Expanding ADC Use in HER2-Low Hormone Receptor–Positive Disease

This segment explores the rapidly evolving treatment landscape for hormone receptor–positive, HER2-low metastatic breast cancer, driven by findings from the DESTINY-Breast04 and DESTINY-Breast06 trials. These studies have reshaped disease classification and treatment sequencing by demonstrating the efficacy of T-DXd earlier in the treatment course. Notably, DESTINY-Breast06 introduced the concept of HER2 “ultra-low” expression, highlighting the need for more precise and standardized pathology reporting to ensure appropriate patient identification.

T-DXd has emerged as a preferred option following endocrine therapy for patients with HER2-low or ultra-low disease, with consistent PFS benefit across both groups. However, clinical decision-making remains nuanced. For patients with indolent, bone-only disease or slow disease kinetics, clinicians may still consider oral chemotherapy options such as capecitabine, particularly when balancing convenience, toxicity, and patient preference against the transition to intravenous ADC therapy. In contrast, patients with higher-risk features, such as visceral or central nervous system involvement, are more likely to benefit from earlier use of T-DXd.

The discussion also addresses the growing role of other ADCs targeting TROP-2, including agents evaluated in the TROPiCS-02 and related trials. These therapies provide additional options after prior chemotherapy, with demonstrated progression-free survival benefit and, in some cases, overall survival improvement. Given similar efficacy across agents, treatment selection is often guided by toxicity profiles, dosing schedules, prior treatment history, and patient-specific factors.

Overall, the segment highlights the expanding complexity and personalization of ADC sequencing in hormone receptor–positive metastatic breast cancer.