Subtyping limited stage small cell lung cancer (LS SCLC) reveals inflammatory subtypes with improved chemoradiotherapy outcomes

BACKGROUND: Concurrent chemoradiotherapy (CRT) remains the primary treatment for limited stage (LS) small cell lung cancer (SCLC). Although most patients respond, the majority relapse and die from the disease, and treatment-related toxicity is common. Molecular subtyping has been extensively investigated in SCLC, but its clinical relevance remains uncertain, and most studies have focused on systemic treatment of extensive-stage SCLC. We analysed baseline tumor samples from a subset of participants (n = 77) in a randomized trial (n = 170) comparing high-dose (60 Gy/40 fractions) with standard-dose (45 Gy/30 fractions) twice-daily thoracic radiotherapy given concurrently with platinum-etoposide chemotherapy for LS SCLC, aiming to characterize molecular subtypes of LS SCLC and evaluate their association with time to progression (TTP) and overall survival (OS). METHODS: Molecular subtypes were defined in 81 samples using non-negative matrix factorization on gene expression data, supported by differential expression and known SCLC markers. RESULTS: Inflamed subtypes were associated with better treatment outcomes. Univariable analysis indicate that SCLC-I-NE (inflamed neuroendocrine) was associated with longer TTP (HR 0.10, 95 % CI 0.01-0.80, p = 0.03), and SCLC-I-nNE (inflamed non-neuroendocrine) was associated with improved OS (HR 0.16, 95 % CI 0.03-0.77, p = 0.02). By contrast, SCLC-N (NEUROD1-driven) was consistently associated with both shorter TTP (HR 6.90, 95 % CI 1.49-31.92, p = 0.01) and OS (HR 4.89, 95 % CI 1.24-19.21, p = 0.02). CONCLUSIONS: For LS SCLC patients receiving CRT, tumors of inflamed subtypes were associated with improved outcomes, whereas SCLC-N tumors were linked to unfavorable TTP and OS.