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Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

Abstract

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3′-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56–5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III–IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.

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References

  1. Kelly H, Goldberg RM . Systemic therapy for metastatic colorectal cancer: current options, current evidence. J Clin Oncol 2005; 23: 4553–4560.

    Article  CAS  PubMed  Google Scholar 

  2. Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 2005; 23: 4866–4875.

    Article  CAS  PubMed  Google Scholar 

  3. Marsh S, McLeod HL . Cancer pharmacogenetics. Br J Cancer 2004; 90: 8–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marsh S, McLeod HL . Pharmacogenetics of irinotecan toxicity. Pharmacogenomics 2004; 5: 835–843.

    Article  CAS  PubMed  Google Scholar 

  5. Popat S, Matakidou A, Houlston RS . Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2004; 22: 529–536.

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Kawakami K, Watanabe G . Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of the thymidylate synthase gene. Cancer Res 2003; 63: 6004–6007.

    CAS  PubMed  Google Scholar 

  8. 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 

  9. Kawakami K, Omura K, Kanehira E, Watanabe Y . Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19: 3249–3252.

    CAS  PubMed  Google Scholar 

  10. Morganti M, Ciantelli M, Giglioni B, Putignano AL, Nobili S, Papi L et al. Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers. Eur J Cancer 2005; 41: 2176–2183.

    Article  CAS  PubMed  Google Scholar 

  11. Kawakami K, Watanabe G . The association of thymidylate synthase mRNA expression with its three gene polymorphisms in colorectal cancer. Proc Am Assoc Cancer Res 2004; 45: 484 (abstr 2104).

    Google Scholar 

  12. 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 

  13. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 2004; 14: 319–327.

    Article  CAS  PubMed  Google Scholar 

  14. Sohn KJ, Croxford R, Yates Z, Lucock M, Kim YI . Effect of the methylenetetrahydrofolate reductase C677 T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 2004; 96: 134–144.

    Article  CAS  PubMed  Google Scholar 

  15. Etienne MC, Ilc K, Formento JL, Laurent-Puig P, Formento P, Cheradame S et al. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: relationships with 5-fluorouracil sensitivity. Br J Cancer 2004; 90: 526–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Watanabe G, Iacopetta B . The folate pool in colorectal cancers is associated with DNA hypermethylation and with a polymorphism in methylenetetrahydrofolate reductase. Clin Cancer Res 2003; 9: 5860–5865.

    CAS  PubMed  Google Scholar 

  17. Paz MF, Avila S, Fraga MF, Pollan M, Capella G, Peinado MA et al. Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 2002; 62: 4519–4524.

    CAS  PubMed  Google Scholar 

  18. Iacopetta B . Methyl-group metabolism and the response of colorectal cancer to 5-Fluorouracil. Crit Rev Oncogenesis 2006; 12: 1–12.

    Article  Google Scholar 

  19. Pommier Y . Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 2006; 6: 789–802.

    Article  CAS  PubMed  Google Scholar 

  20. Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 2000; 60: 6921–6926.

    CAS  PubMed  Google Scholar 

  21. Rouits E, Boisdron-Celle M, Dumont A, Guerin O, Morel A, Gamelin E . Relevance of different UGT1A1 toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res 2004; 10: 5151–5159.

    Article  CAS  PubMed  Google Scholar 

  22. Marcuello E, Altes A, Menoyo A, Del Rio E, Gomez-Pardo M, Baiget M . UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 2004; 91: 678–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Toffoli G, Cecchin E, Corona G, Russo A, Buonadonna A, D'Andrea M et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2006; 24: 3061–3068.

    Article  CAS  PubMed  Google Scholar 

  24. Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K . Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 1991; 51: 4187–4191.

    CAS  PubMed  Google Scholar 

  25. Wu J, Yin MB, Hapke G, Toth K, Rustum YM . Induction of biphasic DNA double strand breaks and activation of multiple repair protein complexes by DNA topoisomerase I drug 7-ethyl-10-hydroxy-camptothecin. Mol Pharmacol 2002; 61: 742–748.

    Article  CAS  PubMed  Google Scholar 

  26. Vallbohmer D, Iqbal S, Yang DY, Rhodes KE, Zhang W, Gordon M et al. Molecular determinants of irinotecan efficacy. Int J Cancer 2006; 119: 2435–2442.

    Article  CAS  PubMed  Google Scholar 

  27. de Boer JG . Polymorphisms in DNA repair and environmental interactions. Mutat Res 2002; 509: 201–210.

    Article  CAS  PubMed  Google Scholar 

  28. Louvet C, de Gramont A, Tournigand C, Artru P, Maindrault-Goebel F, Krulik M . Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma. Cancer 2001; 91: 2033–2038.

    Article  CAS  PubMed  Google Scholar 

  29. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.

    Article  CAS  PubMed  Google Scholar 

  30. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenom J 2001; 1: 65–70.

    Article  CAS  Google Scholar 

  31. Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 2004; 91: 344–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dotor E, Cuatrecases M, Martinez-Iniesta M, Navarro M, Vilardell F, Guino E et al. Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 2006; 24: 1603–1611.

