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

Paolo Tarantino^{1

2

3}, Se-Eun Kim⁴, Melissa E Hughes^{5

6}, Ross J Kusmick⁵, Kalie Smith⁵, Fara Brasó-Maristany^{7

8}, Nay Nwe Nyein Chan⁹, Laia Paré Brunet⁷, Laura Alder¹⁰, Diana Garcia-Cortes^{5

11}, Jorge Gomez Tejeda Zanudo^{5

12

11}, Alyssa M Pereslete⁵, Laura Noteware¹⁰, Heather Moore¹⁰, Amanda E D Van Swearingen¹⁰, Tianyu Li⁴, Hersh Gupta⁵, Olivia D'Amico⁵, Alba Martini⁵, Stefania Morganti^{5

12

11}, Jennifer Spindel⁵, Charmaine Cook⁵, Christine McLaughlin⁵, Kathrin Dvir⁵, Ana C Garrido-Castro^{5

12}, Sarah Sammons^{5

12}, Janet Files⁵, Kerry Sendrick⁵, Simone Buck⁵, Deborah Dillon⁵, Rinath Jeselsohn^{5

12}, Yvonne Y Li^{5

11}, Andrew D Cherniack^{5

12

11}, Patricia LoRusso⁶, Maryam Lustberg⁶, Rosario Vega-León^{13

8}, Francisco Pardo^{7

8}, Justin Davis¹⁴, Claudius Mueller¹⁴, Brian Corgiat¹⁴, Giuseppe Curigliano^{15

16}, Carey K Anders¹⁰, Emanuel F Petricoin¹⁷, David L Rimm⁹, Aleix Prat^{7

8

18}, Nabihah Tayob^{12

4}, Nancy U Lin^{5

12}, Sara M Tolaney^{19

20}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Paolo_Tarantino@dfci.harvard.edu.
² Harvard Medical School, Boston, MA, USA. Paolo_Tarantino@dfci.harvard.edu.
³ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. Paolo_Tarantino@dfci.harvard.edu.
⁴ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Yale School of Medicine, New Haven, CT, USA.
⁷ August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
⁸ Reveal Genomics, Barcelona, Spain.
⁹ Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
¹⁰ Duke Cancer Institute, Durham, NC, USA.
¹¹ Broad Institute of MIT and Harvard, Boston, MA, USA.
¹² Harvard Medical School, Boston, MA, USA.
¹³ Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁴ Ignite Proteomics, Golden, CO, USA.
¹⁵ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
¹⁶ European Institute of Oncology IRCCS, Milan, Italy.
¹⁷ Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
¹⁸ Clínic Barcelona Comprehensive Cancer Center, Barcelona, Spain.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Sara_Tolaney@dfci.harvard.edu.
²⁰ Harvard Medical School, Boston, MA, USA. Sara_Tolaney@dfci.harvard.edu.

PMID: 41826432
DOI: 10.1038/s41698-026-01365-6

Free article

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

Paolo Tarantino et al. NPJ Precis Oncol. 2026.

Free article

. 2026 Mar 13.

doi: 10.1038/s41698-026-01365-6. Online ahead of print.

Authors

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Paolo_Tarantino@dfci.harvard.edu.
² Harvard Medical School, Boston, MA, USA. Paolo_Tarantino@dfci.harvard.edu.
³ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. Paolo_Tarantino@dfci.harvard.edu.
⁴ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Yale School of Medicine, New Haven, CT, USA.
⁷ August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
⁸ Reveal Genomics, Barcelona, Spain.
⁹ Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
¹⁰ Duke Cancer Institute, Durham, NC, USA.
¹¹ Broad Institute of MIT and Harvard, Boston, MA, USA.
¹² Harvard Medical School, Boston, MA, USA.
¹³ Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁴ Ignite Proteomics, Golden, CO, USA.
¹⁵ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
¹⁶ European Institute of Oncology IRCCS, Milan, Italy.
¹⁷ Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
¹⁸ Clínic Barcelona Comprehensive Cancer Center, Barcelona, Spain.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Sara_Tolaney@dfci.harvard.edu.
²⁰ Harvard Medical School, Boston, MA, USA. Sara_Tolaney@dfci.harvard.edu.

PMID: 41826432
DOI: 10.1038/s41698-026-01365-6

Abstract

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.

