Targeted Oncology

, 6:133 | Cite as

Uptake of KRAS mutation testing in patients with metastatic colorectal cancer in Europe, Latin America and Asia

  • Fortunato Ciardiello
  • Sabine Tejpar
  • Nicola Normanno
  • Domenica Mercadante
  • Tracey Teague
  • Bruno Wohlschlegel
  • Eric Van Cutsem
Original Research

Abstract

The mutation status of the KRAS gene in the tumors of patients with metastatic colorectal cancer (mCRC) is a predictive biomarker for the efficacy of epidermal growth factor receptor monoclonal antibody therapy. The establishment of KRAS mutation testing in this setting represents a significant change to standard diagnostic procedures and a major advance in the personalization of cancer care. Against a changing regulatory background, three cross-sectional surveys of physicians in 14 countries in Europe, Latin America and Asia were conducted in 2008, 2009, and 2010 to investigate the uptake and outcome of KRAS testing for patients with mCRC. Physicians in each year answered questions on four patients (last patient seen and last seen in first-, second- and third-line settings). Fieldwork was carried out February–May 2008, January–April 2009, and January–April 2010. Data from 3,819, 3,740 and 3,820 anonymized, uncoded patient records were collated. The frequency of KRAS testing in patients with mCRC increased from 3% in 2008 to 47% in 2009 and 69% in 2010. The 2010 survey revealed that test results were available within 15 days for 82%, 51% and 98% of the 1679, 679, and 261 tested patients in the European, Latin American and Asian regions, respectively. Cetuximab was the most commonly administered targeted agent in tested patients with KRAS wild-type mCRC (798/1607 patients; 50%) and bevacizumab was the most commonly administered targeted agent in tested patients with KRAS mutant tumors (396/893; 44% overall). In conclusion, KRAS testing is now widely established as a routine diagnostic procedure for patients with mCRC and is used increasingly to guide treatment selection.

Keywords

KRAS Predictive EGFR Cetuximab Metastatic colorectal cancer mCRC 

Notes

Acknowledgements

The authors take full responsibility for the content of this publication. They would like to thank Dr. Jim Heighway of Cancer Communications and Consultancy Ltd., funded by Merck KGaA, for his contribution to the development of the manuscript, including analysis and interpretation of the survey data and the provision of medical writing services.

Conflict of interest statement

F. Ciardiello, S. Tejpar, N. Normanno, T. Teague and B. Wohlschlegel reported that no funds were received in support of this study or that no benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. D. Mecadante reported that she has received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript. E. Van Cutsem reported that although he has not received and will not receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript, benefits have been or will be received but are directed solely to a research fund, foundation, educational institution, or other non-profit organization with which he is associated.

