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.

Figure 1.

Distribution of the intrinsic molecular subtypes of breast cancer in clinical HER2 status (cHER2)-negative and cHER2+ disease in the combined the cancer genome atlas and molecular taxonomy of breast cancer international consortium dataset. cHER2 = clinical HER2 status.

Figure 2.

Gene expression patterns of the intrinsic molecular subtypes of breast cancer based on clinical HER2 status (cHER2) status in the molecular taxonomy of breast cancer international consortium (METABRIC) dataset. A) Relative transcript abundance of estrogen receptor gene (ESR1) and HER2 gene (ERBB2) across the intrinsic subtypes and based on HER2 status. The boxes represent the interquartile range (25th and 75th percentiles), and the horizontal line in the box represents the median value. The whiskers show the range of largest and smallest values. B) Hierarchical clustering of the cHER2+ and cHER2-negative intrinsic subtypes (total of 8 classes) with 13497 most variable genes in the METABRIC dataset. Sample and gene expression data from tumor samples of the same subtype, and of the same cHER2 status, have been combined into a single category. For each gene in a class, we calculated the standardized mean difference between the gene′s expression in that class, vs its overall mean expression in the dataset using an 8-class Significance Analyses of Microarrays on the METABRIC dataset. On the right panel, a heatmap of genes located in a selected gene cluster is shown. For both heatmaps, red color represents relative high gene expression, green represents relative low gene expression, and black represents median gene expression.

Figure 3.

Kaplan-Meier 10-year breast cancer-specific survival analyses in the molecular taxonomy of breast cancer international consortium dataset (all patients). A) Based on cHER2 status. B) Based on intrinsic subtype and cHER2 status. Tables of the numbers of patients at risk in each group at various time points are below each graph. Statistically significant differences were determined by two-sided log-rank test.