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

+Author Affiliations

Affiliations of authors: 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).

Correspondence to: Aleix Prat, MD, PhD, Translational Genomics Group, Vall d’Hebron Institute of Oncology, Pg Vall d’Hebron, 119–129, 08035, Barcelona, Spain (e-mail:aprat@vhio.net).

Received November 16, 2013.
Revision received April 18, 2014.
Accepted May 1, 2014.

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.

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