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Conflict of interest statement

Competing interests: The authors declare the following competing interests: P.T. reports consulting fees from AstraZeneca, BioNTech, Daiichi Sankyo, Gilead, Genentech/Roche, Novartis, Menarini/Stemline, Merck, Eli Lilly and Sanofi. J.G.T.Z. reports ownership of stocks in the biotechnology exchange-traded funds CNCR, IDNA, IBB, and XBI; owns stocks in Novo Nordisk and GRAIL; and previously owned stocks in Adaptive Biotechnologies, 2seventy bio, and bluebird bio. N.U.L. reports institutional research support from Genentech, Pfizer, Merck, Seattle Genetics, Zion Pharmaceuticals, Olema Pharmaceuticals, and AstraZeneca; consulting honoraria from Seattle Genetics, Daiichi Sankyo, AstraZeneca, Olema Pharmaceuticals, Stemline/Menarini, Artera Inc., Eisai, Shorla Oncology, Pfizer, and Denali Therapeutics; royalties from Up to date (book); and travel support from Olema, AstraZeneca, and Daiichi Sankyo. S.M.T. reports consulting or advisory roles for Novartis, Pfizer/Seagen, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Bristol Myers Squibb/Systimmune, Daiichi Sankyo, Gilead, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Jazz Pharmaceuticals, Natera, Tango Therapeutics, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, Launch Therapeutics, Zuellig Pharma, Johnson&Johnson/Ambrx, Bicycle Therapeutics, BeiGene Therapeutics, Mersana, Summit Therapeutics, Avenzo Therapeutics, Aktis Oncology, Celcuity, Boehringer Ingelheim, Samsung Bioepis, Olema Pharmaceuticals, Tempus, Boundless Bio, and Denali Therapeutics; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, AstraZeneca, NanoString Technologies, Gilead, Seagen, OncoPep, Daiichi Sankyo, Menarini/Stemline, Jazz Pharmaceuticals, and Olema Pharmaceuticals; and travel support from Lilly, Gilead, Jazz Pharmaceuticals, Pfizer, Arvinas, and Roche. A.D.C. receives research support from Bayer and consults for KaryoVerse. E.F.P. reports consulting for Ignite Proteomics, Perthera, DAiNA, Ceres Nanosciences, Equity for Perthera and Ceres Nanosciencesm Board of Director for Ceres Nanosciences, and royalty/licensing distribution from Ignite Proteomics for GMU assigned patents. C.K.A. reports research funding from PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, Pfizer, Astra Zeneca, Elucida, Caris, Incyclix, Beigene; honoraria from Genentech, Eisai, IPSEN, Seattle Genetics, Astra Zeneca, Novartis, Immunomedics, Elucida, Athenex, Roche; and royalties from UpToDate and Jones and Bartlett. D.L.R. has served as an advisor for AstraZeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, Danaher, Halda Therapeutics, Incendia, Nucleai, PAIGE.AI, and Sanofi. AstraZeneca, Cepheid, Konica Minolta, Leica, NavigateBP, NextCure, Nanostring, and Lilly, have funded or currently fund research in DLR’s lab. H.M. reports consulting fees from AstraZeneca, Lilly, Novartis, Gilead, and Genentech. GC reports honoraria from AstraZeneca, Celcuity, Daiichi Sankyo, Exact Sciences, Lilly, Merck, Novartis, Pfizer, Roche, Veracyte, Ellipsis, Astellas, Blueprint Medicine, BMS, Kymab, Merck, Novartis, Philogen, Relay Therapeutics, Sanofi; and non-financial interests with the Italian National Health Council as Advisor for Ministry of Health ESMO, ESMO as Clinical Practice Guidelines Chair, Europa Donna as Member of the Scientific Council, EUSOMA as member of the Advisory Council, Fondazione Beretta, Lega Italiana Lotta ai Tumori as member of Board of Directors. A.P. reports grants and owns shares from Reveal Genomics during the conduct of the study, other from Reveal Genomics, personal fees from Roche, grants and personal fees from AstraZeneca, Daiichi-Sankyo, Novartis, and Ona Therapeutics, outside the submitted work; in addition, A.P. has a patent HER2DX and DNADX licensed to Reveal Genomics. F.B.M. reports part-time employment by Reveal Genomics and has the HER2DX and DNADX patents licensed to Reveal Genomics. The other authors declare no competing interests.

References

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1. Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N. Engl. J. Med. 387, 9–20 (2022).
1. Curigliano, G. et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). J. Clin. Oncol. 42, LBA1000–LBA1000 (2024).
1. Cortés, J. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat. Med. 30, 2208–2215 (2024).
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Quantitative HER2 tissue and plasma profiling predicts the activity of trastuzumab deruxtecan for breast cancer

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous