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<p>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 <i>ERBB2</i> (HER2) and lower expression of <i>ABCC1</i> (an ATP-binding cassette transporter involved in drug efflux) were significantly associated with longer T-DXd-related overall survival (OS); <i>ABCC1</i> 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 <i>ERBB2</i>, <i>NFE2L2</i> (a transcriptional activator of <i>ABCC1</i>), and <i>KEAP1</i> (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.</p>

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Mechanisms of resistance to trastuzumab deruxtecan in breast cancer elucidated by multi-omic molecular profiling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • George W. Sledge,
  • Joanne Xiu,
  • Reshma L. Mahtani,
  • Ana C. Sandoval Leon,
  • Funda Meric-Bernstam,
  • Jennifer R. Ribeiro,
  • Ninad N. Kulkarni,
  • Dileep R. Rampa,
  • Jangsoon Lee,
  • Naoto T. Ueno,
  • Matthew J. Oberley,
  • Milan Radovich,
  • David B. Spetzler

摘要

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.