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Association of thymidylate synthase polymorphisms with the tumor response to preoperative chemoradiotherapy in rectal cancer: a systematic review and meta-analysis

The Pharmacogenomics Journal volume 17, pages 265–273 (2017)Cite this article

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Abstract

Preoperative chemoradiotherapy (pCRT) followed by surgery is currently the standard therapy for patients with locally advanced rectal cancer. It is very important to develop biomarkers to prior identify the patients who have a higher likelihood of responding to pCRT. Recently, a series of studies have been conducted to investigate the association of thymidylate synthase (TYMS) polymorphisms with the tumor response to pCRT in rectal cancer, but the results were not consistent and conclusive. In the present study, we performed a systematic literature search for relevant studies up to 30 March 2015 and conducted a meta-analysis to summarize and clarify the association between the TYMS polymorphisms and the tumor response to pCRT in rectal cancer. Finally, 7 studies containing 892 cases for TYMS 2R/3R polymorphism, 7 studies involving 715 cases for TYMS 1494del6 polymorphism and 6 studies containing 616 cases for TYMS 5′ untranslated region (UTR) expression allele polymorphism were analyzed in the meta-analysis. The results suggested that TYMS 2R/3R was associated with the response and the patients with 2R/2R or 2R/3R genotype with rectal cancer might benefit more from pCRT than others. On the contrary, neither 1494del6 nor 5′UTR expression allele polymorphisms was associated with the response to pCRT.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.

    Article  PubMed  Google Scholar 

  2. Spolverato G, Pucciarelli S, Bertorelle R, De Rossi A, Nitti D . Predictive factors of the response of rectal cancer to neoadjuvant radiochemotherapy. Cancers (Basel) 2011; 3: 2176–2194.

    Article  Google Scholar 

  3. Dunst J, Reese T, Sutter T, Zuhlke H, Hinke A, Kolling-Schlebusch K et al. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 2002; 20: 3983–3991.

    Article  CAS  PubMed  Google Scholar 

  4. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010; 28: 1638–1644.

    Article  CAS  PubMed  Google Scholar 

  5. Mohiuddin M, Winter K, Mitchell E, Hanna N, Yuen A, Nichols C et al. Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012. J Clin Oncol 2006; 24: 650–655.

    Article  CAS  PubMed  Google Scholar 

  6. Bertolini F, Chiara S, Bengala C, Antognoni P, Dealis C, Zironi S et al. Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2009; 73: 466–472.

    Article  CAS  PubMed  Google Scholar 

  7. Hirsch BR, Zafar SY . Capecitabine in the management of colorectal cancer. Cancer Manag Res 2011; 3: 79–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC et al. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst 2015; 107.

  9. Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012; 13: 579–588.

    Article  CAS  PubMed  Google Scholar 

  10. Bosset JF . Distal rectal cancer: sphincter-sparing is also a challenge for the radiation oncologist. Radiother Oncol 2006; 80: 1–3.

    Article  PubMed  Google Scholar 

  11. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731–1740.

    Article  CAS  PubMed  Google Scholar 

  12. Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24: 4620–4625.

    Article  PubMed  Google Scholar 

  13. Pucciarelli S, Del Bianco P, Efficace F, Serpentini S, Capirci C, De Paoli A et al. Patient-reported outcomes after neoadjuvant chemoradiotherapy for rectal cancer: a multicenter prospective observational study. Ann Surg 2011; 253: 71–77.

    Article  PubMed  Google Scholar 

  14. Minsky BD, Cohen AM, Kemeny N, Enker WE, Kelsen DP, Reichman B et al. Combined modality therapy of rectal cancer: decreased acute toxicity with the preoperative approach. J Clin Oncol 1992; 10: 1218–1224.

    Article  CAS  PubMed  Google Scholar 

  15. Mohiuddin M, Hayne M, Regine WF, Hanna N, Hagihara PF, McGrath P et al. Prognostic significance of postchemoradiation stage following preoperative chemotherapy and radiation for advanced/recurrent rectal cancers. Int J Radiat Oncol Biol Phys 2000; 48: 1075–1080.

    Article  CAS  PubMed  Google Scholar 

  16. Longley DB, Harkin DP, Johnston PG . 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3: 330–338.

    Article  CAS  PubMed  Google Scholar 

  17. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K . Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191–197.

    Article  CAS  PubMed  Google Scholar 

  18. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ et al. A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 2003; 63: 2898–2904.

    CAS  PubMed  Google Scholar 

  19. Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD . Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 2000; 9: 1381–1385.

    CAS  PubMed  Google Scholar 

  20. Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei D, Groshen S, Lenz HJ . Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer. Int J Colorectal Dis 2002; 17: 46–49.

