TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading.

Objectives: Thyroid transcription factor 1 (TTF-1) is a well-established independent prognostic factor in lung adenocarcinoma (LUAD), irrespective of stage. This study aims to determine if TTF-1's prognostic impact is solely based on histomorphological differentiation (tumor grading) or if it independently relates to a biologically more aggressive phenotype. We analyzed a large bi-centric LUAD cohort to accurately assess TTF-1's prognostic value in relation to tumor grade.
Patients and Methods: We studied 447 patients with resected LUAD from major German lung cancer centers (Berlin and Cologne), correlating TTF-1 status and grading with clinical, pathologic, and molecular data, alongside patient outcomes. TTF-1's impact was evaluated through univariate and multivariate Cox regression. Causal graph analysis was used to identify and account for potential confounders, improving the statistical estimation of TTF-1's predictive power for clinical outcomes.
Results: Univariate analysis revealed TTF-1 positivity associated with significantly longer disease-free survival (DFS) (median log HR -0.83; p = 0.018). Higher tumor grade showed a non-significant association with shorter DFS (median log HR 0.30; p = 0,62 for G1 to G2 and 0.68; p = 0,34 for G2 to G3). In multivariate analysis, TTF-1 positivity resulted in a significantly longer DFS (median log HR -0.65; p = 0.05) independent of all other parameters, including grading. Adjusting for potential confounders as indicated by the causal graph confirmed the superiority of TTF-1 over tumor grading in prognostics power.
Conclusions: TTF-1 status predicts relapse and survival in LUAD independently of tumor grading. The prognostic power of tumor grading is limited to TTF-1-positive patients, and the effect size of TTF-1 surpasses that of tumor grading. We recommend including TTF1 status as a prognostic factor in the diagnostic guidelines of LUAD.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)