatic CNS metastases, predominantly extra-axial leptomeningeal lesions.Locoregional treatment options were not feasible, and the patient received off-label first-line systemic therapy with T-DXd.Rapid and marked neurological improvement was observed within weeks.Follow-up MRI at three months demonstrated complete radiologic resolution of all CNS lesions.As of April 2026, after 29 cycles of T-DXd, the patient remains clinically asymptomatic with no evidence of CNS disease on MRI, corresponding to a progression-free survival exceeding 20 months.This case highlights the potential role of T-DXd in symptomatic CNS metastases, particularly leptomeningeal disease, and underscores the need for prospective research into its intracranial efficacy in this distinct and challenging subset of patients.