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Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer

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Abstract

Background

Thymidylate synthase (TYMS) expression in lung cancer tissue affects the therapeutic efficacy of pemetrexed (PMT). TYMS protein expression is primarily assessed using immunohistochemistry (IHC), but this method is not suitable for accurate quantitative analysis. It is not known whether the analysis of TYMS gene copy number using fluorescence in situ hybridization (FISH) is a useful method for assessment of TYMS expression.

Patients and methods

The participants were patients with chemo-naïve advanced NSCLC treated with PMT plus carboplatin (CBDCA) in prospective clinical phase II study. TYMS expression was evaluated in 40 patients by gene copy number and protein expression using FISH and IHC. Therapeutic efficacy was evaluated by investigating the response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Results

TYMS gene amplification was detected in 8 patients (32 %) among 25 patients who could be evaluated for TYMS gene copy number. There were no patients with complete or partial response in the TYMS amplified group. RR and DCR were lower in the TYMS amplified group compared with the TYMS unamplified group (0 versus 35.3 %, p = 0.0539, 62.5 versus 94.1 %, p = 0.0443). PFS and OS were reduced in the TYMS amplified group. The analysis of TYMS gene copy number had higher sensitivity and specificity compared with TYMS protein expression (76.2 versus 50.0 %, 75.0 versus 66.7 %).

Conclusion

The analysis of TYMS gene copy number is more suitable than TYMS protein expression for assessment of TYMS expression. TYMS gene amplification predicts outcome of patients receiving PMT with advanced NSCLC.

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References

  1. Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C. Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009;66:141–9.

    Article  PubMed  Google Scholar 

  2. Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(19):3217–24.

    Article  PubMed  Google Scholar 

  3. Ferguson PJ, Collins O, Dean NM, DeMoor J, Li CS, Vincent MD, et al. Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells. Br J Pharmacol. 1999;127:1777–86.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Flynn J, Berg RW, Wong T, van Aken M, Vincent MD, Fukushima M, et al. Therapeutic potential of antisense oligodeoxynucleotides to down-regulate thymidylate synthase in mesothelioma. Mol Cancer Ther. 2006;5:1423–33.

    Article  PubMed  CAS  Google Scholar 

  5. Lin SB, Ts’o PO, Sun SK, Choo KB, Yang FY, Lim YP, et al. Inhibition of thymidylate synthase activity by antisense oligodeoxynucleotide and possible role in thymineless treatment. Mol Pharmacol. 2001;60:474–9.

    PubMed  CAS  Google Scholar 

  6. Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997;57:1116–23.

    PubMed  CAS  Google Scholar 

  7. Mendelsohn LG, Shih C, Chen VJ, Habeck LL, Gates SB, Shackelford KA. Enzyme inhibition, polyglutamation, and the effect of LY231514 (MTA) on purine biosynthesis. Semin Oncol. 1999;26(2 Suppl 6):42–7.

    PubMed  CAS  Google Scholar 

  8. Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, et al. 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)ethy l]benzoyl]-l-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem. 1992;35:4450–4.

    Article  PubMed  CAS  Google Scholar 

  9. Schultz RM, Patel VF, Worzalla JF, Shih C. Role of thymidylate synthase in the antitumor activity of the multitargeted antifolate, LY231514. AnticancerRes. 1999;19:437–43.

    CAS  Google Scholar 

  10. Sigmond J, Backus HH, Wouters D, Temmink OH, Jansen G, Peters GJ. Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol. 2003;66:431–8.

    Article  PubMed  CAS  Google Scholar 

  11. Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, et al. Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer. 2011;104(10):1594–601.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Shimizu T, Nakanishi Y, Nakagawa Y, Tsujino I, Takahashi N, Nemoto N, et al. Association between expression of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase and efficacy of pemetrexed in advanced non-small cell lung cancer. Anticancer Res. 2012;32:4589–96.

    PubMed  CAS  Google Scholar 

  13. Nakagawa Y, Shimizu T, Takahashi N, Hashimoto S. Impact of thymidylate synthase protein expression on efficacy of chemotherapy in advanced lung cancer patients. Mol Clin Oncol. 2013;1:411–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  14. Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF. Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009;27(8):1323–33.

    Article  PubMed  CAS  Google Scholar 

  15. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–45.

    Article  PubMed  CAS  Google Scholar 

  16. Lenz HJ, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Cohen H, et al. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol. 1996;14:176–82.

    PubMed  CAS  Google Scholar 

  17. Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol. 2001;19:4298–304.

    PubMed  CAS  Google Scholar 

  18. Nishimura R, Nagao K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, et al. Thymidylate synthase levels as a therapeutic and prognostic predictor in breast cancer. Anticancer Res. 1999;19:5621–6.

    PubMed  CAS  Google Scholar 

  19. Takamura M, Nio Y, Yamasawa K, Dong M, Yamaguchi K, Itakura M. Implication of thymidylate synthase in the outcome of patients with invasive ductal carcinoma of the pancreas and efficacy of adjuvant chemotherapy using 5-fluorouracil or its derivatives. Anticancer Drugs. 2002;13:75–85.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Oyaguchi-Kamichou, Itabashi-ku, Tokyo, 173-8610, Japan

    T. Shimizu, Y. Nakagawa, N. Takahashi & S. Hashimoto

Authors
  1. T. Shimizu
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  2. Y. Nakagawa
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  3. N. Takahashi
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  4. S. Hashimoto
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Corresponding author

Correspondence to T. Shimizu.

Ethics declarations

This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by a clinical research judging committee of Nihon University Itabashi hospital. Written informed consent was obtained from all patients.

Conflict of interest

The authors declare that they have no conflict of interest.

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Shimizu, T., Nakagawa, Y., Takahashi, N. et al. Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer. Clin Transl Oncol 18, 107–112 (2016). https://doi.org/10.1007/s12094-015-1359-y

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  • DOI: https://doi.org/10.1007/s12094-015-1359-y

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