Comparison of molecular subtype composition between independent sets of primary and brain metastatic small cell lung carcinoma and matched samples

Introduction: Recent advances in the subclassification of small cell lung carcinomas (SCLCs) may help to overcome the unmet need for targeted therapies and improve survival. However, limited information is available on how the expression of the subtype markers changes during tumour progression. Our study aimed to compare the expression of these markers in primary and brain metastatic SCLCs.

Materials and methods: Immunohistochemical analysis of the subtype markers was performed on 120 SCLCs (including 10 matched samples) and SCLC xenografts.

Results: Compared to primary SCLCs, there was a significant increase in the proportion of mixed subtypes in brain metastases, with a rate of ASCL1^high/NeuroD1^high and ASCL1^high/NeuroD1^high/YAP1^high subtypes increasing to 48 % and 18 %, respectively. The subtype of the paired samples matched in only one-third of the cases. Although we did not observe a significant change after chemotherapy, a continuous decrease in ASCL1 expression coupled with an increase in the NeuroD1 expression was detected in the xenografts in a long-term experiment.

Discussion: Our results indicate that the expression of subtype markers frequently changes during disease progression, and subtype analysis of the primary SCLC may not provide accurate information about the characteristics of the recurrent or metastatic tumour. Therefore, repeated sampling and subtyping may be necessary for subtype-specific targeted therapy.