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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

The HER2MtGx Metagene Score as a Reliable Tool to Select HER2 Breast Cancer Patients for Neoadjuvant Targeted Therapy

by
Daniel Guimarães Tiezzi
1,*,
Isabela Panzeri Carlotti Buzatto
1,
Willian Abraham da Silveira
2,
Anna Clara Monti
3,
Fabiana de Oliveira Buono
1,
Juliana Meola
1,
Omero Benedicto Poli-Neto
1 and
Stefano Maria Pagnotta
4
1
Laboratory for Translational Data Science, Breast Disease Division, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil
2
School of Science, Engineering and Environment, University of Salford, Salford M5 4WT, UK
3
Dipartimento di Diritto, Economia, Management e Metodi Quantitativi, Università degli Studi del Sannio, 82100 Benevento, Italy
4
Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, 82100 Benevento, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(24), 11809; https://doi.org/10.3390/ijms262411809 (registering DOI)
Submission received: 21 October 2025 / Revised: 16 November 2025 / Accepted: 26 November 2025 / Published: 6 December 2025
(This article belongs to the Special Issue Computational Cancer Genomics and Molecular Profile in Breast Cancer)
Review Reports Versions Notes

Abstract

The cHER2+ breast cancer subtype is characterized by the overexpression of the HER2 oncoprotein based on immunohistochemistry (IHC)/or by ERBB2 gene amplification using in situ hybridization (ISH) techniques. Targeted therapies are significantly changing cancer treatment outcomes. However, not all patients benefit from it due to misclassification or intrinsic mechanisms of resistance. Identifying predictive factors of response to therapy is thus crucial for optimizing treatment protocol. In addition, with the development of effective antibody–drug conjugates for targeting HER2-low subtypes, enhancing the HER2 molecular classification is crucial. In this study, a comprehensive analysis of publicly available datasets (TCGA, METABRIC, I-SPY, NOAH and CHER-LOB trials) has been considered. We present a metagene expression score (HER2MtGx 31-gene assay) based on the most informative genes associated with each molecular profile. HER2MtGx scores represent three linear subspaces associated with the HER2, Luminal and Basal-like profiles (STAT). In the METABRIC cohort, the scores are useful to discriminate against the HER2-enriched phenotype and this classification is significantly associated with long-term survival in cHER2+ patients (HR = 1.76; 95%CI = 1.09–2.86). In terms of response to neoadjuvant chemo/target therapy including I-SPY, NOAH, and CHER-LOB trials, the metagene scores are associated with the pathological response to therapy (OR = 2.26; 95%CI = 1.74–2.98). The HER2MtGx assay is a reliable tool for selecting patients for HER2-targeted therapy.
Keywords: breast cancer; molecular profile; predictive factors; targeted therapy breast cancer; molecular profile; predictive factors; targeted therapy

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MDPI and ACS Style

Tiezzi, D.G.; Buzatto, I.P.C.; Silveira, W.A.d.; Monti, A.C.; Buono, F.d.O.; Meola, J.; Poli-Neto, O.B.; Pagnotta, S.M. The HER2MtGx Metagene Score as a Reliable Tool to Select HER2 Breast Cancer Patients for Neoadjuvant Targeted Therapy. Int. J. Mol. Sci. 2025, 26, 11809. https://doi.org/10.3390/ijms262411809

AMA Style

Tiezzi DG, Buzatto IPC, Silveira WAd, Monti AC, Buono FdO, Meola J, Poli-Neto OB, Pagnotta SM. The HER2MtGx Metagene Score as a Reliable Tool to Select HER2 Breast Cancer Patients for Neoadjuvant Targeted Therapy. International Journal of Molecular Sciences. 2025; 26(24):11809. https://doi.org/10.3390/ijms262411809

Chicago/Turabian Style

Tiezzi, Daniel Guimarães, Isabela Panzeri Carlotti Buzatto, Willian Abraham da Silveira, Anna Clara Monti, Fabiana de Oliveira Buono, Juliana Meola, Omero Benedicto Poli-Neto, and Stefano Maria Pagnotta. 2025. "The HER2MtGx Metagene Score as a Reliable Tool to Select HER2 Breast Cancer Patients for Neoadjuvant Targeted Therapy" International Journal of Molecular Sciences 26, no. 24: 11809. https://doi.org/10.3390/ijms262411809

APA Style

Tiezzi, D. G., Buzatto, I. P. C., Silveira, W. A. d., Monti, A. C., Buono, F. d. O., Meola, J., Poli-Neto, O. B., & Pagnotta, S. M. (2025). The HER2MtGx Metagene Score as a Reliable Tool to Select HER2 Breast Cancer Patients for Neoadjuvant Targeted Therapy. International Journal of Molecular Sciences, 26(24), 11809. https://doi.org/10.3390/ijms262411809

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