martes, 9 de septiembre de 2014

Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer

Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer

JNCI J Natl Cancer Inst

Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer

  1. José Baselga
+Author Affiliations
  1. Affiliations of authorsBreast Cancer Unit (AP, BA, MV, JC), Department of Medical Oncology (AP, BA, MV, JC, JT), and Translational Genomics Group (AP, MV), Vall d′Hebron Institute of Oncology Barcelona, Spain; Lineberger Comprehensive Cancer Center (LAC, JSP, CMP), Department of Genetics (CMP), and Department of Pathology and Laboratory Medicine (CMP), University of North CarolinaChapel Hill, NCMemorial Sloan-Kettering Cancer Center, New York (JB).
  1. Correspondence to: Aleix Prat, MD, PhD, Translational Genomics Group, Vall d’Hebron Institute of Oncology, Pg Vall d’Hebron, 119–129, 08035, Barcelona, Spain (
  • Received November 16, 2013.
  • Revision received April 18, 2014.
  • Accepted May 1, 2014.


Background The clinical impact of the biological heterogeneity within HER2-positive (HER2+) breast cancer is not fully understood. Here, we evaluated the molecular features and survival outcomes of the intrinsic subtypes within HER2+ breast cancer.
Methods We interrogated The Cancer Genome Atlas (n = 495) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets (n = 1730) of primary breast cancers for molecular data derived from DNA, RNA and protein, and determined intrinsic subtype. Clinical HER2 status was defined according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines or DNA copy-number aberration by single nucleotide polymorphism arrays. Cox models tested the prognostic significance of each variable in patients not treated with trastuzumab (n = 1711).
Results Compared with clinically HER2 (cHER2)-negative breast cancer, cHER2+ breast cancer had a higher frequency of the HER2-enriched (HER2E) subtype (47.0% vs 7.1%) and a lower frequency of Luminal A (10.7% vs 39.0%) and Basal-like (14.1% vs 23.4%) subtypes. The likelihood of cHER2-positivity in HER2E, Luminal B, Basal-like and Luminal A subtypes was 64.6%, 20.0%, 14.4% and 7.3%, respectively. Within each subtype, only 0.3% to 3.9% of genes were found differentially expressed between cHER2+ and cHER2-negative tumors. Within cHER2+ tumors, HER2 gene and protein expression was statistically significantly higher in the HER2E and Basal-like subtypes than either luminal subtype. Neither cHER2 status nor the new 10-subtype copy number-based classification system (IntClust) added independent prognostic value to intrinsic subtype.
Conclusions When the intrinsic subtypes are taken into account, cHER2-positivity does not translate into large changes in the expression of downstream signaling pathways, nor does it affect patient survival in the absence of HER2 targeting.
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