open access

Vol 5, No 1 (2009)
Review paper
Published online: 2009-02-02
Get Citation

KRAS status as a molecular predictive fac

Aleksandra Łacko, Krzysztof Krzemieniecki
Onkol. Prak. Klin 2009;5(1):9-15.

open access

Vol 5, No 1 (2009)
REVIEW ARTICLES
Published online: 2009-02-02

Abstract

Anti-epidermal growth factor receptor (EGFR) antibodies are new class of agents used in the treatment of metastatic colorectal cancer. Since activity of EGFR-inhibitors in general population is limited, regardless of the agent and regimen, the major issue now is to define factors which can be used in selecting patients for such treatment. In recently reported large clinical studies, KRAS mutations has been shown to be highly predictive of response and survival benefit from EGFR inhibitors. Available data indicates that patients with mutated KRAS are not good candidates for treatment with anti-EGFR monoclonal antibodies because it is ineffective and expose them to unnecessary toxicities. What is more, some data suggest that adding EGFR inhibitor to chemotherapy in this population can even lead to poorer outcome. As KRAS mutational status is a reliable negative predictive biomarker, it must be tested prior to initiating EGFR-targeted therapies.

Abstract

Anti-epidermal growth factor receptor (EGFR) antibodies are new class of agents used in the treatment of metastatic colorectal cancer. Since activity of EGFR-inhibitors in general population is limited, regardless of the agent and regimen, the major issue now is to define factors which can be used in selecting patients for such treatment. In recently reported large clinical studies, KRAS mutations has been shown to be highly predictive of response and survival benefit from EGFR inhibitors. Available data indicates that patients with mutated KRAS are not good candidates for treatment with anti-EGFR monoclonal antibodies because it is ineffective and expose them to unnecessary toxicities. What is more, some data suggest that adding EGFR inhibitor to chemotherapy in this population can even lead to poorer outcome. As KRAS mutational status is a reliable negative predictive biomarker, it must be tested prior to initiating EGFR-targeted therapies.
Get Citation

Keywords

colorectal cancer; predictive factors; anti-EGFR antibodies; KRAS

About this article
Title

KRAS status as a molecular predictive fac

Journal

Oncology in Clinical Practice

Issue

Vol 5, No 1 (2009)

Article type

Review paper

Pages

9-15

Published online

2009-02-02

Bibliographic record

Onkol. Prak. Klin 2009;5(1):9-15.

Keywords

colorectal cancer
predictive factors
anti-EGFR antibodies
KRAS

Authors

Aleksandra Łacko
Krzysztof Krzemieniecki

References (30)
  1. 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(5): 279–286.
  2. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006; 24(30): 4914–4921.
  3. 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(3): 374–379.
  4. Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist. 2002; 7 Suppl 4: 31–39.
  5. Tejpar S, Peeters M, Humblet Y, et al. Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): The EVEREST experience (preliminary data). Journal of Clinical Oncology. 2008; 26(15_suppl): 4001.
  6. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 25(13): 1658–1664.
  7. 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(10): 1626–1634.
  8. 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(3): 508–515.
  9. 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(8): 1166–1169.
  10. Frattini M, Saletti P, Romagnani E, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007; 97(8): 1139–1145.
  11. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007; 25(22): 3230–3237.
  12. Perkins G, Lièvre A, Ramacci C, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006; 66(8): 3992–3995.
  13. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. 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(6): 2643–2648.
  14. Jonker DJ, Karapetis CS, Harbison C, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359(17): 1757–1765.
  15. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. Journal of Clinical Oncology. 2008; 26(15_suppl): 4000.
  16. Cutsem EV, Lang I, D'haens G, et al. 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. Journal of Clinical Oncology. 2008; 26(15_suppl): 2.
  17. Cin L, Tam A, Pomerantz J, et al. Essential role of oncogenic Ras in tumor maintanance. Nature. 1999; 400: 468–472.
  18. Rak J, Mitsuhashi Y, Sheehan C, et al. Oncogenes and tumor angiogenesis : differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithalial cells snd fibroblasts. Cancer Res. 2000; 60: 490–498.
  19. Watnick RS, Cheng YN, Rangarajan A, et al. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 2003; 3(3): 219–231.
  20. 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(13): 981–989.
  21. Hurwitz HI, Yi J, Ince W, et al. 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. 2009; 14(1): 22–28.
  22. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005; 2(1): e17.
  23. Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res. 2007; 13(10): 2890–2896.
  24. Miller VA, Zakowski M, Riely GJ, et al. EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC): Results of a prospective phase II trial. J. Clin. Oncol. 2006; 364(abstr. 7003).
  25. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005; 23(25): 5900–5909.
  26. Zhu CQ, da Cunha Santos G, Ding K, et al. National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008; 26(26): 4268–4275.
  27. Philip PA, Benedetti J, Fenoglio-Preiser C, et al. Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J. Clin. Oncol. 2007; 25(199): abstr. LBA4509.
  28. Moore MJ, Goldstein D, Hamm J, et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007; 25(15): 1960–1966.
  29. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008; 26(35): 5705–5712.
  30. Artale S, Sartore-Bianchi A, Veronese SM, et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol. 2008; 26(25): 4217–4219.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

Wydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl