Identification of subtypes in human epidermal growth factor receptor 2--positive breast cancer reveals a gene signature prognostic of outcome.
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.
Staaf
Johan
J
Department of Oncology, CREATE Health Strategic Center for TranslationalCancer Research, Lund University, Lund, Sweden.
Ringnér
Markus
M
Vallon-Christersson
Johan
J
Jönsson
Göran
G
Bendahl
Pär-Ola
PO
Holm
Karolina
K
Arason
Adalgeir
A
Gunnarsson
Haukur
H
Hegardt
Cecilia
C
Agnarsson
Bjarni A
BA
Luts
Lena
L
Grabau
Dorthe
D
Fernö
Mårten
M
Malmström
Per-Olof
PO
Johannsson
Oskar Th
OT
Loman
Niklas
N
Barkardottir
Rosa B
RB
Borg
Ake
A
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D002280:Basal Cell Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015996:Survival Rate
D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human