HER2 aberration is a potential predictive biomarker for extrapulmonary small cell neuroendocrine carcinoma contrary to small cell lung cancer

In this study, we investigated human epidermal growth factor receptor 2 (HER2) aberrations, including gene amplification and mutation, and protein expression in 123 small cell lung carcinomas (SCLC) and 128 extrapulmonary small cell neuroendocrine carcinomas (EP-SCNC) samples. Among the EP-SCNC cohort, HER2 mutations were found in 5.5% of samples (7/128); urinary bladder (4 cases), and one case each in samples from the colon, anal canal, and uterine cervix. In SCLCs, HER2 mutations were rare, detected in only 0.8% (1/119) of cases. We also identified eight EP-SCNCs and five SCLC cases with HER2 gene variants of uncertain significance (VUS). HER2 gene amplification was detected in 2.3% (3/128) of EP-SCNCs, but no amplification was found in SCLCs. The differences in HER2 mRNA expression were not statistically significant among tumor groups in the EP-SCNCs and SCLCs cohorts. RNA-seq analysis revealed high HER2 mRNA expression in seven EP-SCNCs and four SCLCs. An immunohistochemistry (IHC) analysis of 10 available tumors with high mRNA expression revealed HER2 protein positivity in 8 cases. The prognostic value of HER2 overexpression in EP-SCNC patients was not established in our study. Furthermore, EP-SCNC patients with high HER2 mRNA expression were generally younger, with a mean age of 60 years. These findings highlight the potential of HER2 as a therapeutic target in EP-SCNC, warranting further investigation into its clinical implications.