    Article  CAS  PubMed  Google Scholar 

  33. Jakobsen A, Nielsen JN, Gyldenkerne N, Lindeberg J . Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 2005; 23: 1365–1369.

    Article  CAS  PubMed  Google Scholar 

  34. Marcuello E, Altes A, del Rio E, Cesar A, Menoyo A, Baiget M . Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 2004; 112: 733–737.

    Article  CAS  PubMed  Google Scholar 

  35. Cohen V, Panet-Raymond V, Sabbaghian N, Morin I, Batist G, Rozen R . Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2003; 9: 1611–1615.

    CAS  PubMed  Google Scholar 

  36. Etienne MC, Formento JL, Chazal M, Francoual M, Magne N, Formento P et al. Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients. Pharmacogenetics 2004; 14: 785–792.

    Article  CAS  PubMed  Google Scholar 

  37. Marcuello E, Altes A, Menoyo A, Baiget M . Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 2006; 57: 835–840.

    Article  CAS  PubMed  Google Scholar 

  38. Kealey C, Brown KS, Woodside JV, Young I, Murray L, Boreham CA et al. A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations. Hum Genet 2005; 1160: 347–353.

    Article  Google Scholar 

  39. Pullmann Jr R, Abdelmohsen K, Lal A, Martindale JL, Ladner RD, Gorospe M . Differential stability of thymidylate synthase 3′-untranslated region polymorphic variants regulated by AUF1. J Biol Chem 2006; 281: 23456–23463.

    Article  CAS  PubMed  Google Scholar 

  40. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 1382–1388.

    Article  CAS  PubMed  Google Scholar 

  41. McLeod HL, Parodi L, Sargent DJ, Marsh S, Green E, Abreu P et al. UGT1A1*28, toxicity and outcome in advanced colorectal cancer: results from Trial N9741. Proc Am Soc Clin Oncol 2006; 24: 151 (abstr. 3520).

    Google Scholar 

  42. Schulz C, Schalhorn A, Schwabe W, Haeusler P, Zwingers T, Heinemann V . Impact of gene promoter polymorphism of the UGT1A1-gene on the occurrance of irinotecan-induced side effects and drug effiacy. Proc Am Soc Clin Oncol 2005; 23: 263 (abstr. 3570).

    Google Scholar 

  43. Seymour MT, Braun MS, Richman SD, Daly C, Thompson LC, Meade A et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer (FOCUS Trial Investigators). Proc Am Soc Clin Oncol 2006; 24: 84 (abstr. 2022).

    Google Scholar 

  44. Leonard GD, Fojo T, Bates SE . The role of ABC transporters in clinical practice. Oncologist 2003; 8: 411–424.

    Article  CAS  PubMed  Google Scholar 

  45. Choudhuri S, Klaassen CD . Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol 2006; 25: 231–259.

    Article  CAS  PubMed  Google Scholar 

  46. Carlini LE, Meropol NJ, Bever J, Andria ML, Hill T, Gold P et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res 2005; 11: 1226–1236.

    CAS  PubMed  Google Scholar 

  47. Nagar S, Blanchard RL . Pharmacogenetics of uridine diphosphoglucuronosyltransferase (UGT) 1A family members and its role in patient response to irinotecan. Drug Metab Rev 2006; 38: 393–409.

    Article  CAS  PubMed  Google Scholar 

  48. Savas S, Kim DY, Ahmad MF, Shariff M, Ozcelik H . Identifying functional genetic variants in DNA repair pathway using protein conservation analysis. Cancer Epidemiol Biomarkers Prev 2004; 13: 801–807.

    CAS  PubMed  Google Scholar 

  49. Kiuru A, Lindholm C, Heilimo I, Ceppi M, Koivistoinen A, Ilus T et al. Influence of DNA repair gene polymorphisms on the yield of chromosomal aberrations. Environ Mol Mutagen 2005; 46: 198–205.

    Article  CAS  PubMed  Google Scholar 

  50. Brenneman MA, Weiss AE, Nickoloff JA, Chen DJ . XRCC3 is required for efficient repair of chromosome breaks by homologous recombination. Mutat Res 2000; 459: 89–97.

    Article  CAS  PubMed  Google Scholar 

  51. Araujo FD, Pierce AJ, Stark JM, Jasim N . Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks. Oncogene 2002; 21: 4176–4180.

    Article  CAS  PubMed  Google Scholar 

  52. Arnaudeau C, Lundin C, Helleday T . DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J Mol Biol 2001; 307: 1235–1245.

    Article  CAS  PubMed  Google Scholar 

  53. Savas S, Kim DY, Ahmad MF, Shariff M, Ozcelik H . Identifying functional genetic variants in DNA repair pathway using protein conservation analysis. Cancer Epidemiol Biomarkers Prev 2004; 13: 801–807.

    CAS  PubMed  Google Scholar 

  54. Kweekel DM, Gelderblom H, Guchelaar HJ . Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treat Rev 2005; 31: 90–105.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Consorzio Interuniversitario per le Biotecnologie (CIB) and Fanoateneo for their financial support.

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Correspondence to F Graziano.

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Ruzzo, A., Graziano, F., Loupakis, F. et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharmacogenomics J 8, 278–288 (2008). https://doi.org/10.1038/sj.tpj.6500463

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