    Article  PubMed  Google Scholar 

  21. Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994; 73: 2680–2686.

    Article  CAS  PubMed  Google Scholar 

  22. Dworak O, Keilholz L, Hoffmann A . Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997; 12: 19–23.

    Article  CAS  PubMed  Google Scholar 

  23. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

    Article  CAS  PubMed  Google Scholar 

  24. Begg CB, Mazumdar M . Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–1101.

    Article  CAS  PubMed  Google Scholar 

  25. Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Terrazzino S, Agostini M, Pucciarelli S, Pasetto LM, Friso ML, Ambrosi A et al. A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation. Pharmacogenet Genomics 2006; 16: 817–824.

    Article  CAS  PubMed  Google Scholar 

  27. Spindler KL, Nielsen JN, Lindebjerg J, Jakobsen A . Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum 2007; 50: 1363–1369.

    Article  PubMed  Google Scholar 

  28. Stoehlmacher J, Goekkurt E, Mogck U, Aust DE, Kramer M, Baretton GB et al. Thymidylate synthase genotypes and tumour regression in stage II/III rectal cancer patients after neoadjuvant fluorouracil-based chemoradiation. Cancer Lett 2008; 272: 221–225.

    Article  CAS  PubMed  Google Scholar 

  29. Balboa E, Duran G, Lamas MJ, Gomez-Caamano A, Celeiro-Munoz C, Lopez R et al. Pharmacogenetic analysis in neoadjuvant chemoradiation for rectal cancer: high incidence of somatic mutations and their relation with response. Pharmacogenomics 2010; 11: 747–761.

    Article  CAS  PubMed  Google Scholar 

  30. Paez D, Pare L, Altes A, Josep Sancho-Poch F, Petriz L, Garriga J et al. Thymidylate synthase germline polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy based on 5-fluorouracil. J Cancer Res Clin Oncol 2010; 136: 1681–1689.

    Article  CAS  PubMed  Google Scholar 

  31. Hur H, Kang J, Kim NK, Min BS, Lee KY, Shin SJ et al. Thymidylate synthase gene polymorphism affects the response to preoperative 5-fluorouracil chemoradiation therapy in patients with rectal cancer. Int J Radiat Oncol Biol Phys 2011; 81: 669–676.

    Article  CAS  PubMed  Google Scholar 

  32. Paez D, Salazar J, Pare L, Pertriz L, Targarona E, del Rio E et al. Pharmacogenetic study in rectal cancer patients treated with preoperative chemoradiotherapy: polymorphisms in thymidylate synthase, epidermal growth factor receptor, GSTP1, and DNA repair genes. Int J Radiat Oncol Biol Phys 2011; 81: 1319–1327.

    Article  CAS  PubMed  Google Scholar 

  33. Cecchin E, Agostini M, Pucciarelli S, De Paoli A, Canzonieri V, Sigon R et al. Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy. Pharmacogenomics J 2011; 11: 214–226.

    Article  CAS  PubMed  Google Scholar 

  34. Hu-Lieskovan S, Vallbohmer D, Zhang W, Yang D, Pohl A, Labonte MJ et al. EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients. Clin Cancer Res 2011; 17: 5161–5169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lamas MJ, Duran G, Gomez A, Balboa E, Anido U, Bernardez B et al. X-ray cross-complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients. Int J Radiat Oncol Biol Phys 2012; 82: 138–144.

    Article  CAS  PubMed  Google Scholar 

  36. Sebio A, Salazar J, Paez D, Berenguer-Llergo A, Del Rio E, Tobena M et al. EGFR ligands and DNA repair genes: genomic predictors of complete response after capecitabine-based chemoradiotherapy in locally advanced rectal cancer. Pharmacogenomics J 2015; 15: 77–83.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201504) and the Capital Foundation of Medical Developments (Z20150405090022).

Author contributions

Designed the study: JW and ZTZ. Search databases and collected full-text papers: YCY, GCW, and LJ. Extracted and analyzed the data: KLW, ZGB and YCY. Statistical analyses: GCW and LJ. Wrote the main manuscript text: JW, ZTZ and YCY.

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  1. Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center of Digestive Diseases, Beijing, China

    Y C Yang, G C Wu, L Jin, K L Wang, Z G Bai, J Wang & Z T Zhang

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  1. Y C Yang
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Correspondence to J Wang or Z T Zhang.

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Yang, Y., Wu, G., Jin, L. et al. Association of thymidylate synthase polymorphisms with the tumor response to preoperative chemoradiotherapy in rectal cancer: a systematic review and meta-analysis. Pharmacogenomics J 17, 265–273 (2017). https://doi.org/10.1038/tpj.2016.11

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