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Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review)

  • Authors:
    • Alexandros Georgiou
    • Evangelia Anna Spiteri
    • Demetrios A. Spandidos
    • Sofia Agelaki
    • Vassilis Zoumpourlis
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    Affiliations: School of Medicine, University of Crete, 71003 Heraklion, Greece, Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece, National Hellenic Research Foundation, 11635 Athens, Greece
    Copyright: © Georgiou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 103
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    Published online on: September 30, 2025
       https://doi.org/10.3892/mco.2025.2898
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Abstract

Breast cancer is classified, based on human epidermal growth factor receptor 2 (HER2) status, as HER2‑positive or HER2‑negative, guiding eligibility for HER2‑targeted therapies. A HER2‑low tumor is a type of breast cancer, which is defined by immunohistochemistry scores of 1+ or 2+ with negative in situ hybridization. Technological advances in HER2 testing, along with improved diagnostic precision, have increased the recognition of the HER2‑low subgroup. HER2‑low tumors may represent a distinct biological and clinical entity. Molecular profiling further demonstrates the unique transcriptomic and mutational signatures of HER2‑low tumors, particularly within hormone receptor‑positive contexts. In addition, clinical trials such as DESTINY‑Breast04, demonstrate notable efficacies for novel antibody‑drug conjugates, such as trastuzumab‑deruxtecan, in patients with HER2‑low tumors. This challenges the conventional HER2 stratification and suggests guideline revisions in order to acknowledge the HER2‑low status. The present review synthesized knowledge regarding HER2 biology, pathology and molecular features, and highlighted the clinical relevance and therapeutic implications of redefining HER2 status to include the HER2‑low subgroup. Recognizing HER2‑low as a discrete classification may refine patient stratification, optimize therapeutic selection and improve clinical outcomes in breast cancer management.
View Figures

Figure 1

Laboratory workflow for HER2
assessment in tissue samples of breast cancer, based on guidelines
from the College of American Pathologists (https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-guidelines/recommendations-for-human-epidermal-growth-factor-2-testing-in-breast-cancer).
HER2 assessment usually begins with IHC (scores of 0-1+ are
negative, 2+ are equivocal and 3+ are positive). Molecular
investigation is required for equivocal cases. Single-probe FISH
assesses ERBB2 copy number, while dual-probe FISH compares
ERBB2 to CEP17, which improves the accuracy. IHC,
immunohistochemistry; ISH, in situ hybridization; FISH,
fluorescence ISH; ERBB, erythroblastic oncogene B;
CEP17, chromosome enumeration probe 17. Created in BioRender
(publication license, Georgiou, A. (2025); https://BioRender.com/3140k7k).
View References

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Copy and paste a formatted citation
Spandidos Publications style
Georgiou A, Spiteri E, Spandidos DA, Agelaki S and Zoumpourlis V: Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review). Mol Clin Oncol 23: 103, 2025.
APA
Georgiou, A., Spiteri, E., Spandidos, D.A., Agelaki, S., & Zoumpourlis, V. (2025). Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review). Molecular and Clinical Oncology, 23, 103. https://doi.org/10.3892/mco.2025.2898
MLA
Georgiou, A., Spiteri, E., Spandidos, D. A., Agelaki, S., Zoumpourlis, V."Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review)". Molecular and Clinical Oncology 23.6 (2025): 103.
Chicago
Georgiou, A., Spiteri, E., Spandidos, D. A., Agelaki, S., Zoumpourlis, V."Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review)". Molecular and Clinical Oncology 23, no. 6 (2025): 103. https://doi.org/10.3892/mco.2025.2898
Copy and paste a formatted citation
x
Spandidos Publications style
Georgiou A, Spiteri E, Spandidos DA, Agelaki S and Zoumpourlis V: Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review). Mol Clin Oncol 23: 103, 2025.
APA
Georgiou, A., Spiteri, E., Spandidos, D.A., Agelaki, S., & Zoumpourlis, V. (2025). Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review). Molecular and Clinical Oncology, 23, 103. https://doi.org/10.3892/mco.2025.2898
MLA
Georgiou, A., Spiteri, E., Spandidos, D. A., Agelaki, S., Zoumpourlis, V."Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review)". Molecular and Clinical Oncology 23.6 (2025): 103.
Chicago
Georgiou, A., Spiteri, E., Spandidos, D. A., Agelaki, S., Zoumpourlis, V."Taking the ‘low’ into consideration: Discussions on redefining HER2 status in breast cancer (Review)". Molecular and Clinical Oncology 23, no. 6 (2025): 103. https://doi.org/10.3892/mco.2025.2898
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