Dr Di Federico on an Analysis of TTF-1 Expression in Lung Adenocarcinoma

Alessandro Di Federico, MD, research fellow, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, discusses findings from a study investigating the correlation between TTF-1 expression and outcomes with immunotherapy-based treatments in patients with lung adenocarcinoma, which he presented during the 2023 IASLC World Conference on Lung Cancer.

This study assessed TTF-1 expression in 3,313 patients with lung adenocarcinoma, 15.2% of whom had negative TTF-1 expression. The majority of patients with negative TTF-1 expression were smokers and at had more advanced stages of disease, Di Federico says. In total, 12.1% of TTF-1–negative patients had stage I through III disease, whereas 16.7% of TTF-1–negative patients had stage IV disease. Additionally, 13.7% of TTF-1–negative patients were never smokers, and 19.3% of TTF-1–negative patients had a smoking history.

The proportion of patients with PD-L1–positive disease was significantly higher in the TTF-1–positive group than in the TTF-1–negative group, Di Federico notes, adding that no difference in tumor mutational burden (TMB) was observed between the 2 groups.

When evaluating the proportion of TTF-1–negative patients according to genomic driver mutation, patients with KRAS-driven lung adenocarcinoma had the highest proportion of TTF-1–negative cases. Furthermore, pathogenic mutations in genes such as STK11, KEAP1, SMARCA4, CDK2NA, and NKX2-1, which is the gene that encodes for TTF-1, were enriched in patients with TTF-1–negative disease. Conversely, EGFR and MET mutations were enriched in patients with TTF-1–positive disease. The mutations enriched in patients with TTF-1–negative disease correlated with worse outcomes with immunotherapy, Di Federico emphasizes.

Patients with TTF-1–negative disease treated with chemoimmunotherapy had significantly lower overall response rates (ORRs) andworse progression-free survival (PFS) and overall survival (OS) outcomes compared with those who had TTF-1–positive disease. Similarly, findings from a smaller cohort of patients treated with KRAS G12C inhibitors showed numerically lower ORRs and significantly lower PFS and OS outcomes in patients with TTF-1–negative disease vs those with TTF-1–positive disease.

The ability of negative TTF-1 expression to predict outcomes with immunotherapy and chemotherapy was independent of STK11 and KEAP1 mutation status, PD-L1 expression, TMB, smoking status, performance status, and line of treatment, Di Federico explains. These findings indicate that TTF-1 expression is a proxy for unfavorable tumor biology and an independent prognostic factor in patients with lung adenocarcinoma, Di Federico concludes.