Mechanisms of resistance to trastuzumab deruxtecan in breast cancer elucidated by multi-omic molecular profiling
George W. Sledge, Joanne Xiu, Reshma Mahtani, Ana C. Sandoval Leon, Funda Meric‐Bernstam, Jennifer R. Ribeiro, Ninad Kulkarni, Dileep R. Rampa, Jangsoon Lee, Naoto T. Ueno, Matthew J. Oberley, Milan Radovich, David Spetzler
Abstract
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate successfully used to treat HER2-low and HER2-positive metastatic breast cancer, but resistance consistently develops. Using multivariate Cox proportional hazards in a real-world cohort of 2,799 patients with breast cancer, we aimed to identify clinically relevant T-DXd resistance mechanisms. In patients with samples collected prior to T-DXd treatment, higher expression of ERBB2 (HER2) and lower expression of ABCC1 (an ATP-binding cassette transporter involved in drug efflux) were significantly associated with longer T-DXd-related overall survival (OS); ABCC1 predicted OS independently of HER2. Furthermore, mutations in several genes were enriched in post-T-DXd samples compared to unmatched T-DXd-naïve samples, including ERBB2, NFE2L2 (a transcriptional activator of ABCC1), and KEAP1 (a negative regulator of NFE2L2), indicating plausible resistance mechanisms related to HER2 target levels and ABCC1-mediated drug efflux. Identifying such resistance mechanisms might lead to improved methods of precision oncology and novel therapeutic approaches to overcome resistance.