The molecular subtypes of small cell lung cancer defined by key transcription factors and their clinical significance.

Background: Lung cancer, a prevalent and deadly malignancy, is classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is further subdivided into four molecular subtypes-SCLC-A, SCLC-N, SCLC-P, and SCLC-I-based on key transcription factor expression.

Methods: Immunohistochemistry (IHC) was used to assess ASCL1, NEUROD1, and POU2F3 expression in tumor tissues. The H-Score quantified these results. Clinical characteristics, overall survival (OS), progression-free survival (PFS), and treatment responses were analyzed by subtype, and sensitivity to different treatments was assessed. Risk factors were identified through univariate and multivariate analyses.

Results: IHC and H-Score analysis showed that POU2F3 expression was mutually exclusive with ASCL1 or NEUROD1. Subtype distribution was as follows: SCLC-A (40 %), SCLC-N (33 %), SCLC-P (7 %), and SCLC-I (20 %). There were no significant differences in baseline characteristics, OS (p = 0.829), or PFS (p = 0.924) among subtypes. However, the SCLC-I subtype showed a trend toward improved outcomes with platinum-based doublet chemotherapy plus immune checkpoint inhibitors. Multivariate COX regression identified M stage (HR: 1.72, 95 % CI: 1.13-2.63, p = 0.012) and bone metastasis at diagnosis (HR: 1.58, 95 % CI: 1.02-2.43, p = 0.040) as independent risk factors.

Conclusion: This study confirmed the SCLC subtyping based on key transcription factors. While no significant differences in OS and PFS among subtypes were found, the SCLC-I subtype showed potential benefit from platinum-based chemotherapy combined with immune checkpoint inhibitors. M stage and bone metastasis at diagnosis were identified as independent risk factors for SCLC.