Abstract 48P
Background
HER2 expressing breast cancers (BC) are heterogeneous and vary on a continuous scale from very low(1+) to very high (3+) expression. HER2 gene amplification has been identified as a key driver in HER2 3+ BC but not in case of HER2-low (1+, 2+) tumors, resulting in ineffectiveness of HER2-targeted therapies in HER2-low patients. This issue underscores the imperative need for further investigation and study in HER2 expressing BC.
Methods
Transcriptome profiling was done in HER2 3+ (11 cases), HER2 2+ (5 cases) and HER2 1+ (5 cases) breast cancers. The shortlisted genes from the transcriptome data were validated using RT-PCR in a separate cohorts of cases (Her2 3+: 40 cases, Her2 2+/1+: 25 cases each). All cohorts were compared and correlated with respective clinico-pathologic features.
Results
Transcriptome profiling revealed 30 differentially expressed genes among respective cohorts (Table 48P). The top 5 significantly upregulated genes in HER2 high and HER 2 low tumours were selected for validation. Genes exhibiting statistically significant upregulation in validation cohort include: Table: 48P
Pathways affected from upregulation of selected genes
Gene upregulated in HER2 High tumors | Gene upregulated in HER2 low tumors |
HER2ˆ, PIK3CAˆ, GRB7ˆ, FGFR2#, NEFH#, Nek8#, MMP10#; MRPS35# | PDK1#, AGR3$, and MAP4K5*,SOCS7* |
ˆHer2 signaling; ∗immune regulation, #Tumor progression, $Invasion.
Differential gene expression analysis of HER2 low (1+, 2+) and HER2 high (3+) tumors revealed an increase in the expression of genes related to HER2 receptor signaling and PIK3CA pathway in HER2 high tumors. But in HER2 low tumors, upregulation in genes associated with immune regulatory pathway, this implies the underlying heterogeneity of HER2 BC.
Conclusions
Distinct gene expression profiles as well as the pathways involved in each subtype indicate that these vary at transcriptome level. This study emphasizes on the careful assessment of HER2 status and contributes to the ongoing efforts in biomarker research and precision medicine.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
PGIMER.
Funding
Indian Council of Medical Research.
Disclosure
All authors have declared no conflicts of interest.
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