TTF-1 Negativity Predicts Poor Outcomes in Advanced Non-Squamous NSCLC Also in the Immunotherapy Era: A Multicenter Cohort Study and Meta-Analysis

作者：Leonardo Brunetti, Valentina Santo, Alessandro Galletti, Alain Gelibter, Antonio Lugini, Gian Paolo Spinelli, Daniele Santini, Alessio Cortellini, Alessia Vendittelli, Giuseppina Rita Di Fazio, Fabrizio Citarella, Giulia La Cava, Emanuele Claudio Mingo, M. Fiorenti, Leonardo Cristofani, Sabrina Mariotti, Serena Ricciardi, Francesco Pantano, Bruno Vincenzi, Giuseppe Tonini, Marco Russano · 发表于：Cancers · 年份：2025 · DOI：10.3390/cancers17132188 · 被引用次数：4 · 研究领域：Cancer Immunotherapy and Biomarkers、Colorectal and Anal Carcinomas、Lung Cancer Treatments and Mutations

Background/Objectives: Despite advances in immunotherapy, reliable biomarkers beyond PD-L1 expression are urgently needed to optimize treatment decisions in advanced non-squamous NSCLC. Thyroid Transcription Factor-1 (TTF-1), a biomarker associated with favorable prognosis in chemotherapy-treated patients, has unclear prognostic implications in the immunotherapy era. Methods: We conducted a multicenter retrospective study involving 163 advanced non-squamous NSCLC patients treated with first-line immunotherapy or chemo-immunotherapy and an additional historical chemotherapy-only cohort (n = 37). We evaluated the prognostic significance of TTF-1 expression for progression-free survival (PFS) and overall survival (OS). A systematic review and meta-analysis, performed following PRISMA guidelines, integrated our findings with existing evidence. Hazard ratios (HRs) were calculated using Cox proportional hazards models. Results: TTF-1 negativity was associated with significantly worse median PFS (6.7 vs. 16 months; HR 2.22, 95% CI 1.59–3.13; p < 0.001) and OS (11.5 vs. 26.4 months; HR 2.33, 95% CI 1.64–3.45; p < 0.001) compared to TTF-1 positivity. The prognostic value of TTF-1 was independent of PD-L1 status, with limited predictive relevance of PD-L1 expression observed within TTF-1-negative tumors. Meta-analysis (9 studies, 14 cohorts, n = 2019 patients) confirmed significantly inferior outcomes for TTF-1-negative patients across multiple immunotherapy-based regimens (poole...