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

Lennart Hohmann, Kristin Sigurjonsdottir, Ana Bosch Campos, Deborah F. Nacer, Srinivas Veerla, Frida Rosengren, Poojaswini Thimmaraya Reddy, Jari Häkkinen, Nicklas Nordborg, Johan Vallon-Christersson, Yasin Memari, Daniella Black, Ramsay Bowden, Helen R. Davies, Åke Borg, Serena Nik-Zainal and Johan Staaf ()
Additional contact information
Lennart Hohmann: Lund University
Kristin Sigurjonsdottir: Lund University
Ana Bosch Campos: Lund University
Deborah F. Nacer: Lund University
Srinivas Veerla: Lund University
Frida Rosengren: Lund University
Poojaswini Thimmaraya Reddy: Lund University
Jari Häkkinen: Lund University
Nicklas Nordborg: Lund University
Johan Vallon-Christersson: Lund University
Yasin Memari: University of Cambridge
Daniella Black: University of Cambridge
Ramsay Bowden: University of Cambridge
Helen R. Davies: University of Cambridge
Åke Borg: Lund University
Serena Nik-Zainal: University of Cambridge
Johan Staaf: Lund University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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 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.

Date: 2025
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DOI: 10.1038/s41467-025-57419-z

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