42P - HER2 aberration as a potential predictive biomarker for extrapulmonary small cell neuroendocrine carcinoma

Background

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is an uncommon and aggressive malignancy with a poor prognosis and an incidence rate of less than 0.4%. Most EP-SCNC patients present with metastatic disease, leading to an average overall survival (OS) of less than 12 months. Currently, platinum-based chemotherapy is the standard treatment, but there is no consensus on second-line therapy upon progression. Given the limited effective systemic options for EP-SCNC, identifying new therapeutic targets is crucial. One such target could be the human epidermal growth factor receptor 2 (HER2), a receptor tyrosine kinase involved in various cancer pathways. This pilot study investigates the mutational status and mRNA expression of the HER2 gene in EP-SCNC.

Methods

A cohort of 192 EP-SCNCs (91 genitourinary, 32 gastrointestinal, 21 gynaecological, 13 unknown primary, 12 pancreatic, 8 head and neck, 8 hepatobiliary, 6 breast, and 1 skin) underwent DNA-targeted panel next-generation sequencing of 788 genes, including HER2. mRNA expression analysis of the HER2 gene was conducted using whole-transcriptome RNA-Sequencing data.

Results

Activating mutations of the HER2 gene were detected in 6/128 (4.7%) EP-SCNCs, including 4 urinary bladder tumours, 1 anal canal tumour, and 1 uterine cervix tumour. Copy number variation (CNV) analysis revealed HER2 gene amplification in 3/83 (3.6%) cases. Gene expression analysis of HER2 across all groups showed median values ranging from 13.79 to 26.37 CPM (TMM-adjusted).

Conclusions

Our study found that 7% (9/128) of EP-SCNCs exhibited either mutation or amplification of the HER2 gene. Additionally, HER2 mRNA overexpression was observed in 6 other samples, suggesting potential overexpression of the HER2 protein. Confirming these findings at the protein level is essential and ongoing. Our preliminary results indicate that HER2 aberration could serve as a potential molecular target for treatment in EP-SCNCs.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Ministry of Health, Czech Republic (MH CZ AZV NU22-03-00130 and DRO-VFN 64165).

Disclosure

All authors have declared no conflicts of interest.