Identification of subtypes in human epidermal growth factor receptor 2--positive breast cancer reveals a gene signature prognostic of outcome

Johan Staaf, Markus Ringnér, Johan Vallon-Christersson, Göran Jönsson, Pär-Ola Bendahl, Karolina Holm, Adalgeir Arason, Haukur Gunnarsson, Cecilia Hegardt, Bjarni A Agnarsson, Lena Luts, Dorthe Grabau, Mårten Fernö, Per-Olof Malmström, Oskar Th Johannsson, Niklas Loman, Rosa B Barkardottir, Ake Borg

Research output: Contribution to journalArticlepeer-review


PURPOSE Human epidermal growth factor receptor 2 (HER2) gene amplification or protein overexpression (HER2 positivity) defines a clinically challenging subgroup of patients with breast cancer (BC) with variable prognosis and response to therapy. We aimed to investigate the heterogeneous biologic appearance and clinical behavior of HER2-positive tumors using molecular profiling. PATIENTS AND METHODS Hierarchical clustering of gene expression data from 58 HER2-amplified tumors of various stage, histologic grade, and estrogen receptor (ER) status was used to construct a HER2-derived prognostic predictor that was further evaluated in several large independent BC data sets. RESULTS Unsupervised analysis identified three subtypes of HER2-positive tumors with mixed stage, histologic grade, and ER status. One subtype had a significantly worse clinical outcome. A prognostic predictor was created based on differentially expressed genes between the subtype with worse outcome and the other subtypes. The predictor was able to define patient groups with better and worse outcome in HER2-positive BC across multiple independent BC data sets and identify a sizable HER2-positive group with long disease-free survival and low mortality. Significant correlation to prognosis was also observed in basal-like, ER-negative, lymph node-positive, and high-grade tumors, irrespective of HER2 status. The predictor included genes associated with immune response, tumor invasion, and metastasis. CONCLUSION The HER2-derived prognostic predictor provides further insight into the heterogeneous biology of HER2-positive tumors and may become useful for improved selection of patients who need additional treatment with new drugs targeting the HER2 pathway.

Other keywords

  • Breast Neoplasms
  • Carcinoma, Basal Cell
  • Female
  • Gene Amplification
  • Gene Expression Profiling
  • Humans
  • Lymph Nodes
  • Middle Aged
  • Neoplasm Staging
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Receptor, erbB-2
  • Receptors, Estrogen
  • Survival Rate
  • Tumor Markers, Biological


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