Skip to main content

Advertisement

SpringerLink
Log in

Incidence of KRAS status in ongoing adjuvant trials in colon cancer

  • Published:
Current Colorectal Cancer Reports

Abstract

The current standard for adjuvant treatment of stage III colon cancer is chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin for 6 months. Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is effective and safe in combination with an oxaliplatin-based regimen in patients with metastatic colorectal cancer. Based on these data, two large randomized, multicenter, phase 3 trials opened in 2005 to compare the efficacy of cetuximab combined with chemotherapy with that of chemotherapy alone in curatively R0 resected stage III colon cancer. The primary end point of these two trials is disease-free survival. The recent findings on tumor KRAS mutational status and efficacy of cetuximab in the metastatic setting have led to amendments to the protocols of both trials to enroll only patients with wild-type KRAS tumors. As a consequence, the sample sizes have increased and both trials will enroll more than 6000 patients in nine European countries and the United States. The first interim analyses are planned for 2011. This review summarizes current knowledge regarding stage III colon cancer adjuvant therapy, anti-EGFR therapy, KRAS status and its prognostic and predictive value in advanced colorectal cancer, and how to deal with these new scientific paradigms in the adjuvant setting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Ferlay J, Bray F, Pisani P, et al.: GLOBOCAN 2002. Cancer Incidence, Mortality and Prevalence Worldwide. IARC Cancer Base No. 5, Version 2.0. Lyon, France: IARC Press; 2004.

    Google Scholar 

  2. Boyle P, Ferlay J: Cancer incidence and mortality in Europe, 2004. Ann Oncol 2005, 16:481–488.

    Article  CAS  PubMed  Google Scholar 

  3. Skibber JM, Minsky BD, Hoff PM: Cancer of the colon. In Cancer Principles and Practice of Oncology, edn 6. Edited by DeVita VT, Hellman S, Rosenberg SA. Philadelphia: Lippincott Williams & Wilkins; 2001:1217.

    Google Scholar 

  4. Arnold D, Schmoll HJ: (Neo-)adjuvant treatments in colorectal cancer. Ann Oncol 2005, 16:ii133–ii140.

    Article  PubMed  Google Scholar 

  5. Andre T, Boni C, Mounedji-Boudiaf L, et al.: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004, 350:2343–2351.

    Article  CAS  PubMed  Google Scholar 

  6. Laurent-Puig P, Lièvre A, Blons H, et al.: Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res 2009, 15:1133–1139.

    Article  CAS  PubMed  Google Scholar 

  7. Lemmon MA, Schlessinger J: Regulation of signal transduction and signal diversity by receptor oligomerization. Trend Biochem Sci 1994, 19:459–463.

    Article  CAS  PubMed  Google Scholar 

  8. Ono M, Kuwano M: Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 2006, 12:7242–7251.

    Article  CAS  PubMed  Google Scholar 

  9. Wong SF: Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther 2005, 27:684–694.

    Article  CAS  PubMed  Google Scholar 

  10. Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004, 351:337–345.

    Article  CAS  PubMed  Google Scholar 

  11. Bokemeyer C, Bondanrenko I, Makhson A, et al.: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009, 27:663–671.

    Article  CAS  PubMed  Google Scholar 

  12. Karapetis CS, Khambata-Ford S, Jonker DJ, et al.: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008, 359:1757–1765.

    Article  CAS  PubMed  Google Scholar 

  13. Van Cutsem E, Köhne CH, Hitre E, et al.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009, 360:1408–1417.

    Article  PubMed  Google Scholar 

  14. Taieb J, Laurent-Puig P, Bedenne L: Cetuximab plus FOLFOX-4 for fully resected stage III colon carcinoma: scientific background and the ongoing PETACC-8 trial. Expert Rev Anticancer Ther 2008, 8:183–189.

