Efficacy and safety of T-DXd in patients with HER2-positive and HER2-low metastatic breast cancer: a real-world study.

Abstract

Background: The DESTINY-Breast trials established trastuzumab deruxtecan (T-DXd) as a treatment significantly improving outcomes in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low metastatic breast cancer (MBC). However, real-world effectiveness is susceptible to confounding factors. This multicenter, real-world study aims to systematically evaluate the efficacy and safety of T-DXd in patients with HER2-positive and HER2-low MBC. Key clinicopathological parameters were to be integrated to develop an individualized prognostic prediction model, facilitating precision medicine implementation in clinical practice.

Methods: A retrospective analysis was conducted on clinical data from 142 patients with advanced breast cancer who received T-DXd therapy at multiple centers in Jiangsu and Anhui provinces between January 1, 2021, and August 31, 2024. The primary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and the incidence of adverse events (AEs). Univariate and multivariate Cox proportional hazards regression analyses were utilized to identify clinicopathological variables significantly associated with clinical outcomes and to develop a dynamic risk prediction model. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) to assess discriminative ability, Bootstrap calibration curves to determine predictive accuracy, and K-fold cross-validation to examine model stability and reproducibility.

Results: The median PFS in the total population was 9.5 months [95% confidence interval (CI): 7.2-11.9], with ORR and DCR of 30.3% and 88.7%, respectively. Subgroup analysis revealed significantly longer median PFS in HER2-positive patients compared to HER2-low patients (12.5 vs. 8.1 months, P=0.02) and superior efficacy with frontline (1^st-2^nd line) vs. later-line therapy (12.0 vs. 8.3 months, P=0.041). Additionally, dose reduction (98/142, 69.0%) did not significantly impact PFS overall (P=0.74) or in HER2 subgroups (positive: P=0.77; low: P=0.23). Based on the results of Cox analysis, this study established a nomogram model providing visual risk prediction [concordance index (C-index) =0.65, AUC =0.760] to achieve individualized prognostic visualization assessment and assist in clinical decision-making for T-DXd treatment. In this study, hematological AEs were most common (leukopenia: 56.3%, anemia: 69.0%). Non-hematological reactions included fatigue (46.5%) and hepatic dysfunction (40.1%), etc. The incidence of interstitial lung disease (ILD) was 4.9%, and all were mild cases.

Conclusions: Real-world evidence confirms T-DXd maintains clinical trial-aligned efficacy and safety. Earlier-line administration enhances survival benefit, while efficacy is preserved with dose reduction and remains acceptable in patients with limited physical capacity. Neutropenia and anemia predominated as hematologic toxicities; ILD incidence was lower than internationally reported. Key prognostic factors were integrated into a predictive model demonstrating good discrimination, stability, and consistency, supporting individualized treatment decisions.