TTF-1 Expression in Lung Adenocarcinoma: Clinicopathologic, Genomic, and Immunophenotypic Correlates and Outcomes to Immunotherapy-Based Treatments and KRASG12C Inhibitors.
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Di Federico Alessandro, Hong Lingzhi, Elkrief Arielle, Thummalapalli Rohit, Cooper Alissa J, Ricciuti Biagio, Digumarthy Subba, Alessi Joao V, Gogia Pooja, Hambelton Grace M, Pecci Federica, Makarem Maisam, Gandhi Malini M, Garbo Edoardo, De Giglio Andrea, Gagliano Ambrogio, Sperandi Francesca, Gelsomino Francesco, Scalera Stefano, Cipriani Laura, Marinelli Daniele, Lamberti Giuseppe, Shaverdian Narek, Haradon Jessica, Nguyen Tom, Voligny Emma, Ladanyi Marc, Zhang Jianjun, Gibbons Don L, Heymach John V, Nishino Mizuki, Rodig Scott J, Pfaff Kathleen, Wang Xinan, Rekhtman Natasha, Sholl Lynette M, Luo Jia, Johnson Bruce E, Janne Pasi A, Arvind Ravi, Gainor Justin F, Maugeri-Saccà Marcello, Ardizzoni Andrea, Heist Rebecca S, Arbour Kathryn C, Schoenfeld Adam J, Vokes Natalie I, Awad Mark M
Аннотация
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.