Efficacy and safety of trastuzumab emtansine versus trastuzumab deruxtecan in HER2-positive breast cancer with anti-HER2 therapy resistance: a multicenter retrospective study

Resistance to anti-HER2 targeted therapy remains a major clinical challenge in the management of HER2-positive breast cancer, with limited data comparing the efficacy and safety of trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (DS-8201) in this patient population. This study aimed to evaluate the therapeutic outcomes of the two antibody-drug conjugates (ADCs) and identify prognostic factors for progression-free survival (PFS) in patients with anti-HER2 therapy-resistant HER2-positive breast cancer. A multicenter, retrospective cohort study was conducted at five medical centers in China (Zhejiang Provincial People’s Hospital, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Taizhou Central Hospital, Linyi Central Hospital, and Ningbo First People’s Hospital). Baseline characteristics were well balanced between the two groups, except for a significantly higher metastatic burden in the DS-8201 group (brain metastasis: 37.7% vs. 20.0%, p = 0.032; visceral metastasis: 80.3% vs. 38.3%, p < 0.001). The DS-8201 group achieved a significantly higher objective response rate (ORR) (19.7% vs. 5.0%, Fisher exact p = 0.025) and comparable disease control rate (DCR) (78.7% vs. 73.3%, Fisher exact p = 0.529) compared to the T-DM1 group. Regarding survival, the DS-8201 group had significantly longer median progression-free survival (PFS) (11.20 months, 95%CI: 10.79–11.61 vs. 8.85 months, 95%CI: 8.44–9.26, p < 0.001) and median overall survival (OS) (32.80 months, 95%CI: 32.04–33.56 vs. 26.60 months, 95%CI: 25.98–27.22, p < 0.001), with higher 1-year PFS (47.5% vs. 31.7%, p = 0.045) and 1-year OS rates (86.9% vs. 75.0%, p = 0.048). Safety profiles were manageable in both groups, with distinct hematological adverse event (AE) patterns: the DS-8201 group had a higher incidence of neutropenia (44.3% vs. 26.7%, p = 0.043) but a lower incidence of thrombocytopenia (31.1% vs. 50.0%, p = 0.035), while the incidence of severe AEs (grade 3–4) was comparable. Multivariate Cox regression identified DS-8201 treatment (HR = 0.618, 95%CI: 0.397–0.962, p = 0.033), HER2 3 + status (HR = 0.625, 95%CI: 0.391–0.993, p = 0.045), and ECOG score 0 (HR = 1.795, 95%CI: 1.128–2.857, p = 0.013) as independent prognostic factors for PFS. Additionally, target lesion shrinkage rate was strongly correlated with both PFS (R²=0.794, p < 0.001) and OS (R²=0.659, p < 0.001). In patients with anti-HER2 therapy-resistant HER2-positive breast cancer, DS-8201 demonstrates superior antitumor efficacy (higher ORR, longer DOR and OS) compared to T-DM1, even in the context of higher baseline metastatic burden. Both ADCs have acceptable and manageable safety profiles with distinct AE patterns. DS-8201 treatment, HER2 3 + status, and better performance status are favorable prognostic factors, and target lesion shrinkage rate can serve as a reliable predictive marker for survival. Our exploratory real-world data indicates DS-8201 may provide promising anti-tumor and survival benefits in this refractory patient subgroup.