Treatment status, survival and gene expression analysis of large-cell neuroendocrine lung carcinoma: a real-world study in China.

Background: Large-cell neuroendocrine lung carcinoma (LCNEC) is a rare subtype of lung cancer that lacks standard treatment at present.

Purpose: This study aimed to investigate the treatment status, failure pattern, survival outcome, and gene expression profile of LCNEC in China.

Design: This is a real-world retrospective study combined with transcriptome sequencing of LCNEC tumors.

Methods: Patients with newly diagnosed LCNEC at Beijing Chest Hospital from 2015 to 2022 were retrospectively reviewed. Treatment, failure pattern, and survival were analyzed. Transcriptome sequencing of LCNEC and non-small-cell lung cancer was conducted for differentiated expressed genes exploration and enrichment analysis.

Results: In all, 151 eligible patients met the criteria: stage I (24.5%), II (9.9%), IIIA (13.9%), and IIIB-IV (51.7%). Median progression-free survival (PFS) and overall survival (OS) were 7.9 and 17.8 months for an entire cohort of patients. For stage I/II and IIIA patients receiving radical operation or chemoradiation, 47 out of 77 cases developed treatment failure with 2-year cumulative systemic/distant failure (SF), locoregional failure (LRF), and overall failure rates of 65.2%, 52.7%, and 30.8%, respectively. Failure incidence increased with stage development. Stage III disease presented with a significantly higher cumulative SF rate (2-year, 57.3% vs 29.7%; p = 0.010) but a similar LRF rate (2-year, 41.5% vs 37.6%, p = 0.369) than stage I/II, achieving favorable SF-free survival and comparable LRF-free survival. Adding adjuvant chemotherapy to surgery reduced distant dissemination which translated into survival benefit (2-year SF, 53.7% vs 41.3%, p = 0.055; 2-year OS, 37.1% vs 79.9%, p < 0.001). For advanced LCNEC, immunochemotherapy and chemotherapy alone achieved PFS of 10.3 and 4.7 months, respectively (p = 0.045). Differential gene expression analysis revealed that antigen presentation/processing, chemokine signaling, CXCR4, and IFN-γ pathways were upregulated in LCNEC, suggesting the vulnerability of LCNEC to immunotherapy. Besides, MMP9, AGT, COL1A2, COL1A1, and CXCL9 may play vital roles in the LCNEC pathogenesis.

Conclusion: LCNEC is a highly aggressive disease and incorporation of immunotherapy might be an effective treatment option.