Quantitative HER2 tissue and plasma profiling predicts the activity of trastuzumab deruxtecan for breast cancer
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.
Authors
- Amanda E.D. Van Swearingen (ORCID: https://orcid.org/0000-0002-4287-9741)
- Laia Paré Brunet (ORCID: https://orcid.org/0000-0003-3894-6996)
- Sarah Sammons (ORCID: https://orcid.org/0000-0003-2589-9422)
- Carey K. Anders (ORCID: https://orcid.org/0000-0001-9165-4074)
- Melissa E. Hughes (ORCID: https://orcid.org/0000-0001-6190-9101)
- Kathrin Dvir (ORCID: https://orcid.org/0000-0002-3866-9290)
- Janet Files
- David L. Rimm (ORCID: https://orcid.org/0000-0001-5820-4397)
- Nay Chan (ORCID: https://orcid.org/0009-0006-1633-6125)
- Claudius Mueller
- Rinath M. Jeselsohn (ORCID: https://orcid.org/0000-0001-7996-7529)
- Stefania Morganti (ORCID: https://orcid.org/0000-0001-5284-9944)
- Alyssa Pereslete (ORCID: https://orcid.org/0000-0001-7995-7507)
- Jennifer Spindel (ORCID: https://orcid.org/0000-0002-5908-4611)
- Laura Alder (ORCID: https://orcid.org/0000-0003-2228-4094)
- Kalie Smith (ORCID: https://orcid.org/0000-0003-0461-8118)
- Hersh Gupta (ORCID: https://orcid.org/0000-0002-5136-6403)
- Diana García-Cortés (ORCID: https://orcid.org/0000-0003-1562-7319)
- Paolo Tarantino (ORCID: https://orcid.org/0000-0001-8686-0228)
- Laura Noteware (ORCID: https://orcid.org/0000-0001-9554-8930)
- Kerry Sendrick
- Ross J. Kusmick
- Alba Martini
- Simone Buck
- Andrew D. Cherniack
- Se-Eun Kim
- Patricia LoRusso
- Francisco Pardo
- Nancy U. Lin
- Sara M. Tolaney
- Deborah Dillon
- Emanuel F. Petricoin
- Fara Brasó-Maristany
- Brian Corgiat
- Justin Davis
- Rosario Vega- León
- Heather Moore
- Olivia D’Amico
- Jorge Gomez Tejeda Zanudo
- Giuseppe Curigliano
- Yvonne Y. Li
- Christine McLaughlin
- Tianyu Li
- Aleix Prat
- Nabihah Tayob
- Charmaine Cook
- Ana C. Garrido-Castro
- Maryam Lustberg
Institutions
- Broad Institute (US)
- Harvard University (US)
- George Mason University (US)
- University of Milan (IT)
- Yale University (US)
- Abterra Biosciences (United States) (US)
- Ospedale San Paolo (IT)
- Dana-Farber Cancer Institute (US)
- Cancer Clinic (US)
- Oryzon Genomics (Spain) (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Vall d'Hebron Institute of Oncology (ES)
- Duke Cancer Institute
- European Institute of Oncology (IT)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2026-03-13
- DOI
- https://doi.org/10.1038/s41698-026-01365-6
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Breast Cancer Research Foundation
- METAvivor
- Terri Brodeur Breast Cancer Foundation
- European Commission
- Fundación Científica Asociación Española Contra el Cáncer
- Instituto de Salud Carlos III