Skip to main content
SpringerLink
Log in

Prognostic and Predictive Value of RAS Gene Mutations in Colorectal Cancer: Moving Beyond KRAS Exon 2

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

The advent of anti-EGFR (epidermal growth factor receptor) therapy resulted in significant progress in the treatment of metastatic colorectal cancer patients. However, many patients do not respond to this therapy or develop acquired resistance within a few months after the start of treatment. Since 2008, anti-EGFR therapy is restricted to KRAS wild-type patients as it has been shown that KRAS exon 2-mutated patients do not respond to this therapy. Still, up to 60 % of KRAS exon 2 wild-type patients show primary resistance to this treatment. Recently, several studies investigating the predictive and prognostic role of RAS mutations other than in KRAS exon 2 demonstrated that patients with these mutations are not responding to therapy. However, the role of these mutations has long been questioned as The National Comprehensive Cancer Network Guidelines in Oncology and the European Medicines Agency indications had already been changed in order to restrict anti-EGFR therapy to all RAS wild-type colorectal cancer patients, while the Food and Drug Administration guidelines remained unchanged. Recently, the Food and Drug Administration guidelines have also been changed, which implies the importance of RAS mutations beyond KRAS exon 2 in colorectal cancer. In this review, we discuss the most important studies regarding the predictive and prognostic role of RAS mutations other than in KRAS exon 2 in order to demonstrate the importance of these RAS mutations in patients with metastatic colorectal cancer treated with anti-EGFR therapy.

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

Fig. 1

Similar content being viewed by others

References

  1. Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med. 2012;4(162):162ra54. doi:10.1126/scitranslmed.3004742.

    Article  Google Scholar 

  2. Dressman D, Yan H, Traverso G, Kinzler KW, Vogelstein B. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci USA. 2003;100(15):8817–22. doi:10.1073/pnas.1133470100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist. 2010;15(7):699–731. doi:10.1634/theoncologist.2010-0025.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Laurent-Puig P, Pekin D, Normand C, Kotsopoulos SK, Nizard P, Perez-Toralla K, et al. Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2015;21(5):1087–97. doi:10.1158/1078-0432.CCR-14-0983.

    Article  CAS  Google Scholar 

  5. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–40. doi:10.1038/nature11219.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7(Suppl 4):2–8.

    Article  CAS  PubMed  Google Scholar 

  7. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(31):4706–13. doi:10.1200/JCO.2009.27.6055.

    Article  CAS  Google Scholar 

  8. Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–5. doi:10.1158/0008-5472.CAN-06-0191.

    Article  PubMed  Google Scholar 

  9. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65. doi:10.1056/NEJMoa0804385.

    Article  CAS  PubMed  Google Scholar 

  10. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(10):1626–34. doi:10.1200/JCO.2007.14.7116.

    Article  CAS  Google Scholar 

  11. National Comprehensive Cancer Network. Clinical practice guidelines in oncology (NCCN guidelines). Colon Cancer. NCCN.org.

  12. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45. doi:10.1056/NEJMoa033025.

    Article  CAS  PubMed  Google Scholar 

  13. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, 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 Off J Am Soc Clin Oncol. 2007;25(13):1658–64. doi:10.1200/JCO.2006.08.1620.

    Article  Google Scholar 

  14. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(7):1201–8. doi:10.1200/JCO.2004.10.182.

    Article  CAS  Google Scholar 

  15. Custodio A, Feliu J. Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: beyond KRAS mutations. Crit Rev Oncol/Hematol. 2013;85(1):45–81. doi:10.1016/j.critrevonc.2012.05.001.

    Article  Google Scholar 

  16. Peeters M, Cohn A, Kohne CH, Douillard JY. Panitumumab in combination with cytotoxic chemotherapy for the treatment of metastatic colorectal carcinoma. Clin Colorectal Cancer. 2012;11(1):14–23. doi:10.1016/j.clcc.2011.06.010.

    Article  CAS  PubMed  Google Scholar 

  17. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, 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):2643–8. doi:10.1158/0008-5472.CAN-06-4158.

    Article  CAS  PubMed  Google Scholar 

  18. Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(12):2091–6. doi:10.1200/JCO.2009.21.9170.

    Article  Google Scholar 

  19. Fakih M, Wong R. Efficacy of the monoclonal antibody EGFR inhibitors for the treatment of metastatic colorectal cancer. Curr Oncol. 2010;17(Suppl 1):S3–17.

