TROP2 H-score in PDXs correlated with TROP2 expression in matched patients (r= 0.7264, p<0.0001), however expression was lower in PDXs (p= 0.04). Dato-DXd caused R/SD in 2 of 9 models at 1 mg/kg, and in 4 of 9 models at 10 mg/kg. All models that regressed with Dato-DXd expressed TROP2. TROP2 expression was associated with higher antitumor activity compared to IgG-DXd based on T/C ratio (r= -0.7448, p= 0.0213) and EFS-2 (r= 0.9318, p= 0.0068) at 10 mg/kg but not at 1 mg/kg.Dato-DXd is a promising therapy for breast cancer patients including those resistant to standard chemotherapy. Additional biomarkers may better integrate DXd sensitivity into patient selection.