48P - Transcriptome profiling highlights distinct gene signatures in HER2 high (HER2 3+) and HER 2 low (Her2 1+/2+) breast cancers

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

^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.