    PubMed Central  PubMed  Google Scholar 

  20. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34. doi:10.1056/NEJMoa1305275.

    Article  CAS  PubMed  Google Scholar 

  21. Peeters M, Oliner KS, Parker A, Siena S, Van Cutsem E, Huang J, et al. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2013;19(7):1902–12. doi:10.1158/1078-0432.CCR-12-1913.

    Article  CAS  Google Scholar 

  22. European Medicines Agency. Erbitux. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000558/human_med_000769.jsp&mid=WC0B01AC058001D124. Accessed 29 Dec 2014.

  23. European Medicines Agency. Vectibix. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000741/human_med_001128.jsp&mid=WC0B01AC058001D124. Accessed 29 Dec 2014.

  24. Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Suppl 4):S3–8.

    Article  CAS  PubMed  Google Scholar 

  25. Mahipal A, Kothari N, Gupta S. Epidermal growth factor receptor inhibitors: coming of age. Cancer Control J Moffitt Cancer Cent. 2014;21(1):74–9.

    Google Scholar 

  26. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer. 2001;92(5):1331–46.

    Article  CAS  PubMed  Google Scholar 

  27. Campanella C, Mottolese M, Cianciulli A, Torsello A, Merola R, Sperduti I, et al. Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab. J Transl Med. 2010;8:36. doi:10.1186/1479-5876-8-36.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol. 2004;44:195–217. doi:10.1146/annurev.pharmtox.44.101802.121440.

    Article  CAS  PubMed  Google Scholar 

  29. Ashraf N, Kothari N, Kim R. Predictive biomarkers for anti-epidermal growth factor receptor therapy: beyond KRAS testing. J Natl Compr Cancer Netw JNCCN. 2014;12(10):1433–42.

    CAS  PubMed  Google Scholar 

  30. Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, et al. Raf family kinases: old dogs have learned new tricks. Genes Cancer. 2011;2(3):232–60. doi:10.1177/1947601911407323.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Charette N, Vandeputte C, Starkel P. Ras in digestive oncology: from molecular biology to clinical implications. Curr Opin Oncol. 2014;26(4):454–61. doi:10.1097/CCO.0000000000000088.

    Article  PubMed  Google Scholar 

  32. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11(11):761–74. doi:10.1038/nrc3106.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Grewal T, Koese M, Tebar F, Enrich C. Differential regulation of RasGAPs in cancer. Genes Cancer. 2011;2(3):288–97. doi:10.1177/1947601911407330.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64(9):3014–21.

    Article  CAS  PubMed  Google Scholar 

  35. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell. 2000;100(4):387–90.

  36. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(14):2311–9. doi:10.1200/JCO.2007.13.1193.

    Article  CAS  Google Scholar 

  37. Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014;4(11):1269–80. doi:10.1158/2159-8290.CD-14-0462.

    Article  CAS  PubMed  Google Scholar 

  38. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17. doi:10.1056/NEJMoa0805019.

    Article  PubMed  Google Scholar 

  39. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2008;19(3):508–15. doi:10.1093/annonc/mdm496.

    Article  Google Scholar 

  40. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. 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 Off J Am Soc Clin Oncol. 2010;28(31):4697–705. doi:10.1200/JCO.2009.27.4860.

    Article  CAS  Google Scholar 

  41. Peeters M, Douillard JY, Van Cutsem E, Siena S, Zhang K, Williams R, et al. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(6):759–65. doi:10.1200/JCO.2012.45.1492.

    Article  CAS  Google Scholar 

  42. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(3):374–9. doi:10.1200/JCO.2007.12.5906.

    Article  CAS  Google Scholar 

  43. Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007;96(8):1166–9. doi:10.1038/sj.bjc.6603685.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103–14. doi:10.1016/S0140-6736(11)60613-2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8. doi:10.1056/NEJMoa071834.

    Article  CAS  PubMed  Google Scholar 

  46. Deschoolmeester V, Boeckx C, Baay M, Weyler J, Wuyts W, Van Marck E, et al. KRAS mutation detection and prognostic potential in sporadic colorectal cancer using high-resolution melting analysis. Br J Cancer. 2010;103(10):1627–36. doi:10.1038/sj.bjc.6605959.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Cetuximab (Erbitux) and Panitumumab (Vectibix). US Food and Drug Administration Web Site. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm172905. Accessed 29 Dec 2014.

