Absence of thyroid transcription factor-1 expression is associated with poor survival in patients with advanced pulmonary adenocarcinoma treated with pemetrexed-based chemotherapy
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Adenocarcinoma is the commonest histologic subtype of lung cancer and is often identified by immunohistochemical staining for thyroid transcription factor-1 (TTF-1). However, up to 20% of lung adenocarcinomas do not express TTF-1, and there is uncertainty regarding the significance of this. We aimed to evaluate the prognostic effect of TTF-1 expression status on survival in patients treated with pemetrexed-based chemotherapy for advanced adenocarcinoma of the lung.
This retrospective study included patients treated with pemetrexed-based chemotherapy for stage IIIB/IV lung adenocarcinoma, who had known TTF-1 expression status. Clinical and demographic data were obtained from medical records. Overall survival (OS) was estimated using the Kaplan-Meier method, and differences in survival between groups assessed using the Cox proportional hazards model.
Forty-four patients were identified with documented TTF-1 expression: 35 with TTF-1-positive and 9 with TTF-1-negative disease. Patients in the TTF-1-negative group had poorer performance scores than those in the TTF-1-positive group (ECOG 2: 67 vs 20%, p = 0.008), and received less chemotherapy (median cycles 2 vs 4, p = 0.009), and were fewer in treatment with doublet regimens (22 vs 69%, p = 0.013). OS was significantly shorter in the TTF-1-negative group than in the TTF-1-positive group (2.4 vs 11.5 months, HR 8.38, p < 0.0001).
In this group of patients treated with pemetrexed-based chemotherapy for advanced pulmonary adenocarcinoma, absence of TTF-1 expression was associated with an aggressive tumor phenotype, poorer performance status, and poor survival. This subgroup of patients should be recognized as having a distinct clinical course, with limited benefit from standard chemotherapy.
KeywordsBiomarker Chemotherapy Non-small cell lung cancer Pemetrexed Thyroid transcription factor-1 TTF-1
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Pemetrexed is manufactured by Eli Lilly, Indianapolis, IN, USA. This company had no role in this work.
Compliance with ethical standards
This study involved human participants and was performed in accordance with the ethical standards of the Declaration of Helsinki.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer, LyonGoogle Scholar
- 3.Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551CrossRefGoogle Scholar
- 6.Bohinski RJ, Di Lauro R, Whitsett JA (1994) The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis. Mol Cell Biol 14:5671–5681CrossRefGoogle Scholar
- 9.Tanaka H, Yanagisawa K, Shinjo K, Taguchi A, Maeno K, Tomida S, Shimada Y, Osada H, Kosaka T, Matsubara H, Mitsudomi T, Sekido Y, Tanimoto M, Yatabe Y, Takahashi T (2007) Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res 67:6007–6011CrossRefGoogle Scholar
- 12.Puglisi F, Barbone F, Damante G, Bruckbauer M, di Lauro V, Beltrami CA, di Loreto C (1999) Prognostic value of thyroid transcription factor-1 in primary, resected, non-small cell lung carcinoma. Mod Pathol 12:318–324Google Scholar
- 17.Gronberg BH, Lund-Iversen M, Strom EH et al (2013) Associations between TS, TTF-1, FR-alpha, FPGS, and overall survival in patients with advanced non-small-cell lung cancer receiving pemetrexed plus carboplatin or gemcitabine plus carboplatin as first-line chemotherapy. J Thorac Oncol 8:1255–1264CrossRefGoogle Scholar
- 19.Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG (1992) A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 35:4450–4454CrossRefGoogle Scholar
- 20.Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar W, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, Andis SL, Bewley JR, Rayl EA, Moroson BA, Beardsley GP, Kohler W, Ratnam M, Schultz RM (1997) LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57:1116–1123Google Scholar
- 22.Nicolson MC, Fennell DA, Ferry D, O'Byrne K, Shah R, Potter V, Skailes G, Upadhyay S, Taylor P, André V, Nguyen TS, Myrand SP, Visseren-Grul C, Das M, Kerr KM (2013) Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial. J Thorac Oncol 8:930–939CrossRefGoogle Scholar