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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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Abstract

Introduction

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.

Methods

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.

Results

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).

Conclusions

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.

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References

  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, Lyon

    Google Scholar 

  2. Devesa SS, Bray F, Vizcaino AP, Parkin DM (2005) International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rates rising. Int J Cancer 117:294–299

    Article  CAS  PubMed  Google 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 26:3543–3551

    Article  CAS  PubMed  Google Scholar 

  4. Civitareale D, Lonigro R, Sinclair AJ, di Lauro R (1989) A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO J 8:2537–2542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Minoo P, Su G, Drum H, Bringas P, Kimura S (1999) Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(−/−) mouse embryos. Dev Biol 209:60–71

    Article  CAS  PubMed  Google 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 14:5671–5681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kaufmann O, Dietel M (2000) Thyroid transcription factor-1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to surfactant proteins A and B. Histopathology 36:8–16

    Article  CAS  PubMed  Google Scholar 

  8. Winslow MM, Dayton TL, Verhaak RG et al (2011) Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 473:101–104

    Article  CAS  PubMed  PubMed Central  Google 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 67:6007–6011

    Article  CAS  PubMed  Google Scholar 

  10. Berghmans T, Paesmans M, Mascaux C, Martin B, Meert AP, Haller A, Lafitte JJ, Sculier JP (2006) Thyroid transcription factor 1—a new prognostic factor in lung cancer: a meta-analysis. Ann Oncol 17:1673–1676

    Article  CAS  PubMed  Google Scholar 

  11. Qian HH, Xu TS, Cai XQ, Ji TL, Guo HX (2015) Prognostic value of TTF-1 expression in patients with non-small cell lung cancer: a meta-analysis. Clin Chim Acta 451:208–214

    Article  CAS  PubMed  Google 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 12:318–324

    CAS  PubMed  Google Scholar 

  13. Pelosi G, Fraggetta F, Pasini F, Maisonneuve P, Sonzogni A, Iannucci A, Terzi A, Bresaola E, Valduga F, Lupo C, Viale G (2001) Immunoreactivity for thyroid transcription factor-1 in stage I non-small cell carcinomas of the lung. Am J Surg Pathol 25:363–372

    Article  CAS  PubMed  Google Scholar 

  14. Chung KP, Huang YT, Chang YL, Yu CJ, Yang CH, Chang YC, Shih JY, Yang PC (2012) Clinical significance of thyroid transcription factor-1 in advanced lung adenocarcinoma under epidermal growth factor receptor tyrosine kinase inhibitor treatment. Chest 141:420–428

    Article  CAS  PubMed  Google Scholar 

  15. Martins SJ, Takagaki TY, Silva AG et al (2009) Prognostic relevance of TTF-1 and MMP-9 expression in advanced lung adenocarcinoma. Lung Cancer 64:105–109

    Article  PubMed  Google Scholar 

  16. Sun JM, Han J, Ahn JS, Park K, Ahn MJ (2011) Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. J Thorac Oncol 6:1392–1399

    Article  PubMed  Google 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 8:1255–1264

    Article  CAS  PubMed  Google Scholar 

  18. Elsamany SA, Al-Fayea TM, Alzahrani AS et al (2015) Thyroid transcription factor-1 expression in advanced non-small cell lung cancer: impact on survival outcome. Asian Pac J Cancer Prev 16:2987–2991

    Article  PubMed  Google 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 35:4450–4454

    Article  CAS  PubMed  Google 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 57:1116–1123

    CAS  PubMed  Google Scholar 

  21. Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K (2011) Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer 104:1594–1601

    Article  CAS  PubMed  PubMed Central  Google 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 8:930–939

    Article  CAS  PubMed  Google Scholar 

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Funding source

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.

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Authors and Affiliations

  1. Cancer Clinical Trials and Research Unit, Beaumont Hospital, Dublin, Ireland

    Mark K. Doherty, Emer O’Connor, David Hannon, Aine O’Reilly, Daphne Yen, Liam M. Grogan, Bryan T. Hennessy, Oscar S. Breathnach & Patrick G. Morris

  2. Department of Pathology, Beaumont Hospital, Dublin, Ireland

    Maeve Redmond

  3. Royal College of Surgeons of Ireland, Dublin, Ireland

    Bryan T. Hennessy & Patrick G. Morris

  4. Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland

    Liam M. Grogan, Bryan T. Hennessy, Oscar S. Breathnach & Patrick G. Morris

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  1. Mark K. Doherty
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  2. Emer O’Connor
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  3. David Hannon
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  4. Aine O’Reilly
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  9. Oscar S. Breathnach
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Correspondence to Patrick G. Morris.

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This study involved human participants and was performed in accordance with the ethical standards of the Declaration of Helsinki.

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The authors declare that they have no conflict of interest.

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Doherty, M.K., O’Connor, E., Hannon, D. et al. Absence of thyroid transcription factor-1 expression is associated with poor survival in patients with advanced pulmonary adenocarcinoma treated with pemetrexed-based chemotherapy. Ir J Med Sci 188, 69–74 (2019). https://doi.org/10.1007/s11845-018-1839-5

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  • DOI: https://doi.org/10.1007/s11845-018-1839-5

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