  48. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. 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. 2010;11(8):753–62. doi:10.1016/S1470-2045(10)70130-3.

    Article  PubMed  Google Scholar 

  49. De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 2011;12(6):594–603. doi:10.1016/S1470-2045(10)70209-6.

    Article  PubMed  Google Scholar 

  50. Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(35):5924–30. doi:10.1200/JCO.2008.21.6796.

    Article  CAS  Google Scholar 

  51. US Food and Drug Administration. VECTIBIX. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed 29 Dec 2014.

  52. US Food and Drug Administration. ERBITUX. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed 29 Dec 2014.

  53. De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. Jama. 2010;304(16):1812–20. doi:10.1001/jama.2010.1535.

    Article  PubMed  Google Scholar 

  54. Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C, Van Cutsem E. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(29):3570–7. doi:10.1200/JCO.2012.42.2592.

    Article  CAS  Google Scholar 

  55. Molinari F, Felicioni L, Buscarino M, De Dosso S, Buttitta F, Malatesta S, et al. Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(14):4901–14. doi:10.1158/1078-0432.CCR-10-3137.

    Article  CAS  Google Scholar 

  56. Guerrero S, Casanova I, Farre L, Mazo A, Capella G, Mangues R. K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Res. 2000;60(23):6750–6.

    CAS  PubMed  Google Scholar 

  57. Guerrero S, Figueras A, Casanova I, Farre L, Lloveras B, Capella G, et al. Codon 12 and codon 13 mutations at the K-ras gene induce different soft tissue sarcoma types in nude mice. FASEB J Off Publ Fed Am Soc Exp Biol. 2002;16(12):1642–4. doi:10.1096/fj.02-0050fje.

    CAS  Google Scholar 

  58. Smith G, Bounds R, Wolf H, Steele RJ, Carey FA, Wolf CR. Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours—implications for personalised cancer medicine. Br J Cancer. 2010;102(4):693–703. doi:10.1038/sj.bjc.6605534.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Alamo P, Gallardo A, Di Nicolantonio F, Pavon MA, Casanova I, Trias M, et al. Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model. FASEB J Off Publ Fed Am Soc Exp Biol. 2014. doi:10.1096/fj.14-262303.

    Google Scholar 

  60. Schirripa M, Lonardi S, Cremolini C, Loupakis F, Salvatore L, Bergamo F, et al. Phase II study of single-agent cetuximab in KRAS G13D mutant metastatic colorectal cancer (mCRC). J Clin Oncol Off J Am Soc Clin Oncol. 2014;32:5s (suppl; abstr 3524).

  61. Gajate P, Sastre J, Bando I, Alonso T, Cillero L, Sanz J, et al. Influence of KRAS p. G13D mutation in patients with metastatic colorectal cancer treated with cetuximab. Clin Colorectal Cancer. 2012;11(4):291–6. doi:10.1016/j.clcc.2012.02.003.

    Article  CAS  PubMed  Google Scholar 

  62. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, et al. 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. 2009;101(4):715–21. doi:10.1038/sj.bjc.6605177.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–75. doi:10.1016/S1470-2045(14)70330-4.

    Article  CAS  PubMed  Google Scholar 

  64. Ciardiello F, Bianco R, Caputo R, Caputo R, Damiano V, Troiani T, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(2):784–93.

    Article  CAS  Google Scholar 

  65. Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 2001;61(13):5090–101.

    CAS  PubMed  Google Scholar 

  66. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2011;22(7):1535–46. doi:10.1093/annonc/mdq632.

    Article  CAS  Google Scholar 

  67. Bokemeyer C, Kohne CH, Ciardiello F, Lenz H, Heinemann V, Klinkhardt U, et al. Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32:5s (suppl; abstr 3505).

  68. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(15):2011–9. doi:10.1200/JCO.2010.33.5091.

    Article  Google Scholar 

  69. Ciardiello F, Lenz H, Kohne CH, Heinemann V, Tejpar S, Esser R, et al. Effect of KRAS and NRAS mutational status on first-line treatment with FOLFIRI plux cetuximab in patients with metastatic colorectal cancer (mCRC): New results from the CRYSTAL trial. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32 (suppl; abstr LBA443).

  70. Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2015. doi:10.1200/JCO.2014.59.4812.

    Google Scholar 

  71. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncology Off J Eur Soc Med Oncol/ESMO. 2014;25(7):1346–55. doi:10.1093/annonc/mdu141.

