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. 2025 Dec 27.
doi: 10.1007/s11684-025-1187-6. Online ahead of print.

Prognostic utility of baseline ASCL1/INSM1 expression and neutrophil-lymphocyte ratio in unresectable SCLC treated with first-line chemoimmunotherapy with or without radiotherapy

Yanli Zhu #  1 , Sheng Li #  2 , Hanxiao Chen #  2 , Guangqian Ji #  3 , Haiyue Wang  1 , Xinting Diao  1 , Xiuli Ma  1 , Minglei Zhuo  4 , Dongmei Lin  5
Affiliations

Prognostic utility of baseline ASCL1/INSM1 expression and neutrophil-lymphocyte ratio in unresectable SCLC treated with first-line chemoimmunotherapy with or without radiotherapy

Yanli Zhu et al. Front Med. .

Abstract

While immune checkpoint inhibitors have revolutionized small cell lung carcinoma (SCLC) management, clinical benefits remain restricted to a subset of patients. This study investigates baseline biomarkers for predicting outcomes in unresectable SCLC patients receiving first-line chemoimmunotherapy with or without radiotherapy. We retrospectively analyzed treatment-naïve, unresectable SCLC patients undergoing first-line chemoimmunotherapy at Peking University Cancer Hospital (between June 2020 and November 2022). Clinicopathological parameters, pretreatment hematologic indices, and immunohistochemical profiles (ASCL1, NEUROD1, POU2F3, YAP1, PD-L1, CD8, MHC-I, and Rb) were correlated with survival outcomes using Cox proportional hazards models. Composite biomarker strategies were evaluated for therapeutic stratification. A total of 143 SCLC patients were included (LS=41, ES=102). The SCLC-A subtype demonstrated optimal median overall survival (OS) than other subtypes (18 months vs. 11 months, P = 0.02), and SCLC-P patients exhibited poorer prognosis than NE phenotypes (SCLC-A, SCLC-N, SCLC-AN). Multivariate analysis identified VALSG stage (P = 0.02) and bone metastases (P = 0.045) as independent OS predictors in the entire cohort. Patients stratified by ASCL1/INSM1 positivity and NLR thresholds showed markedly divergent outcomes, with ASCL1+/NLRlow group and or INSM1+/NLRlow group achieving superior OS in the overall cohort, LS-SCLC, and ES-SCLC. The ASCL1/INSM1-NLR composite biomarker stratifies survival outcomes for unresectable SCLC patients treated with first-line chemoimmunotherapy with or without radiotherapy. Prospective multicenter validation is required.

Keywords: NLR; SCLC; chemoimmunotherapy; molecular subtype; neutrophil-to-lymphocyte ratio; prognosis; small cell lung carcinoma.

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Conflict of interest statement

Compliance with ethics guidelines. Conflicts of interest Yanli Zhu, Sheng Li, Hanxiao Chen, Guangqian Ji, Haiyue Wang, Xinting Diao, Xiuli Ma, Minglei Zhuo, and Dongmei Lin declare no conflict of interest. The study was approved (or granted exemption) by the appropriate institutional and/or national research ethics committee (including the name of the ethics committee) and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

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