Aya Mohamed, Associate Lecturer of Medical Oncology, Member of ASCO, shared a post about a paper by Wanyi Chen et al. on X, adding:
”A key mechanism of resistance to trastuzumab deruxtecan (T-DXd), particularly in HER2-low breast cancers, is the loss of HER2 expression – reported in approximately 41% of HER2 1+, 16% of 2+, and 5% of 3+ tumors.”
Title: Trastuzumab Deruxtecan (T-DXd) Resistance via Loss of HER2 Expression and Binding
Authors: Wanyi Chen, Avantika Gupta, Nicholas Mai, Sharanya Nag, Joshua S. Lau, Sukrit Singh, John D. Chodera, Bo Liu, Elisa de Stanchina, Fresia Pareja, Atif Ali. Hashmi, Miriam M. Lieberman, Shanu Modi, Jacqueline Bromberg, Pedram Razavi, Joshua Z. Drago, Sarat Chandarlapaty
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This resistance pattern reflects the limited biological dependence of HER2-low tumors on HER2 signaling. Under selective pressure from HER2-directed ADC therapy, cells with higher HER2 expression are eradicated, while HER2-negative subclones proliferate, ultimately leading to antigen loss and diminished T-DXd binding and internalization.
HER2+ Breast Cancer identified 9 biomarkers driving lapatinib resistance — 7 of them reported for the first time Multi-omics profiling shows resistant cells silence most genes but keep these active, enhancing invasion and aggressiveness.
Title: Integrative proteo-genomic profiling uncovers key biomarkers of lapatinib resistance in HER2-positive breast cancer
Authors: J. Steggall, V. Rajeeve, N. Al-Subaie, A. Naeem, A. Ikram, A. Naeem, A. Hayat
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An important step toward biomarker-guided therapies in HER2-positive disease.
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