title: Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer.
abstract: 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.
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB). aprat@vhio.net.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: Barbara
authors.initials: B
authors.lastname: Adamo
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: Maria
authors.initials: M
authors.lastname: Vidal
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: : Breast 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 Carolina, Chapel Hill, NC; Memorial Sloan-Kettering Cancer Center, New York (JB).
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D015986:Confounding Factors, Epidemiologic; D056915:DNA Copy Number Variations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human