Clinical Implications of Progression After First-Line T-DXd in HER2 Positive Metastatic Breast Cancer

This segment introduces a patient with HER2 positive metastatic breast cancer who experiences disease progression after a prolonged and meaningful response to first-line trastuzumab deruxtecan–based therapy. The discussion emphasizes why optimal first-line selection remains critical, as early treatment choices influence depth of response, duration of disease control, and downstream sequencing opportunities. Panelists interpret the pattern of hepatic progression with limited, asymptomatic CNS involvement as reflective of ongoing HER2 dependence rather than aggressive endocrine or molecular escape. The conversation explores what a long initial response suggests about tumor biology, including sustained sensitivity to HER2 targeted therapy, while acknowledging that eventual progression is expected. This segment frames progression not as treatment failure, but as a predictable transition point that requires thoughtful reassessment of disease behavior, therapeutic goals, and next-line strategy.