Clinical outcomes and genomic landscape of anti-HER2 antibody-drug conjugates in HER2-positive and HER2-low metastatic breast cancer
Xiujuan Gui, Haizhu Chen, Jianli Zhao, Hongna Lai, Simin Luo, Jie Chai, Yangyang Cai, Wenjing Wu, Yinduo Zeng, Maojian Chen, Ying Wang, Herui Yao, Linxiaoxiao DingBackground
Anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) have revolutionized the treatment for HER2-positive and HER2-low metastatic breast cancer (MBC). However, the comparative efficacy, safety, and molecular predictors of response to various anti-HER2 ADCs remain limited.
Objectives
To evaluate real-world clinical outcomes, safety profiles, and genomic alterations associated with response to anti-HER2 ADCs in patients with HER2-positive or HER2-low MBC.
Design
Retrospective single-center cohort study.
Methods
Patients with HER2-positive or HER2-low MBC who received anti-HER2 ADCs (T-DXd, SHR-A1811, RC48, or T-DM1) between September 1, 2020, and September 1, 2024, were enrolled. Progression-free survival (PFS), overall survival, objective response rate (ORR), and safety were assessed. Targeted next-generation sequencing was performed to identify genomic correlates of response.
Results
A total of 322 patients were included, comprising 183 HER2-positive and 139 HER2-low cases. The ORR in the HER2-positive group and the HER2-low group were 32.8% versus 20.8%, respectively, and median PFS were 9.9 months versus 4.1 months. Median PFS in the T-DXd, SHR-A1811, RC48, and T-DM1 groups were 9.3 months, 25.8 months, 3.2 months, and 7.6 months, respectively (p<0.001). HER2 expression, prior lines of therapy, and ADC type independently predicted PFS. Common adverse events included hematologic toxicity, fatigue, and nausea; pneumonitis occurred in 7.3% of T-DXd recipients. Genomic profiling identified
Conclusions
This study provides descriptive real-world data on four anti-HER2 ADCs in HER2-positive and HER2-low MBC. Distinct genomic alterations, especially