Journal Mobile Options
Table of Contents
Vol. 77, No. 3-4, 2009
Issue release date: September 2009
Section title: Clinical Study
Oncology 2009;77:224–230
(DOI:10.1159/000236046)

The Role of KRAS Mutations in Predicting the Efficacy of Cetuximab-Plus-Irinotecan Therapy in Irinotecan-Refractory Korean Metastatic Colorectal Cancer Patients

Sohn B.S. · Kim T.W. · Lee J.-L. · Ryu M.-H. · Chang H.M. · Kang Y.-K. · Park H.S. · Na Y.-S. · Jang S.J. · Kim J.C. · Lee J.S.
Departments of aInternal Medicine, bOncology, cPathology and dColon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Do you have an account?

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





Contact Information









I have read the Karger Terms and Conditions and agree.

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





Contact Information









I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger (new!)
  • Unrestricted printing, no saving restrictions for personal use
  • Reduced rates with a PPV account
read more

Direct: USD 38.00
Account: USD 26.50

Select

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restriction apply

Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe

  • Automatic perpetual access to all articles of the subscribed year(s)
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates


Select


Article / Publication Details

First-Page Preview
Abstract of Clinical Study

Received: 1/22/2009
Accepted: 4/28/2009
Published online: 9/7/2009

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 3

ISSN: 0030-2414 (Print)
eISSN: 1423-0232 (Online)

For additional information: http://www.karger.com/OCL

Abstract

Objective: This study evaluated the clinical relevance of KRAS and BRAF mutational status in 66 irinotecan-refrac- tory Korean metastatic colorectal cancer (mCRC) patients treated with cetuximab-plus-irinotecan-based chemotherapy. Methods: A total of 66 irinotecan-refractory mCRC patients treated with cetuximab-plus-irinotecan-based chemotherapy were included. Tumors were screened for KRAS mutations (codons 12 and 13) and a BRAF mutation (V600E) using direct sequencing and the Snapshot assay. Results: The objective response rate (RR) for treatment was 21.2% (14/66) and skin rashes were observed in 43 (65.2%) of the 66 patients. A KRAS mutation was detected in 27 (40.9%) tumors, and was associated with lower RR (wild-type vs. mutated KRAS: 33.3 vs. 3.7%, p = 0.005) and shorter progression-free survival (PFS) and overall survival (OS; PFS: 6.4 vs. 2.0 months, p = 0.005; OS: 17.8 vs. 7.1 months, p = 0.001). Severe skin toxicity was associated with better RR and longer PFS and OS. BRAF mutations were not detected. Multivariate analysis revealed that KRAS status and skin toxicity were independent predictive factors of PFS and OS. Conclusions: This study indicates the clinical relevance of KRAS mutations in predicting the efficacy of cetuximab-plus-irinotecan-based chemotherapy in irinotecan-refractory Korean mCRC patients.


Article / Publication Details

First-Page Preview
Abstract of Clinical Study

Received: 1/22/2009
Accepted: 4/28/2009
Published online: 9/7/2009

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 3

ISSN: 0030-2414 (Print)
eISSN: 1423-0232 (Online)

For additional information: http://www.karger.com/OCL


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. American Cancer Society: Cancer Facts and Figures 2008. Atlanta, American Cancer Society, 2008, pp 12–13.
  2. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kroning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA III: Epic: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311–2319.
  3. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.
  4. Van Cutsem E, Lang I, D’haens G, Moiseyenko V, Zaluski J, Folprecht G, Tejpar S, Kisker O, Stroh C, Rougier P: 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. ASCO Meeting Abstracts 2008;26:2.
  5. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB III: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539–1544.
  6. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.
  7. Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A: 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.
  8. 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: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992–3995.
  9. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 2007;67:2643–2648.
  10. 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: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626–1634.
  11. 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: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663–671.
  12. Calistri D, Rengucci C, Seymour I, Leonardi E, Truini M, Malacarne D, Castagnola P, Giaretti W: KRAS, p53 and BRAF gene mutations and aneuploidy in sporadic colorectal cancer progression. Cell Oncol 2006;28:161–166.
  13. 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: 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.
  14. 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: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 2007;96:1166–1169.
  15. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705–5712.
  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: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765.
  17. Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH: Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int 2008;58:104–113.
  18. 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: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26:374–379.
  19. Nagasaka T, Sasamoto H, Notohara K, Cullings HM, Takeda M, Kimura K, Kambara T, MacPhee DG, Young J, Leggett BA, Jass JR, Tanaka N, Matsubara N: Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol 2004;22:4584–4594.
  20. Ikehara N, Semba S, Sakashita M, Aoyama N, Kasuga M, Yokozaki H: BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms. Int J Cancer 2005;115:943–950.
  21. Miyaki M, Iijima T, Yamaguchi T, Kadofuku T, Funata N, Mori T: Both BRAF and KRAS mutations are rare in colorectal carcinomas from patients with hereditary nonpolyposis colorectal cancer. Cancer Lett 2004;211:105–109.
  22. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.
  23. Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, Oh DY, Kim JH, Kim DW, Chung DH, Im SA, Kim YT, Lee JS, Heo DS, Bang YJ, Kim NK: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005;23:2493–2501.
  24. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.
  25. Finocchiaro G, Cappuzzo F, Janne PA, Bencardino K, Carnaghi C, Franklin WA, Roncalli M, Crino L, Santoro A, Varella-Garcia M: EGFR, HER2 and KRAS as predictive factors for cetuximab sensitivity in colorectal cancer. J Clin Oncol 2007;25:4021.

    External Resources

  26. 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 III, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ: Expression of epiregu8lin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007;25:3230–3237.
  27. Juan T, Suggs S, Wolf M, Sarosi I, Freeman D, Oliner K, et al: A comparability study of 4 commercial KRAS tests; in Proceedings of the 99th Annual Meeting of the American Association for Cancer Research, San Diego, April 2008. Philadelphia, AACR, 2008, abstract No. 1811.
  28. Loupakis F, Pollina L, Stasi I, Masi G, Funel N, Scartozzi M, Petrini I, Santini D, Cascinu S, Falcone A: Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment. J Clin Oncol 2008;26:4003.
  29. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, Hamilton A, Pan D, Schrag D, Schwartz L, Klimstra DS, Fridman D, Kelsen DP, Saltz LB: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23:1803–1810.
  30. Bibeau F, Lopez-Crapez E, Di Fiore F, Thezenas S, Ychou M, Blanchard F, Lamy A, Penault-Llorca F, Frebourg T, Michel P, Sabourin JC, Boissiere-Michot F: Impact of FcγRIIa-FcγRIIIa 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.
  31. Kim CJ, Lee JH, Song JW, Cho YG, Kim SY, Nam SW, Yoo NJ, Park WS, Lee JY: Chk1 frameshift mutation in sporadic and hereditary non-polyposis colorectal cancers with microsatellite instability. Eur J Surg Oncol 2007;33:580–585.
  32. Park HW, Kang HC, Kim IJ, Jang SG, Kim K, Yoon HJ, Jeong SY, Park JG: Correlation between hypermethylation of the RASSF2A promoter and K-ras/BRAF mutations in microsatellite-stable colorectal cancers. Int J Cancer 2007;120:7–12.