Prognostic index for predicting outcomes of trastuzumab deruxtecan in HER2 expressing metastatic breast cancer: a real-world multicenter study.

Background: Trastuzumab deruxtecan (T-DXd) has shown efficacy in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low metastatic breast cancer (MBC), but real-world prognostic data in heavily pre-treated patients are limited. This study evaluates T-DXd's real-world efficacy and identifies predictive factors.

Methods: Our study included 317 patients (HER2-positive: n = 173; HER2-low: n = 144) treated with T-DXd between January 3, 2020, and September 9, 2024. Outcomes included real-world progression-free survival (rwPFS), overall survival (rwOS), objective response rate (ORR), and safety. A prognostic index was developed using clinical parameters.

Results: In the HER2-positive cohort, ORR was 44.5%, with a median rwPFS of 10.5 months and rwOS of 29.9 months. Early-line T-DXd use (first or second line) improved rwPFS and rwOS compared with later lines (P < .0001), while prior tubulin-inhibitor antibody-drug conjugates (ADCs) were associated with inferior outcomes. In the HER2-low cohort, ORR was 24.3%, with a median rwPFS of 5.6 months, and rwOS of 18.5 months. Prior exposure to topoisomerase-inhibitor-payload ADCs significantly reduced rwPFS (1.97 vs. 5.97 months, P < .0001) and rwOS (5.77 vs. 18.9 months, P < .0001). Primary resistance rates were higher in HER2-low disease (24.3% vs. 12.7%, P = .011). Prognostic index incorporating treatment lines, HER2 expression, and prior ADC exposure effectively stratified patients into risk groups with distinct survival outcomes.

Conclusions: T-DXd shows clinical benefit in HER2-expressing MBC, with efficacy influenced by treatment line, HER2 expression, and prior ADC payload type. The prognostic index could aid in personalizing therapy, optimizing patient selection for T-DXd in real-world practice.