Navigating Treatment Selection for HER2-Low and -Ultralow Metastatic Breast Cancer

Real-World ADC Outcomes and HER2 Expression Considerations

Recent real-world evidence from over 4000 patients with HER2-negative metastatic breast cancer provides insights into comparative antibody-drug conjugate (ADC) effectiveness across different HER2 expression levels. Analysis of insurance claims data comparing T-DXd vs sacituzumab govitecan in hormone receptor–positive disease showed longer time on treatment for trastuzumab deruxtecan, though this difference was not significant in triple-negative disease. This real-world validation supports clinical trial findings in hormone receptor–positive disease populations.

Particularly intriguing findings emerged regarding HER2-null disease, where patients appeared to achieve better outcomes with sacituzumab govitecan compared with T-DXd. This observation suggests potential biomarker-driven selection strategies, with patients with HER2-null disease potentially benefiting more from TROP2-targeted therapy rather than HER2-targeted approaches. These findings raise important questions about sequencing decisions based on HER2 expression levels within the broadly defined HER2-negative disease population.

The implications for clinical practice include consideration of HER2 expression intensity when selecting initial ADC therapy. Patients with HER2-low or -ultralow expression may derive greater benefit from trastuzumab deruxtecan, whereas those with HER2-null disease might achieve better outcomes with sacituzumab govitecan as first-line ADC therapy. This nuanced approach to biomarker-driven ADC selection represents an evolution in personalized cancer treatment within the HER2-negative spectrum.