    Article  CAS  PubMed  Google Scholar 

  15. Amado RG, Wolf M, Peeters M, et al.: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008, 26:1626–1634.

    Article  CAS  PubMed  Google Scholar 

  16. Laurie JA, Moertel CG, Fleming TR, et al.: Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil: the North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 1989, 7:1447–1456.

    CAS  PubMed  Google Scholar 

  17. Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990, 32:352–358.

    Google Scholar 

  18. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990, 264:1444–1450.

  19. Wolmark N, Rockette H, Fisher B, et al.: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993, 11:1879–1887.

    CAS  PubMed  Google Scholar 

  20. International Multicenter Pooled Analysis of Colon Cancer Trials (IMPACT) Investigators: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995, 345:939–944.

    Article  Google Scholar 

  21. O’Connell MJ, Laurie JA, Kahn M, et al.: Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998, 16:295–300.

    PubMed  Google Scholar 

  22. André T, Colin P, Louvet C, et al.: Semi-monthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003, 21:2896–2903.

    Article  PubMed  CAS  Google Scholar 

  23. de Gramont A, Boni C, Navarro M, et al.: Oxaliplatin/5-FU/LV in stage II and III colon cancer: updated results (as of January 04) for efficacy and neurotoxicity of the MOSAIC trial. Ann Oncol 2004, 15(Suppl 3):iii73.

    Google Scholar 

  24. Kuebler JP, Wieand HS, O’Connell MJ, et al.: Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007, 25:2198–2204.

    Article  CAS  PubMed  Google Scholar 

  25. Saltz LB, Niedzwiecki D, Hollis D, et al.: Irinotecan plus fluorouracil/leucovorin alone (IFL) in stage III colon cancer (intergroup trial CALGB C89803) [abstract]. J Clin Oncol 2004, 22(Suppl 14):3500.

    Google Scholar 

  26. Ychou M, Raoul JL, Douillard JY, et al.: A phase III trial of LV5FU2 +CPT11 vs LV5FU2 alone in adjuvant high risk colon cancer (FNLCC Accord 002/FFCD 9802) [abstract]. J Clin Oncol 2005, 23(Suppl 16):3502.

    Google Scholar 

  27. Van Cutsem E, Labianca R, Hossfeld D, et al.: Randomized phase III trial comparing infused-irinotecan/5-fluorouracil (5FU)/folinic acid (IF) vs 5FU/FA (F) in stage III colon cancer patients (PETACC-3; V307) [abstract]. J Clin Oncol 2005, 23(Suppl 16):8.

    Google Scholar 

  28. Weiner GJ: Monoclonal antibody mechanisms of action in cancer. Immunol Res 2007, 39:271–278.

    Article  CAS  PubMed  Google Scholar 

  29. Saltz LB, Meropol NJ, Loehrer PJ, et al.: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004, 22:1201–1208.

    Article  CAS  PubMed  Google Scholar 

  30. Lenz HJ, Mayer RJ, Mirtsching B, et al.: Consistent response to treatment with cetuximab monotherapy in patients with metastatic colorectal cancer [abstract]. J Clin Oncol 2005, 23(Suppl 16):3536.

    PubMed  Google Scholar 

  31. Rougier P, Raoul JL, Van Laethem JL, et al.: Cetuximab + FOLFIRI as first-line treatment for metastatic colorectal CA [abstract]. J Clin Oncol 2004, 22(Suppl 14):3513.

    Google Scholar 

  32. Folprecht G, Lutz MP, Schöffski P, et al.: Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 2006, 17:450–456.

    Article  CAS  PubMed  Google Scholar 

  33. Tabernero J, Van Cutsem E, Diaz-Rubio E, et al.: Phase II trial of cetuximab in combination with fluorouracil, leucovorin and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2007, 25:5225–5232.

    Article  CAS  PubMed  Google Scholar 

  34. Venook A, Niedzwiecki D, Hollis D, et al.: Phase III study of irinotecan 5FU LV (FOLFIRI) or oxaliplatin 5FU LV (FOLFOX) cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results [abstract]. J Clin Oncol 2006, 24(Suppl 18):3509.

