Current Colorectal Cancer Reports

, Volume 3, Issue 3, pp 143–149

Adjuvant therapy for colon cancer based on pharmacogenomics?

  • Erick Gamelin
  • Michele Boisdron-Celle
  • Alain Morel
  • Olivier Capitain
  • Olivier Coqueret
Article
  • 30 Downloads

Abstract

The impact of adjuvant chemotherapy for patients with localized colon adenocarcinoma is obvious for stage III and high-risk stage II patients but remains somewhat controversial for low-risk stage II. Until now, the decision of an adjuvant chemotherapy is based on pathologic and clinical data. However, some important questions remain. In stage III, how can we improve the results? In low-risk stage II patients, who will benefit from adjuvant chemotherapy? In the event that an adjuvant therapy is decided, which drugs will be chosen, and is the patient at high risk of toxicity because of metabolic deficiency? Different approaches have been developed: 1) genetics to detect DNA mutations or variants in the primary tumor or the patient himself, 2) RNA expression quantification either based on microarray or with real-time quantitative reverse transcriptase-polymerase chain reaction, and 3) protein expression by immunohistochemistry. Despite promising results from retrospective or prospective studies, the available data remain insufficient to draw guidelines. Genetics with the detection of microsatellite instability status and loss of heterozygoty is investigated for validation in large international prospective ongoing clinical trials. Some genes, such as excision repair cross complementing 1, thymidylate synthase, mismatch repair seem to be very good candidates to predict sensitivity to certain drugs. Clearly, the major potential interest of biologic markers highlights the need of multicentric prospective clinical trials to answer crucial questions about adjuvant therapy.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Andre T, Sargent D, Tabernero J, et al.: Current issues in adjuvant treatment of stage II colon cancer. Ann Surg Oncol 2006, 13:887–898.PubMedCrossRefGoogle Scholar
  2. 2.
    Andre T, Boni C, Mouinedji-Boudiaf L, et al.: Oxaliplatin, fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004, 350:2343–2351.PubMedCrossRefGoogle Scholar
  3. 3.
    Buyse M, Piedbois P: Should Dukes’ B patients receive adjuvant therapy? A statistical perspective. Semin Oncol 2001, 28:20–24.PubMedCrossRefGoogle Scholar
  4. 4.
    Mamounas E, Wieand S, Wolmark N, et al.: Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999, 17:1349–1355.PubMedGoogle Scholar
  5. 5.
    Benson AB 3rd, Schrag D, Somerfield MR, et al.: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004, 22:3408–3419.PubMedCrossRefGoogle Scholar
  6. 6.
    Boyer J, Allen WL, McLean EG, et al.: Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res 2006, 66:2765–2777.PubMedCrossRefGoogle Scholar
  7. 7.
    Mariadason JM, Arango D, Shi Q, et al.: Gene expression profiling-based prediction of response of colon carcinoma cells to 5-fluorouracil and camptothecin. Cancer Research 2003, 63:8791–8812.PubMedGoogle Scholar
  8. 8.
    Wang Y, Jatkoe T, Zhang Y, et al.: Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol 2004, 22:1538–1539.CrossRefGoogle Scholar
  9. 9.
    Barrier A, Lemoine A, Boelle PY, et al.: Colon cancer prognosis prediction by gene expression profiling. Oncogene 2005, 24:6155–6164.PubMedCrossRefGoogle Scholar
  10. 10.
    Barrier A, Boelle PY, Roser F, et al.: Stage II colon cancer prognosis prediction by tumor gene expression profiling. J Clin Oncol 2006, 24:4685–4691.PubMedCrossRefGoogle Scholar
  11. 11.
    Eschrich S, Yang I, Bloom G, et al.: Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 2005, 23:3526–3535.PubMedCrossRefGoogle Scholar
  12. 12.
    Rosati G, Chiacchio R, Reggiardo G, et al.: Thymidylate synthase expression, p53, bcl-2, Ki-67 and p27 in colorectal cancer: relationships with tumor recurrence and survival. Tumour Biol 2004, 25:258–263.PubMedCrossRefGoogle Scholar
  13. 13.
    Edler D, Glimelius B, Hallstrom M, et al.: Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J Clin Oncol 2002, 20:1711–1713.CrossRefGoogle Scholar
  14. 14.
    Hoos A, Nissan A, Stojadinovic A, et al.: Tissue microarray molecular profiling of early, node-negative adenocarcinoma of the rectum: a comprehensive analysis. Clin Cancer Res 2002, 8:3841–3849.PubMedGoogle Scholar
  15. 15.
    Allegra CJ, Parr AL, Wold LE, et al.: Investigation of the prognostic and predictive value of thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon cancer. J Clin Oncol 2002, 20:1735–1743.PubMedCrossRefGoogle Scholar
  16. 16.
    Garrity MM, Burgart LJ, Mahoney MR, et al.: Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes’ B2 or C colon cancer: a North Central Cancer Treatment Group Study. J Clin Oncol 2004, 22:1572–1582.PubMedCrossRefGoogle Scholar