    Article  CAS  Google Scholar 

  72. Andre T, Blons H, Mabro M, Chibaudel B, Bachet JB, Tournigand C, et al. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncology Off J Eur Soc Med Oncol/ESMO. 2013;24(2):412–9. doi:10.1093/annonc/mds465.

    Article  CAS  Google Scholar 

  73. Patterson SD, Peeters M, Siena S, Van Cutsem E, Humblet Y, Van Laethem JL, et al. Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408). J Clin Oncol Off J Am Soc Clin Oncol. 2013;31 (suppl; abstr 3617).

  74. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(21):2240–7. doi:10.1200/JCO.2013.53.2473.

    Article  CAS  Google Scholar 

  75. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Final results from a randomized phase 3 study of FOLFIRI ± panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncology Off J Eur Soc Med Oncol/ESMO. 2014;25(1):107–16. doi:10.1093/annonc/mdt523.

    Article  CAS  Google Scholar 

  76. Peeters M, Oliner KS, Price T, Cervantes A, Sobrero AF, Ducreux M, et al. Updated analysis of KRAS/NRAS and BRAF mutations in study 20050181 of panitumumab (pmab) plus FOLFIRI for second-line treatment (tx) of metastatic colorectal cancer (mCRC). J Clin Oncol Off J Am Soc Clin Oncol. 2014;32:5s (suppl; abstr 3568).

  77. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncology Off J Eur Soc Med Oncol/ESMO. 2015;26(1):13–21. doi:10.1093/annonc/mdu378.

    Article  CAS  Google Scholar 

  78. Schirripa M, Cremolini C, Loupakis F, Morvillo M, Bergamo F, Zoratto F, et al. Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. Int J Cancer J Int du Cancer. 2015;136(1):83–90. doi:10.1002/ijc.28955.

    Article  CAS  Google Scholar 

  79. Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, et al. 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 Off J Am Soc Clin Oncol. 2009;27(35):5931–7. doi:10.1200/JCO.2009.22.4295.

    Article  CAS  Google Scholar 

  80. Stremitzer S, Stift J, Gruenberger B, Tamandl D, Aschacher T, Wolf B, et al. KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab. Br J Surg. 2012;99(11):1575–82. doi:10.1002/bjs.8909.

    Article  CAS  PubMed  Google Scholar 

  81. Vauthey JN, Zimmitti G, Kopetz SE, Shindoh J, Chen SS, Andreou A, et al. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg. 2013;258(4):619–26. doi:10.1097/SLA.0b013e3182a5025a (discussion 26–7).

    Article  PubMed  Google Scholar 

  82. Yaeger R, Cowell E, Chou JF, Gewirtz AN, Borsu L, Vakiani E, et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer. 2014. doi:10.1002/cncr.29196.

    Google Scholar 

  83. Mise Y, Zimmitti G, Shindoh J, Kopetz S, Loyer EM, Andreou A, et al. RAS mutations predict radiologic and pathologic response in patients treated with chemotherapy before resection of colorectal liver metastases. Ann Surg Oncol. 2014. doi:10.1245/s10434-014-4042-6.

    PubMed Central  Google Scholar 

  84. Wang Y, Carlton VE, Karlin-Neumann G, Sapolsky R, Zhang L, Moorhead M, et al. High quality copy number and genotype data from FFPE samples using Molecular Inversion Probe (MIP) microarrays. BMC Med Genomics. 2009;2:8. doi:10.1186/1755-8794-2-8.

    Article  PubMed Central  PubMed  Google Scholar 

  85. Srinivasan M, Sedmak D, Jewell S. Effect of fixatives and tissue processing on the content and integrity of nucleic acids. Am J Pathol. 2002;161(6):1961–71. doi:10.1016/S0002-9440(10)64472-0.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Song S, Nones K, Miller D, Harliwong I, Kassahn KS, Pinese M, et al. qpure: a tool to estimate tumor cellularity from genome-wide single-nucleotide polymorphism profiles. PLoS One. 2012;7(9):e45835. doi:10.1371/journal.pone.0045835.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Atreya CE, Corcoran RB, Kopetz S. Expanded RAS: refining the patient population. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(7):682–5. doi:10.1200/JCO.2014.58.9325.

    Article  Google Scholar 

  88. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92. doi:10.1056/NEJMoa1113205.

