TTF-1 Expression in Lung Adenocarcinoma: Clinicopathologic, Genomic, and Immunophenotypic Correlates and Outcomes to Immunotherapy-Based Treatments and KRASG12C Inhibitors

INTRODUCTION:Thyroid transcription factor-1 (TTF-1) expression, routinely assessed through immunohistochemistry in the diagnostic evaluation of lung adenocarcinomas (LUADs), is negative (TTF-1Neg) in approximately 15% to 20% of cases. Although worse outcomes have been reported for these tumors compared with TTF-1-positive (TTF-1Pos) LUAD, a comprehensive characterization of TTF-1 negativity is currently lacking. METHODS:Patients with LUAD and available TTF-1 immunohistochemistry from five institutions, The Cancer Genome Atlas, the Stand Up To Cancer-Mark Foundation, and the POPLAR/OAK data sets, were included. Features and outcomes were analyzed according to TTF-1 expression. RESULTS:Among 3297 patients, TTF-1Neg (15%, n = 496), compared with TTF-1Pos (85%, n = 2801), was associated with a more frequent tobacco use history and lower PD-L1 expression. TTF-1Neg LUAD was enriched for STK11, KEAP1, SMARCA4, NKX2-1, CDKN2A, and KRAS mutations (q < 0.05). Patients with metastatic TTF-1Neg LUAD treated with immune checkpoint inhibitors (n = 233), compared with TTF-1Pos cases (n = 1179), had worse objective response rates (ORR, 17% versus 28%, p = 0.001), median progression-free survival (mPFS, 2.5 versus 4.4 mo, p < 0.0001), and median overall survival (mOS, 9.6 versus 20.2 mo, p < 0.0001). Similarly, TTF-1Neg cases had worse outcomes to chemoimmunotherapy (ORR, 26% versus 41%, p < 0.0001; mPFS, 4.6 versus 8.2 mo, p < 0.0001; mOS, 11.2 versus 23.4 mo, p < 0.0001), durvalumab after chemoradiation for unresectable stage III disease (mPFS, 8.0 versus 24.8 mo, p = 0.016; mOS, 20.0 mo versus not reached, p = 0.004), and KRASG12C inhibitors in KRASG12C-mutant LUAD (ORR, 13% versus 36%, p = 0.03; mPFS, 2.7 versus 5.9 mo, p < 0.0001; mOS, 4.4 versus 12.1 mo, p < 0.0001). CONCLUSIONS:TTF-1 negativity identifies a subset of LUAD with worse outcomes to immunotherapy, chemoimmunotherapy, and KRASG12C inhibitors.