  17. 17.
    Diep CB, Thorstensen L, Meling GI, et al.: Genetic tumor markers with prognostic impact in Dukes’ stages B and C colorectal cancer patients. J Clin Oncol 2003, 21:820–829.PubMedCrossRefGoogle Scholar
  18. 18.
    Barratt PL, Seymour MT, Stenning SP, et al.: DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 2002, 360:1381–1391.PubMedCrossRefGoogle Scholar
  19. 19.
    Watanabe T, Wu TT, Catalano PJ, et al.: Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2003, 349:1774–1776.CrossRefGoogle Scholar
  20. 20.
    Ward RL, Cheong K, Ku SL, et al.: Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 2003, 21:3729–3736.PubMedCrossRefGoogle Scholar
  21. 21.
    Van Rijnsoever M, Elsaleh H, Joseph D, et al.: CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluororuacil in stage III colorectal cancer. Clin Cancer Res 2003, 9:2898–2903.PubMedGoogle Scholar
  22. 22.
    Wallner M, Herbst A, Behrens A, et al.: Methylation of serum DNA is an independent prognostic marker in colorectal cancer. Clin Cancer Res 2006, 12:7347–7352.PubMedCrossRefGoogle Scholar
  23. 23.
    Shirota Y, Stoehlmacher J, Brabender J, et al.: ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001, 19:4298–4304.PubMedGoogle Scholar
  24. 24.
    Vallbohmer D, Iqbal S, Yang DY, et al.: Molecular determinants of irinotecan efficacy. Int J Cancer 2006, 119:2435–2442.PubMedCrossRefGoogle Scholar
  25. 25.
    Van Kuilenburg AB, Meinsma R, van Gennip AH: Pyrimidine degradation defects and severe 5-fluorouracil toxicity. Nucleosides Nucleotides & Nucleic Acids 2004, 23:1371–1375.CrossRefGoogle Scholar
  26. 26.
    Rouits E, Boisdron-Celle M, Dumont A, et al.: Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res 2004, 10:5151–5159.PubMedCrossRefGoogle Scholar
  27. 27.
    Gamelin L, Boisdron-Celle M, Delva R, et al.: Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res 2004, 10:4055–4061.PubMedCrossRefGoogle Scholar
  28. 28.
    Diasio RB, Johnson MR: Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res 1999, 5:2672–2673.PubMedGoogle Scholar
  29. 29.
    Fleming R, Milano G, Thyss A, et al.: Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res 1992, 52:2899–2902.PubMedGoogle Scholar
  30. 30.
    Remaud G, Boisdron-Celle M, Hameline C, et al.: An accurate dihydrouracil/uracil determination using improved high performance liquid chromatography method for preventing fluoropyrimidines-related toxicity in clinical practice. J Chromatogr B Analyt Technol Biomed Life Sci 2005, 823:98–107.PubMedCrossRefGoogle Scholar
  31. 31.
    Mattison LK, Fourie J, Hirao Y, et al.: The uracil breath test in the assessment of dihydropryrimidine dehydrogenase activity: pharmacokinetic relationship between expired 13CO2 and plasma [2–13C] dihydrouracil. Clin Cancer Res 2006, 12:549–555.PubMedCrossRefGoogle Scholar
  32. 32.
    Morel A, Boisdron-Celle M, Fey L, et al.: Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms (SNP) upon 5-fluorouracil tolerance in a prospective clinical study in a french caucasian population. Mol Cancer Ther 2006, 5:2895–2904.PubMedCrossRefGoogle Scholar
  33. 33.
    Boisdron-Celle M, Remaud G, Traore S, et al.: 5-fluororuacil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropy-rimidine dehydrogenase deficiency. Cancer Lett 2007, 249:271–282.PubMedCrossRefGoogle Scholar
  34. 34.
    Raijmakers MT, Jansen PL, Steegers EA, Peters WH: Association of human liver bilirubin UDP-glucuronyl transferase activity with a polymorphism in the promoter region of the UGT1A1 gene. J Hepatol 2000, 33:348–351.PubMedCrossRefGoogle Scholar
  35. 35.
    Iyer L, Das S, Janisch L, et al.: UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002, 2:43–47.PubMedCrossRefGoogle Scholar
  36. 36.
    Pusztai L: Chips to bedside: incorporation of microarray data in clinical practice. Clin Cancer Res 2006, 12:7209–7214.PubMedCrossRefGoogle Scholar
  37. 37.
    Potti A, Dressman HK, Bild A, et al.: Genomic signatures to guide the use of chemotherapeutics. Nat Med 2006, 12:1294–1300.PubMedCrossRefGoogle Scholar
  38. 38.
    Barbado M, Preisser L, Boisdron-Celle M, et al.: Tumor quantification of several fluoropyrimidines resistance gene expression with a unique quantitative RT-PCR method. Implications for pretherapeutic determination of tumor resistance. Cancer Lett 2006, 242:168–179.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Erick Gamelin
    • 1
  • Michele Boisdron-Celle
  • Alain Morel
  • Olivier Capitain
  • Olivier Coqueret
  1. 1.Oncopharmacology-Pharmacogenetics Laboratory, INSERM UAnticancer Center Paul PapinAngers Cedex 9France

Personalised recommendations