Little Molecular Difference and No Prognostic Effect of Clinical HER2 Status in Context of Intrinsic Breast Cancer Subtypes
In a study reported in the Journal of the National Cancer Institute, Prat et al found that there was little difference in downstream gene or protein expression according to intrinsic breast cancer subtypes among clinical HER2-positive vs -negative breast cancers and that clinical HER2 status did not add prognostic information to intrinsic subtypes in the absence of HER2-targeted therapy.
Study Details
The study involved interrogation of The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium datasets of primary breast cancers for molecular data derived from DNA, RNA, and protein. Intrinsic subtypes were determined. Clinical HER2 status was defined according to American Society of Clinical Oncology/College of American Pathologists guidelines or DNA copy-number aberration by single nucleotide polymorphism arrays.
Subtypes According to Clinical HER2 Status
Data from a total of 1,744 clinical HER2-negative and 481 clinical HER2-positive patients not treated with anti-HER2 therapy were included. Compared with clinical HER2-negative breast cancer, clinical HER2-positive breast cancer had a higher frequency of the HER2-enriched subtype (47.0% vs 7.1%), a lower frequency of luminal A (10.7% vs 39.0%) and basal-like (14.1% vs 23.4%) subtypes, and a similar frequency of luminal B subtype (28.2% vs 30.4%). The likelihood of clinical HER2-positivity was 64.6% in HER2-enriched, 20.0% in luminal B, 14.4% in basal-like, and 7.3% in luminal B subtypes.
Molecular Differences
Within each subtype, 0.3% to 3.9% of genes out of 25,186 evaluated and 3.5% to 7.0% of all proteins or phosphoproteins evaluated were differentially expressed between clinical HER2-positive and clinical HER2-negative tumors. Among clinical HER2-positive tumors, HER2 gene expression was significantly higher in HER2-enriched and basal-like tumors than in luminal A or luminal B tumors.
Effect on Survival
When evaluated alone, clinical HER2-positive status was associated with significantly poorer breast cancer-specific survival vs clinical HER2-negative status (hazard ratio [HR] = 1.53, P < .001) and clinical HER2 status provided independent prognostic information beyond that provided by clinicopathologic variables. However, the significant effect of clinical HER2 status was no longer evident when intrinsic subtypes were included in analysis, with subtypes providing independent prognostic information beyond that of clinical HER2 status. No significant impact of clinical HER2-positivity was observed for disease-specific survival in any of the four subtypes. For example, among patients with luminal A tumors, there was no difference in survival between those with clinical HER2-positive and those with clinical HER2-negative tumors (HR = 1.34, P = .46), and both of these subgroups had better survival compared with other subtypes irrespective of clinical HER2 status. In a similar analysis, the new 10-subtype copy number-based classification system (IntClust) also added no independent prognostic information to intrinsic subtype.
The investigators concluded: “When the intrinsic subtypes are taken into account, [clinical] HER2-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.”
Aleix Prat, MD, PhD, of Vall d’Hebron Institute of Oncology, Barcelona, is the corresponding author for the Journal of the National Cancer Institute article.
The study was supported by grants from the Susan G. Komen Foundation, National Cancer Institute, Banco Bilbao Vizcaya Argentaria Foundation, and Breast Cancer Research Foundation.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
