Background Both trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2), and anti-trophoblast cell-surface antigen 2 (TROP2) ADCs are recommended therapeutic options for patients with HER2-low advanced breast cancer. However, direct comparative studies between these two strategies remain lacking.

Objective To compare the efficacy and safety of T-DXd versus anti-TROP2 ADCs in patients with HER2-low advanced breast cancer (ABC).

Methods Clinical data about patients with HER2-low ABC treated with T-DXd or anti-TROP2 ADCs (including SG, Dato-DXd, and SKB264) at the Fifth Medical Center of PLA General Hospital from May 2021 to July 2025 were analyzed. Inverse probability of treatment weighting (IPTW) was utilized to balance baseline characteristics and adjust for confounding factors. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), and safety.

Results A total of 220 patients were included (T-DXd group: n=138, median age 52 IQR: 46-59 years; anti-TROP2 ADC group: n=82, median age 53 IQR: 45-59 years). After IPTW adjustment, the standardized mean differences (SMDs) of all covariates were reduced to below 0.1. In the overall population, the T-DXd group demonstrated superior median PFS compared to the anti-TROP2 ADC group (6.5 vs 4.5 months; HR=0.60; 95% CI: 0.44 - 0.81; P < 0.001). Multivariable Cox regression analysis identified ADC category as the sole independent predictor of PFS: compared to anti-TROP2 ADCs, T-DXd significantly reduced the risk of disease progression (aHR=0.50; 95% CI: 0.35 - 0.72; P < 0.001), while other clinical features showed no statistically significant difference after adjustment (all P > 0.05). Subgroup analysis revealed consistent PFS benefits with T-DXd across multiple prespecified subgroups. A significant interaction was observed between HR status and treatment regimen (P_interaction=0.002). Specifically, T-DXd provided a significant survival advantage in the HR-positive subgroup (HR= 0.40; 95% CI: 0.27 - 0.61; P < 0.001), whereas no significant difference in PFS was observed in the HR-negative subgroup (HR=1.29; P=0.392). Hematologic adverse events were the most frequent; the incidences of leukopenia in the T-DXd and anti-TROP2 ADC groups were 67.4% and 50.0%, with grade 3/4 neutropenia occurring in 9.4% and 14.6% of patients.

Conclusion In patients with HER2-low advanced breast cancer, T-DXd demonstrated more pronounced survival benefit and favorable safety compared to anti-TROP2 ADCs, with potentially greater efficacy in the HER2 IHC 2+ population. Furthermore, the benefit of T-DXd was particularly pronounced among HR-positive patients, suggesting that HR status may be an important determinant of T-DXd efficacy. These findings suggest that integrating HR status with HER2 expression profiles is essential for optimizing personalized ADC selection in clinical practice.