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Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer

Hohmann, Lennart LU orcid ; Sigurjonsdottir, Kristin LU ; Campos, Ana Bosch LU ; Nacer, Deborah F. LU orcid ; Veerla, Srinivas LU orcid ; Rosengren, Frida LU ; Reddy, Poojaswini Thimmaraya LU ; Häkkinen, Jari LU orcid ; Nordborg, Nicklas LU and Vallon-Christersson, Johan LU orcid , et al. (2025) In Nature Communications 16. p.1-17
Abstract

ER-positive/HER2-negative (ERpHER2n) breast cancer classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a small high-risk patient subgroup. In this study, we investigate genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors using two primary ERpHER2n cohorts comprising a total of 5640 patients. We show that ERpHER2n-HER2E tumors exhibit aggressive clinical features and poorer clinical outcomes compared to Luminal A and Luminal B tumors. Furthermore, ERpHER2n-HER2E breast cancer does not consist of misclassified or HER2-low cases, has little impact of ERBB2, is highly proliferative and less ER dependent than other luminal subtypes. It is not an obvious biological entity but is nevertheless associated... (More)

ER-positive/HER2-negative (ERpHER2n) breast cancer classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a small high-risk patient subgroup. In this study, we investigate genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors using two primary ERpHER2n cohorts comprising a total of 5640 patients. We show that ERpHER2n-HER2E tumors exhibit aggressive clinical features and poorer clinical outcomes compared to Luminal A and Luminal B tumors. Furthermore, ERpHER2n-HER2E breast cancer does not consist of misclassified or HER2-low cases, has little impact of ERBB2, is highly proliferative and less ER dependent than other luminal subtypes. It is not an obvious biological entity but is nevertheless associated with potentially targetable molecular features, notably a high immune response and high FGFR4 expression. Strikingly, molecular features that define the HER2E subtype in luminal disease are also consistent in HER2-positive disease, including an epigenetic mechanism for high FGFR4 expression in breast cancer.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
article number
2208
pages
1 - 17
publisher
Nature Publishing Group
external identifiers
  • pmid:40044693
  • scopus:86000563682
ISSN
2041-1723
DOI
10.1038/s41467-025-57419-z
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
d40087c1-dd94-4dce-9689-88344f750146
date added to LUP
2025-04-01 23:06:59
date last changed
2025-07-23 07:49:47
@article{d40087c1-dd94-4dce-9689-88344f750146,
  abstract     = {{<p>ER-positive/HER2-negative (ERpHER2n) breast cancer classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a small high-risk patient subgroup. In this study, we investigate genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors using two primary ERpHER2n cohorts comprising a total of 5640 patients. We show that ERpHER2n-HER2E tumors exhibit aggressive clinical features and poorer clinical outcomes compared to Luminal A and Luminal B tumors. Furthermore, ERpHER2n-HER2E breast cancer does not consist of misclassified or HER2-low cases, has little impact of ERBB2, is highly proliferative and less ER dependent than other luminal subtypes. It is not an obvious biological entity but is nevertheless associated with potentially targetable molecular features, notably a high immune response and high FGFR4 expression. Strikingly, molecular features that define the HER2E subtype in luminal disease are also consistent in HER2-positive disease, including an epigenetic mechanism for high FGFR4 expression in breast cancer.</p>}},
  author       = {{Hohmann, Lennart and Sigurjonsdottir, Kristin and Campos, Ana Bosch and Nacer, Deborah F. and Veerla, Srinivas and Rosengren, Frida and Reddy, Poojaswini Thimmaraya and Häkkinen, Jari and Nordborg, Nicklas and Vallon-Christersson, Johan and Memari, Yasin and Black, Daniella and Bowden, Ramsay and Davies, Helen R. and Borg, Åke and Nik-Zainal, Serena and Staaf, Johan}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  pages        = {{1--17}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-57419-z}},
  doi          = {{10.1038/s41467-025-57419-z}},
  volume       = {{16}},
  year         = {{2025}},
}