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

  • 0Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Nature Communications +

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March 5, 2025

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March 5, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

The HER2-enriched subtype of ER-positive/HER2-negative breast cancer (ERpHER2n-HER2E) shows aggressive traits and poorer outcomes. This high-risk group has distinct molecular features, including high FGFR4 expression and immune response.

Area Of Science

  • Oncology
  • Genomics
  • Molecular Biology

Background

  • Estrogen receptor-positive/HER2-negative (ERpHER2n) breast cancer is common, but a subset classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a high-risk group.
  • Understanding the unique biological and clinical characteristics of ERpHER2n-HER2E tumors is crucial for improving patient outcomes.

Purpose Of The Study

  • To investigate the genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors.
  • To compare ERpHER2n-HER2E tumors with other luminal subtypes (Luminal A and Luminal B) and HER2-positive disease.

Main Methods

  • Analysis of two large ERpHER2n cohorts totaling 5640 patients.
  • Integration of genomic, transcriptomic, and clinical data to characterize the ERpHER2n-HER2E subtype.
  • Comparative analysis against Luminal A, Luminal B, and HER2-positive breast cancer subtypes.

Main Results

  • ERpHER2n-HER2E tumors exhibit more aggressive clinical features and poorer outcomes than Luminal A and Luminal B tumors.
  • This subtype is highly proliferative, less estrogen receptor-dependent, and not characterized by misclassified HER2-low cases.
  • Key molecular features include a strong immune response and elevated FGFR4 expression, with conserved epigenetic mechanisms for high FGFR4 in both luminal and HER2-positive disease.

Conclusions

  • The ERpHER2n-HER2E subtype, while not a distinct biological entity, presents a high-risk profile with aggressive clinical behavior.
  • Elevated FGFR4 expression and a significant immune response are notable molecular characteristics offering potential therapeutic targets.
  • Findings highlight conserved molecular features, particularly FGFR4 regulation, across different breast cancer subtypes.