    Article  CAS  PubMed  Google Scholar 

  89. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90. doi:10.1038/nm.1789.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Board RE, Ellison G, Orr MC, Kemsley KR, McWalter G, Blockley LY, et al. Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study. Br J Cancer. 2009;101(10):1724–30. doi:10.1038/sj.bjc.6605371.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Lefebure B, Charbonnier F, Di Fiore F, Tuech JJ, Le Pessot F, Michot F, et al. Prognostic value of circulating mutant DNA in unresectable metastatic colorectal cancer. Ann Surg. 2010;251(2):275–80. doi:10.1097/SLA.0b013e3181c35c87.

    Article  PubMed  Google Scholar 

  92. Chen H, Tu H, Meng ZQ, Chen Z, Wang P, Liu LM. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur J surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. 2010;36(7):657–62. doi:10.1016/j.ejso.2010.05.014.

    CAS  Google Scholar 

  93. Yen LC, Yeh YS, Chen CW, Wang HM, Tsai HL, Lu CY, et al. Detection of KRAS oncogene in peripheral blood as a predictor of the response to cetuximab plus chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15(13):4508–13. doi:10.1158/1078-0432.CCR-08-3179.

    Article  CAS  Google Scholar 

  94. Barbazan J, Muinelo-Romay L, Vieito M, Candamio S, Diaz-Lopez A, Cano A, et al. A multimarker panel for circulating tumor cells detection predicts patient outcome and therapy response in metastatic colorectal cancer. Int J Cancer J Int du Cancer. 2014;135(11):2633–43. doi:10.1002/ijc.28910.

    Article  CAS  Google Scholar 

  95. Mostert B, Jiang Y, Sieuwerts AM, Wang H, Bolt-de Vries J, Biermann K, et al. KRAS and BRAF mutation status in circulating colorectal tumor cells and their correlation with primary and metastatic tumor tissue. Int J Cancer J Int du Cancer. 2013;133(1):130–41. doi:10.1002/ijc.27987.

    Article  CAS  Google Scholar 

  96. van Krieken JH, Jung A, Kirchner T, Carneiro F, Seruca R, Bosman FT, et al. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch Int J Pathol. 2008;453(5):417–31. doi:10.1007/s00428-008-0665-y.

    Article  Google Scholar 

  97. Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68. doi:10.1126/scitranslmed.3003726.

    Article  PubMed  Google Scholar 

  98. Cancer Genome Atlas. N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. doi:10.1038/nature11252.

    Article  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Center for Oncological Research Antwerp, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, Wilrijk, 2610, Antwerp, Belgium

      Nele Boeckx, Marc Peeters, Patrick Pauwels, Ken Op de Beeck & Vanessa Deschoolmeester

    2. Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, Edegem, 2650, Antwerp, Belgium

      Marc Peeters

    3. Center for Medical Genetics, University of Antwerp, Antwerp University Hospital, Campus Drie Eiken, Universiteitsplein 1, Wilrijk, 2610, Antwerp, Belgium

      Nele Boeckx, Guy Van Camp & Ken Op de Beeck

    4. Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, Edegem, 2650, Antwerp, Belgium

      Patrick Pauwels & Vanessa Deschoolmeester

    Authors
    1. Nele Boeckx
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Marc Peeters
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Guy Van Camp
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Patrick Pauwels
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ken Op de Beeck
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Vanessa Deschoolmeester
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Nele Boeckx.

    Ethics declarations

    Funding

    This work was supported by a grant from the National Cancer Plan, Belgium (grant: NKP 29_38).

    Conflicts of interest

    Nele Boeckx has no conflict of interest to declare. Prof. Dr Marc Peeters has received grants from Amgen, Roche, Novartis, and Bayer and consulting fees and payment for lectures from Amgen, Bayer, Novartis, Sanofi, and Merck Serono. Prof. Dr Guy Van Camp has no conflict of interest to declare. Prof. Dr Patrick Pauwels has received fees from Merck for advisory board meetings and lectures. Dr Ken Op de Beeck has no conflict of interest to declare. Dr Vanessa Deschoolmeester has no conflict of interest to declare.

    Additional information

    K. Op de Beeck and V. Deschoolmeester contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Boeckx, N., Peeters, M., Van Camp, G. et al. Prognostic and Predictive Value of RAS Gene Mutations in Colorectal Cancer: Moving Beyond KRAS Exon 2. Drugs 75, 1739–1756 (2015). https://doi.org/10.1007/s40265-015-0459-x

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s40265-015-0459-x

    Keywords

    Search

    Navigation