Prolonged survival in a HER2 positive metastatic breast cancer patient with brain metastases treated with TDM1 after failure of next generation HER2 targeted therapies

Background: Brain metastases (BM) occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC) and represent a major clinical challenge due to limited CNS drug penetration. In recent years, novel anti-HER2 agents—such as trastuzumab deruxtecan (T-DXd) and tucatinib—have shown promising intracranial efficacy and are now recommended after progression on first-line therapies. However, no prospective data are available to guide optimal treatment sequencing, particularly in the CNS setting. Case Presentation: We report the case of a 37-year-old woman with HER2-positive, hormone receptor-negative MBC and symptomatic BM who progressed after treatment with T-DXd and a tucatinib-based regimen. Remarkably, fourth-line therapy with T-DM1 resulted in a durable intracranial response, maintained over 24 months, with good clinical tolerance and manageable side effects. Results: this case underscores the potential of T-DM1 to remain an effective treatment option even after the failure of next-generation HER2-targeted therapies. The sustained response may be attributed to tumor biology, prior radiotherapy-induced modulation of the blood–brain barrier, or enhanced drug delivery to CNS lesions. Given its favorable toxicity profile and ease of administration, T-DM1 retains clinical relevance in selected patients. Conclusion: T-DM1 may offer meaningful benefit in HER2+ MBC with BM, especially where newer agents fail or are contraindicated. Further studies are needed to clarify optimal sequencing strategies.