Clinically significant radiation necrosis following trastuzumab-deruxtecan and brain stereotactic radiosurgery: A case series in breast cancer patients

An estimated 15% of breast cancers in the United States overexpress human epidermal growth factor receptor 2 (HER2), and patients with HER2+ breast cancer have an increased risk of developing brain metastases. The recent development of HER2-targeted agents, including trastuzumab deruxtecan (T-DXd), has resulted in improved systemic disease control, including disease metastasized to the brain. Because many patients with brain metastases have received both T-DXd and have also undergone brain stereotactic radiosurgery (SRS), it is important to explore the interaction of these treatment modalities. Here, we present two cases of clinically significant radiation necrosis (CSRN) occurring in patients with metastatic breast cancer with a treatment history including brain SRS and T-DXd. We also briefly describe two additional cases of CSRN in patients with the additional remote treatment history of trastuzumab emtansine (T-DM1) prior to T-DXd, as T-DM1 has also been reported to cause increased rates of CSRN in patients with HER2+ metastatic breast cancer with a history of SRS-treated brain metastases. While case reports and series have illustrated this phenomenon with T-DM1, no existing literature has described these findings with T-DXd. We describe these cases and review the potential etiologies for CSRN in this specific patient population, thus highlighting the need for a more thorough understanding of the potential adverse events caused by the intersection of treatment modalities, namely brain SRS and HER2-directed antibody-drug conjugates as the landscape of targeted therapies continues to evolve.