Molecular subtypes of small cell lung cancer transformed from adenocarcinoma after EGFR tyrosine kinase inhibitor treatment

Background: A certain proportion of non-small cell lung cancer (NSCLC) with activating EGFR mutations showed resistance to tyrosine kinase inhibitors (TKIs) by transforming their histology into small cell lung cancer (SCLC). In this study, we evaluated the molecular characteristics of transformed SCLCs. Methods: Eighteen SCLC tissue samples transformed after EGFR TKI treatment were used for the analysis. Immunohistochemistry was conducted to evaluate the molecular subtype using antibodies representative of the major transcriptional factor-based molecular subtypes, ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1. Subtypes were categorized based on a predefined criteria. Results: Among the study population (n=18), most of the patients were initially diagnosed with adenocarcinoma (n=17), and one patient was diagnosed with adenosquamous histology. Eight patients (44.4%) were never-smokers, and nine patients were women (50.0%). Staining of pre-transformation sample was conducted in six patients, and five of them showed no discernible expression for ASCL1, NEUROD1, or POU2F3. However, the proportion of molecular subtypes after SCLC transformation was predominantly SCLC-N (n=9, 50.0%), followed by SCLC-Triple Negative (SCLC-TN; n=5, 27.8%) and SCLC-A (n=4, 22.2%). The median overall survival from TKI initiation was longer in patients who transformed to SCLC-A (P=0.009) than in those who transformed to either SCLC-N or SCLC-TN. However, the overall survival difference since SCLC transformation was not significant (P=0.370). Conclusions: In our series, SCLC-N subtype was prevalent in SCLC transformed after EGFR TKI treatment. In addition, overall survival and the time to SCLC transformation from the EGFR TKI treatment were longer in patients who transformed to the SCLC-A type. Large-scale data will be required to confirm our findings.