Abstract
BACKGROUND: Trastuzumab deruxtecan (T-DXd) significantly improves human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) outcomes. However, understanding of resistance mechanisms to T-DXd remains limited. Here, we present a case of a luminal B, HER2-positive MBC who displayed a partial response to T-DXd following five lines of prior HER2-targeted therapy but developed acquired resistance after 14 months of treatment. Organoid drug screening identified the potential strategy to overcome T-DXd resistance. Next-generation sequencing (NGS) of 550 cancer-associated genes was performed prior to T-DXd administration, and repeated after the emergence of T-DXd resistance. CASE DESCRIPTION: We present a case of a luminal B, HER2-positive MBC. T-DXd was administered as the sixth-line regimen, resulting in a dramatic clinical response with near-complete resolution of the gluteal mass. After 14 months of therapy, the patient developed progressive cervical lymphadenopathy. Patient-derived organoids were generated, and subsequent drug screening was performed, which identified anlotinib plus T-DXd as a potential candidate regimen. She was then treated with anlotinib and T-DXd and had disease control for 6 months before progressive liver metastases were observed. Genomic analysis further revealed aberrations in the ErbB signaling and cell cycle pathways that might be implicated in the emergence of T-DXd resistance. CONCLUSIONS: This case suggests that T-DXd resistance may be attributed to dysregulation in the ErbB signaling and cell cycle pathways. In vitro experiments are being conducted to ascertain the potential benefits of targeted inhibition of angiogenesis or cell cycle proteins in overcoming T-DXd resistance. Nevertheless, more cases and follow-up information are needed to support these views.