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: Aleix Prat, Lisa A Carey, Barbara Adamo, Maria Vidal, Josep Tabernero, Javier Cortés, Joel S Parker, Charles M Perou, José Baselga
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 106 Issue 8 (Aug 2014) ISSN: 1460-2105 [Electronic] United States
• PMID: 25139534 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism, mortality)
• Confounding Factors, Epidemiologic
• DNA Copy Number Variations
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Molecular Targeted Therapy
• Polymorphism, Single Nucleotide
• Receptor, ErbB-2 (drug effects, genetics)
• Signal Transduction