    Google Scholar 

  35. Personeni N, Hendlisz A, Gallez J, et al.: Correlation between the response to cetuximab alone or in combination with irinotecan and the activated/phosphorylated epidermal growth factor receptor in metastatic colorectal cancer. Semin Oncol 2005, 32(Suppl 9):S59–S62.

    Article  CAS  PubMed  Google Scholar 

  36. Personeni N, Fieuws S, Piessevaux H, et al.: Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 2008, 14:5869–5876.

    Article  CAS  PubMed  Google Scholar 

  37. Moroni M, Veronese S, Benvenuti S, et al.: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005, 6:279–286.

    Article  CAS  PubMed  Google Scholar 

  38. Vallböhmer D, Zhang W, Gordon M, et al.: Molecular determinants of cetuximab efficacy. J Clin Oncol 2005, 23:3536–3544.

    Article  PubMed  CAS  Google Scholar 

  39. Frattini M, Saletti P, Romagnani E, et al.: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal patients. Br J Cancer 2007, 97:1139–1145.

    Article  CAS  PubMed  Google Scholar 

  40. Bibeau F, Lopez-Crapez E, Di Fiore F, et al.: Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009, 27:1122–1129.

    Article  CAS  PubMed  Google Scholar 

  41. Lièvre A, Bachet JB, Le Corre D, et al.: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006, 66:3992–3995.

    Article  PubMed  Google Scholar 

  42. Lièvre A, Bachet JB, Boige V, et al.: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008, 26:374–379.

    Article  PubMed  CAS  Google Scholar 

  43. Di Fiore F, Blanchard F, Charbonnier F, et al.: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 2007, 96:1166–1169.

    Article  PubMed  CAS  Google Scholar 

  44. Malumbres M, Barbacid M: RAS oncogenes: the first 30 years. Nat Rev Cancer 2003, 3:459–465.

    Article  CAS  PubMed  Google Scholar 

  45. Andreyev HJ, Norman AR, Cunningham D, et al.: Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 2001, 85:692–696.

    Article  CAS  PubMed  Google Scholar 

  46. Esteller M, Gonzalez S, Risques RA, et al.: K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol 2001, 19:299–304.

    CAS  PubMed  Google Scholar 

  47. Ince WL, Jubb AM, Holden SN, et al.: Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 2005, 97:981–989.

    Article  CAS  PubMed  Google Scholar 

  48. De Roock W, Piessevaux H, De Schutter J, et al.: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008, 19:508–515.

    Article  PubMed  Google Scholar 

  49. Etienne-Grimaldi MC, Formento JL, Francoual M, et al.: KRas mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res 2008, 14:4830–4835.

    Article  CAS  PubMed  Google Scholar 

  50. Santini D, Loupakis F, Vincenzi B, et al.: High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist 2008, 13:1270–1275.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang W, Gordon M, Schultheis AM, et al.: FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor-expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007, 25:3712–3718.

    Article  CAS  PubMed  Google Scholar 

  52. Musolino A, Naldi N, Bortesi B, et al.: Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neupositive metastatic breast cancer. J Clin Oncol 2008, 26:1789–1796.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Service d’Hépato-Gastro-Entérologie, Hopital Européen Georges Pompidou, Université René Descartes, Paris 5, 20 rue Leblanc, 75015, Paris, France

    Julien Taieb

Authors
  1. Julien Taieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Laurent-Puig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven Alberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julien Taieb.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taieb, J., Laurent-Puig, P. & Alberts, S. Incidence of KRAS status in ongoing adjuvant trials in colon cancer. Curr colorectal cancer rep 5, 171–178 (2009). https://doi.org/10.1007/s11888-009-0025-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-009-0025-6

Keywords

Search

Navigation