The Role of T-DXd in the Frontline Setting for HER2+ mBC and Treatment Personalization

The Destiny-Breast09 trial findings demonstrated improved progression-free survival (PFS) with T-DXd plus pertuzumab compared with the standard Cleopatra regimen in first-line HER2-positive metastatic breast cancer. However, interpretation requires careful consideration of study design nuances, as many patients in the control arm received only trastuzumab plus pertuzumab maintenance after taxane induction rather than continuous chemotherapy. The monotherapy T-DXd arm data remain pending. These will provide crucial information for treatment decision-making.

Patient selection for frontline T-DXd plus pertuzumab should focus on those requiring rapid response or having high-risk features such as extensive disease, visceral involvement, or central nervous system metastases where T-DXd demonstrates particular activity. The approach should not represent universal escalation for all patients, as some may achieve adequate disease control with less intensive regimens. For patients with hormone receptor–positive disease achieving response, de-escalation strategies such as switching to the PATINA regimen (endocrine therapy plus palbociclib with dual HER2 blockade) merit consideration.

Treatment personalization must balance the high efficacy of frontline T-DXd against potential overtreatment and the reality that up to 50% of patients may not receive subsequent therapies due to clinical deterioration. Quality-of-life considerations, patient preferences, and individual risk factors, including disease-free interval, tumor burden, and genomic characteristics, should guide treatment selection. The availability of proven second-line options such as T-DXd (Destiny-Breast03 findings showing 29-month PFS and overall survival benefit) supports reserve strategies for appropriate patients, emphasizing the importance of individualized treatment approaches over universal protocols.