Medical Oncology

, Volume 27, Issue 4, pp 1066–1072

MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer

  • Bernard Paule
  • Vincent Castagne
  • Véronique Picard
  • Raphaël Saffroy
  • René Adam
  • Catherine Guettier
  • Robert Farinotti
  • Laurence Bonhomme-Faivre
Original Paper

Abstract

The aim of the study was to evaluate the influence of the MDR1 C3435T polymorphism on the therapeutic response in 23 patients treated with cetuximab plus irinotecan for irinotecan refractory liver metastatic colorectal cancer considering their KRAS status. Indeed, irinotecan and its active metabolite (SN-38) are both substrates of P-glycoprotein (P-gp) encoded by MDR1. Patients received cetuximab and irinotecan up to progression. The overall survival was 55% at 10 months. Overall, four patients had an undetermined KRAS status and two patients with mutated KRAS were in progression disease. The response to treatment was observed after 3 months among the 17 wild-type KRAS patients. Two patients presented a progressive disease (1 TT and 1 CT), eight patients had a stable disease (5 CC and 3CT) and five patients had a partial response (3 CC and 2 CT). Importantly, 2 patients (2 TT) were in complete response and still alive 5 years after starting the treatment, which suggests that the combination of wild-type KRAS and MDR1 3435 TT may be a factor of good prognosis. These results suggest that EGFR inhibition by cetuximab may overcome this irinotecan resistance by abrogating drug efflux depending on MDR1 3435 polymorphism. Among patients resistant to irinotecan, it is still possible to use the association of cetuximab plus irinotecan to obtain a complete resection of hepatic metastases that is necessary to improve their survival.

Keywords

KRAS mutation Cetuximab Irinotecan P-glycoprotein MDR1 polymorphism EGFR Colorectal cancer 

References

  1. 1.
    Cunningham D, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Adam R, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol. 2007;25:4593–602.PubMedCrossRefGoogle Scholar
  3. 3.
    Lièvre A, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Karapetis CS, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.PubMedCrossRefGoogle Scholar
  5. 5.
    De Roock W, 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(3):508–15.PubMedCrossRefGoogle Scholar
  6. 6.
    Arimori K, et al. Effect of P-glycoprotein modulator, cyclosporin A, on the gastrointestinal excretion of irinotecan and its metabolite SN-38 in rats. Pharm Res. 2003;20(6):910–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Iyer L, et al. Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice. Cancer Chemother Pharmacol. 2002;49(4):336–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Chu XY, Kato Y, Sugiyama Y. Possible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats. Drug Metab Dispos. 1999;27(4):440–1.PubMedGoogle Scholar
  9. 9.
    Sen WJ, et al. CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein. Br J Cancer. 1998;77(3):359–65.CrossRefGoogle Scholar
  10. 10.
    Evans WE, McLeod HL. Pharmacogenomics-drug disposition, drug targets, and side effects. N Engl J Med. 2003;348:538–49.PubMedCrossRefGoogle Scholar
  11. 11.
    Hoffmeyer S, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000;97:3473–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Johne A, et al. Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther. 2002;72:584–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Marsh S, McLeod HL. Pharmacogenetics of irinotecan toxicity. Pharmacogenomics. 2004;5:835–43.PubMedCrossRefGoogle Scholar
  14. 14.
    McLeod HL, King CR, Marsh S. Application of pharmacogenomics in the individualization of chemotherapy for gastrointestinal malignancies. Clin Colorectal Cancer. 2004;Suppl 1:S43–7.CrossRefGoogle Scholar
  15. 15.
    Mathijssen RH, et al. Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res. 2003;9:3246–53.PubMedGoogle Scholar
  16. 16.
    Lièvre A, Laurent-Puig P. Facteurs prédictifs de réponse aux traitements anti-REGF dans le cancer colorectal. Bulletin du Cancer. 2008;95(1):133–40.PubMedGoogle Scholar
  17. 17.
    Bonhomme-Faivre L, et al. MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients. Transplantation. 2004;78(1):21–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Ettlinger DE, et al. In vivo disposition of irinotecan (CPT-11) and its metabolites in combination with the monoclonal antibody cetuximab. Anticancer Res. 2006;26(2B):1337–41.PubMedGoogle Scholar
  19. 19.
    Delbaldo C, et al. Pharmacokinetic profile of cetuximab alone and in combination with irinotecan in patients with advanced EGFR-positive adenocarcinoma. Eur J Cancer. 2005;41(12):1739–45.PubMedCrossRefGoogle Scholar
  20. 20.
    Kitazaki T, et al. Gefitnib and EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer. 2005;49(3):337–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Polli JW, et al. The role of efflux and uptake transporters in N-{3-chloro-4-[(3fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2furyl] 4 quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos. 2008;36(4):695–701.PubMedCrossRefGoogle Scholar
  22. 22.
    Chu C, et al. Disposition of everolimus in MDR1a-/1b- mice and after a pre-treatment of lapatinib in Swiss mice. Biochem Pharmacol. 2009;77(10):1629–34.PubMedCrossRefGoogle Scholar
  23. 23.
    Canaparo R, et al. Expression of cytochromes P450 3A and P-glycoprotein in human large intestine in paired tumour and normal samples. Basic Clin Pharmacol Toxicol. 2007;100(4):240–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Mathijssen RH, et al. Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res. 2003;9:3246–53.PubMedGoogle Scholar
  25. 25.
    Illmer T, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res. 2002;62(17):4955–62.PubMedGoogle Scholar
  26. 26.
    Han JY, et al. Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan pharmacokinetics and clinical outcome in patients with advanced non small cell lung cancer. Cancer. 2007;110(1):138–47.PubMedCrossRefGoogle Scholar
  27. 27.
    Xu Y, Villalona-Calero MA. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 2002;13(12):1841–51.PubMedCrossRefGoogle Scholar
  28. 28.
    Adam R, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27(11):1829–35.PubMedCrossRefGoogle Scholar
  29. 29.
    Meyers MB, Yu P, Mendelsohn J. Crosstalk between epidermal growth factor receptor and P-glycoprotein in actinomycin D-resistant Chinese hamster lung cells. Biochem Pharmacol. 1993;46(10):1841–8.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Bernard Paule
    • 1
  • Vincent Castagne
    • 2
  • Véronique Picard
    • 4
  • Raphaël Saffroy
    • 5
  • René Adam
    • 1
  • Catherine Guettier
    • 3
  • Robert Farinotti
    • 4
  • Laurence Bonhomme-Faivre
    • 2
    • 4
  1. 1.Centre Hépatobiliaire, Paul Brousse University HospitalVillejuifFrance
  2. 2.Department of Pharmacy-PharmacologyPaul Brousse University HospitalVillejuifFrance
  3. 3.Department of PathologyPaul Brousse University HospitalVillejuifFrance
  4. 4.UPRES 2706 Barrière et Passage des médicamentsUniversité Paris Sud 11, Faculté de PharmacieParis XIFrance
  5. 5.Department of Biochemistry, INSERM U602Paul Brousse University HospitalVillejuifFrance

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