Diffuse and Strong TTF-1 Expression Predicts Response to Pemetrexed-Based Immunochemotherapy in Advanced Lung Adenocarcinoma

Abstract

Jun Yamada,1 Naoe Jimbo,2 Nanami Yamasaki,3,&ast; Yukihisa Hatakeyama,3,&ast; Tatsunori Kiriu,4,&ast; Natsuhiko Iwamoto,5,&ast; Kanoko Matsumura,5,&ast; Masahiro Katsurada,6,&ast; Keiko Okuno,6,&ast; Kyosuke Nakata,7,&ast; Motoko Tachihara1 1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 2Department of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan; 3Department of Respiratory Medicine, Akashi Medical Center, Akashi, Japan; 4Department of Respiratory Medicine, Hyogo Prefectural Awaji Medical Center, Sumoto, Japan; 5Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Japan; 6Department of Respiratory Medicine, Hyogo Prefectural Tamba Medical Center, Tamba, Japan; 7Department of Respiratory Medicine, Konan Medical Center, Kobe, Japan&ast;These authors contributed equally to this workCorrespondence: Motoko Tachihara, Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan, Tel [phone], Email [email protected]: Thyroid transcription factor-1 (TTF-1) is a good prognostic factor for non-small cell lung carcinoma (NSCLC). It is unclear how much TTF-1 staining is sufficient to predict therapeutic response in immunochemotherapy. We evaluated the cut-off of TTF-1 considering the percentage of positive cells and staining intensity as a predictive factor.Patients and Methods: We conducted a retrospective multicenter study of patients with advanced lung adenocarcinoma or NSCLC favor adenocarcinoma treated with immunochemotherapy. One pathologist centrally examined the immunohistochemical staining of TTF-1 using 8G7G3/1 and provided scores of 0– 5 based on the staining intensity and ratio.Results: We analyzed 95 patients. As TTF-1 has previously been shown to be a predictive factor for pemetrexed, there were significant differences in PFS of patients treated with pemetrexed-based immunochemotherapy between TTF-1 scores of 5 (diffuse and strong staining) and ≤ 4, but not between 0 (no staining) and 2– 4 (partial or weak staining). We defined a TTF-1 score of ≥ 5 as positive for the predictive factor and the positivity ratio was 61.1%. Patients who tested negative for TTF-1 had a significantly higher proportion of programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1%. Excluding mutation-positive patients, PFS in TTF-1 positivity was significantly longer than in negativity (8.0 and 5.9, hazard ratio (HR): 0.58 (0.34– 0.98), p = 0.04), while TTF-1 negativity was not inferior to positivity in PFS with taxane-based immunochemotherapy. Patients treated with pemetrexed-based immunochemotherapy who tested positive for TTF-1 had significantly longer PFS than those who tested negative (HR: 0.51 (0.27– 0.99), p = 0.045) in the multivariate analysis incorporating age, PD-L1, PS, and TTF-1.Conclusion: Diffuse and strong TTF-1 positivity may be useful for the predictive factor for pemetrexed-based immunochemotherapy. TTF-1 staining may be desirable to develop a more optimal immunochemotherapy for lung adenocarcinoma. Keywords: TTF-1, advanced lung adenocarcinoma, immunochemotherapy, immunohistochemical staining

Keywords

• TTF-1
• advanced lung adenocarcinoma
• immunochemotherapy
• immunohistochemical staining