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<p>Trastuzumab deruxtecan (T-DXd) is commonly used for treating metastatic breast cancer (MBC); however, traditional HER2 immunohistochemistry has largely failed to predict T-DXd activity. We reviewed survival outcomes and tested the reliability of multiple HER2 quantitative assays in predicting T-DXd’s performance among 191 patients with MBC. We demonstrate that T-DXd’s activity varies depending on the temporal evolution of HER2 immunohistochemical expression, with the longest activity observed among patients with HER2-positive disease or maintaining HER2-low disease across primary and metastatic settings. Quantitative HER2 assessment on pre-T-DXd samples showed that time-to-next treatment progressively increased by High Sensitivity-HER2 quartiles, Reverse Phase Protein Array HER2 quartiles, HER2DX ERBB2 mRNA scores and plasma-based DNADX HER2 signature tertiles (all with log-rank <i>p</i> &lt; 0.05). Conversely, HER2 immunohistochemical subtypes showed limited predictive value for clinical outcomes. Additionally, elevated TOPO1 expression was associated with worse outcomes with T-DXd in HER2-negative breast cancer, suggesting potential relevance for payload-related markers in predicting T-DXd performance.</p>

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Quantitative HER2 tissue and plasma profiling predicts the activity of trastuzumab deruxtecan for breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Paolo Tarantino,
  • Se-Eun Kim,
  • Melissa E. Hughes,
  • Ross J. Kusmick,
  • Kalie Smith,
  • Fara Brasó-Maristany,
  • Nay Nwe Nyein Chan,
  • Laia Paré Brunet,
  • Laura Alder,
  • Diana Garcia-Cortes,
  • Jorge Gomez Tejeda Zanudo,
  • Alyssa M. Pereslete,
  • Laura Noteware,
  • Heather Moore,
  • Amanda E. D. Van Swearingen,
  • Tianyu Li,
  • Hersh Gupta,
  • Olivia D’Amico,
  • Alba Martini,
  • Stefania Morganti,
  • Jennifer Spindel,
  • Charmaine Cook,
  • Christine McLaughlin,
  • Kathrin Dvir,
  • Ana C. Garrido-Castro,
  • Sarah Sammons,
  • Janet Files,
  • Kerry Sendrick,
  • Simone Buck,
  • Deborah Dillon,
  • Rinath Jeselsohn,
  • Yvonne Y. Li,
  • Andrew D. Cherniack,
  • Patricia LoRusso,
  • Maryam Lustberg,
  • Rosario Vega- León,
  • Francisco Pardo,
  • Justin Davis,
  • Claudius Mueller,
  • Brian Corgiat,
  • Giuseppe Curigliano,
  • Carey K. Anders,
  • Emanuel F. Petricoin,
  • David L. Rimm,
  • Aleix Prat,
  • Nabihah Tayob,
  • Nancy U. Lin,
  • Sara M. Tolaney

摘要

Trastuzumab deruxtecan (T-DXd) is commonly used for treating metastatic breast cancer (MBC); however, traditional HER2 immunohistochemistry has largely failed to predict T-DXd activity. We reviewed survival outcomes and tested the reliability of multiple HER2 quantitative assays in predicting T-DXd’s performance among 191 patients with MBC. We demonstrate that T-DXd’s activity varies depending on the temporal evolution of HER2 immunohistochemical expression, with the longest activity observed among patients with HER2-positive disease or maintaining HER2-low disease across primary and metastatic settings. Quantitative HER2 assessment on pre-T-DXd samples showed that time-to-next treatment progressively increased by High Sensitivity-HER2 quartiles, Reverse Phase Protein Array HER2 quartiles, HER2DX ERBB2 mRNA scores and plasma-based DNADX HER2 signature tertiles (all with log-rank p < 0.05). Conversely, HER2 immunohistochemical subtypes showed limited predictive value for clinical outcomes. Additionally, elevated TOPO1 expression was associated with worse outcomes with T-DXd in HER2-negative breast cancer, suggesting potential relevance for payload-related markers in predicting T-DXd performance.