References

  1. 1.
    Gonzalez-Angulo AM, Hennessy BT, Mills GB (2010) Future of personalized medicine in oncology: a systems biology approach. J Clin Oncol 28:2777–2783PubMedCrossRefGoogle Scholar
  2. 2.
    Alymani NA, Smith MD, Williams DJ, Petty RD (2010) Predictive biomarkers for personalised anti-cancer drug use: discovery to clinical implementation. Eur J Cancer 46:869–879PubMedCrossRefGoogle Scholar
  3. 3.
    Ferte C, Andre F, Soria JC (2010) Molecular circuits of solid tumors: prognostic and predictive tools for bedside use. Nat Rev Clin Oncol 7:367–380PubMedCrossRefGoogle Scholar
  4. 4.
    De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11:753–762PubMedCrossRefGoogle Scholar
  5. 5.
    Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F (2009) Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 6:519–527PubMedCrossRefGoogle Scholar
  6. 6.
    De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508–515PubMedCrossRefGoogle Scholar
  7. 7.
    Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboue R, Tuech JJ, Queuniet AM, Paillot B, Sabourin JC, Michot F, Michel P, Frebourg T (2007) Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96:1166–1169PubMedCrossRefGoogle Scholar
  8. 8.
    Freeman DJ, Juan T, Reiner M, Hecht JR, Meropol NJ, Berlin J, Mitchell E, Sarosi I, Radinsky R, Amado RG (2008) Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin Colorectal Cancer 7:184–190PubMedCrossRefGoogle Scholar
  9. 9.
    Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA 3rd, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230–3237PubMedCrossRefGoogle Scholar
  10. 10.
    Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouche O, Landi B, Louvet C, Andre T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379PubMedCrossRefGoogle Scholar
  11. 11.
    Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995PubMedCrossRefGoogle Scholar
  12. 12.
    Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F (2009) KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 101:715–721PubMedCrossRefGoogle Scholar
  13. 13.
    Tabernero J, Cervantes A, Rivera F, Martinelli E, Rojo F, von Heydebreck A, Macarulla T, Rodriguez-Braun E, Eugenia Vega-Villegas M, Senger S, Ramos FJ, Rosello S, Celik I, Stroh C, Baselga J, Ciardiello F (2010) Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study. J Clin Oncol 28:1181–1189PubMedCrossRefGoogle Scholar
  14. 14.
    Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634PubMedCrossRefGoogle Scholar
  15. 15.
    Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671PubMedCrossRefGoogle Scholar
  16. 16.
    Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765PubMedCrossRefGoogle Scholar
  17. 17.
    Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417PubMedCrossRefGoogle Scholar
  18. 18.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705PubMedCrossRefGoogle Scholar
  19. 19.
  20. 20.
    US Food and Drug Administration: Full Prescribing Information—Erbitux: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125084s168lbl.pdf. Accessed 14 July 2010
  21. 21.
  22. 22.
    US Food and Drug Administration: Full Prescribing Information - Vectibix: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125147s080lbl.pdf. Accessed 22 July 2010
  23. 23.
    Jackson PE, Hall CN, Badawi AF, O'Connor PJ, Cooper DP, Povey AC (1996) Frequency of Ki-ras mutations and DNA alkylation in colorectal tissue from individuals living in Manchester. Mol Carcinog 16:12–19PubMedCrossRefGoogle Scholar
  24. 24.
    Burmer GC, Loeb LA (1989) Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma. Proc Natl Acad Sci USA 86:2403–2407PubMedCrossRefGoogle Scholar
  25. 25.
    Zhu D, Keohavong P, Finkelstein SD, Swalsky P, Bakker A, Weissfeld J, Srivastava S, Whiteside TL (1997) K-ras gene mutations in normal colorectal tissues from K-ras mutation-positive colorectal cancer patients. Cancer Res 57:2485–2492PubMedGoogle Scholar
  26. 26.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532PubMedCrossRefGoogle Scholar
  27. 27.
    Santini D, Loupakis F, Vincenzi B, Floriani I, Stasi I, Canestrari E, Rulli E, Maltese PE, Andreoni F, Masi G, Graziano F, Baldi GG, Salvatore L, Russo A, Perrone G, Tommasino MR, Magnani M, Falcone A, Tonini G, Ruzzo A (2008) High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist 13:1270–1275PubMedCrossRefGoogle Scholar
  28. 28.
    Cejas P, Lopez-Gomez M, Aguayo C, Madero R, de Castro CJ, Belda-Iniesta C, Barriuso J, Moreno Garcia V, Larrauri J, Lopez R, Casado E, Gonzalez-Baron M, Feliu J (2009) KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis. PLoS ONE 4:e8199PubMedCrossRefGoogle Scholar
  29. 29.
    Artale S, Sartore-Bianchi A, Veronese SM, Gambi V, Sarnataro CS, Gambacorta M, Lauricella C, Siena S (2008) Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol 26:4217–4219PubMedCrossRefGoogle Scholar
  30. 30.
    Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A (2009) Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract 205:858–862PubMedCrossRefGoogle Scholar
  31. 31.
    Fakih MM (2010) KRAS mutation screening in colorectal cancer: From paper to practice. Clin Colorectal Cancer 9:22–30PubMedCrossRefGoogle Scholar
  32. 32.
    Carotenuto P, Roma C, Rachiglio AM, Tatangelo F, Pinto C, Ciardiello F, Nappi O, Iaffaioli RV, Botti G, Normanno N (2010) Detection of KRAS mutations in colorectal carcinoma patients with an integrated PCR/sequencing and real-time PCR approach. Pharmacogenomics 11:1169–1179PubMedCrossRefGoogle Scholar
  33. 33.
    Van Cutsem E, Lang I, D'haens G, Moiseyenko V, Zaluski J, Folprecht G, Tejpar S, Kisker O, Stroh C, Rougier P (2008) KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26:(May 20 suppl; abstr 22)Google Scholar
  34. 34.
    Bokemeyer C, Bondarenko I, Hartmann JT, De Braud FG, Volovat C, Nippgen J, Stroh C, Celik I, Koralewski P (2008) KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26:(May 20 suppl; abstr 4000)Google Scholar
  35. 35.
    Freeman D, Juan T, Meropol NJ, Hecht JR, Berlin J, Van Cutsem E, M R, Radinsky R, Amado RG, Peeters M (2007) Association of somatic KRAS gene mutations and clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) receiving panitumumab monotherapy. EJC Suppl 5:239 (abstr 3014)Google Scholar
  36. 36.
    Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O (2009) The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist 14:22–28PubMedCrossRefGoogle Scholar
  37. 37.
    Van Cutsem E, Nordlinger B, Cervantes A (2010) Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol 21(Suppl 5):v93–v97PubMedCrossRefGoogle Scholar
  38. 38.
    Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P (2009) KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 27:5931–5937PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Fortunato Ciardiello
    • 1
  • Sabine Tejpar
    • 2
  • Nicola Normanno
    • 3
  • Domenica Mercadante
    • 4
  • Tracey Teague
    • 5
  • Bruno Wohlschlegel
    • 5
  • Eric Van Cutsem
    • 2
  1. 1.Division of Medical Oncology, Department of Experimental and Clinical Medicine and Surgery “F. Magrassi and A. Lanzara”Second University of NaplesNaplesItaly
  2. 2.Digestive Oncology UnitUniversity Hospital GasthuisbergLeuvenBelgium
  3. 3.Cell Biology and Biotherapy UnitINT-Fondazione PascaleNaplesItaly
  4. 4.IMS HealthMilanItaly
  5. 5.Merck KGaADarmstadtGermany

Personalised recommendations