Biomarkers and anti-EGFR therapies for KRAS wild-type metastatic colorectal cancer

  • Jose A. García-Sáenz
  • Javier Sastre
  • Eduardo Díaz-Rubio García


Therapy for metastatic colorectal cancer has been improved in terms of response rate, time to progression and overall survival by the emergence of anti-EGFR monoclonal antibodies (cetuximab and panitumumab) in combination with standard cytotoxic chemotherapy (oxaliplatin or CPT-11-based combinations). However, the benefits of cetuximab and panitumumab are confined to KRAS wild-type (KRAS-wt) colorectal tumours; KRAS-mutated tumours rarely respond to these drugs. Of all colorectal tumours, 65% are KRAS-wt tumours, but anti-EGFR therapies are effective for only 60–70% of these. Therefore, other biomarkers and molecular pathways must be involved in the response to anti-EGFR therapies in KRASwt colorectal tumours. Factors that may explain the lack of response include EGFR ligands, EGFR phosphorylation levels, the number of EGFR copies, the status of the KRAS effector B-RAF and the alternative intracellular PIK3CA/PTEN/AKT and JAK/STAT signalling pathways. A battery of biomarkers is needed to select the patients that will be most sensitive to anti-EGFR therapies. Such patterns may be a novel and cost-effective tool to develop tailored treatments. This manuscript will review biomarkers and molecular pathways that are involved in the tumour response to anti-EGFR therapies.


KRAS wild-type Colorectal cancer B-RAF Panitumumab Cetuximab 


  1. 1.
    Winer E, Gralow J, Diller L et al (2009) Clinical cancer advances 2008: major research advances in cancer treatment, prevention, and screening: a report from the American Society of Clinical Oncology. J Clin Oncol 27:812–826PubMedCrossRefGoogle Scholar
  2. 2.
    Cassidy J, Clarke S, Díaz-Rubio E et al (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006–2012PubMedCrossRefGoogle Scholar
  3. 3.
    Díaz-Rubio E, Tabernero J, Gómez-España A et al (2007) Phase III study of capecitabine plus oxaliplatin versus continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 20:4224–4230CrossRefGoogle Scholar
  4. 4.
    Saltz LB, Clarke S, Díaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019PubMedCrossRefGoogle Scholar
  5. 5.
    Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905–914PubMedCrossRefGoogle Scholar
  6. 6.
    Presta LG, Chen H, O’Connor SJ et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599PubMedGoogle Scholar
  7. 7.
    Bianco R, Daniele G, Ciardiello F, Tortora G (2005) Monoclonal antibodies targeting the epidermal growth factor receptor. Curr Drug Targets 6:275–287PubMedCrossRefGoogle Scholar
  8. 8.
    Eggstein S, Manthey G, Hirsch T et al (1996) Raf-1 kinase, epidermal growth factor receptors, and mutant Ras proteins in colonic carcinomas. Dig Dis Sci 41:1069–1075PubMedCrossRefGoogle Scholar
  9. 9.
    Salomon DS, Brandt R, Ciardello F, Normanno N (1995) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183–232PubMedCrossRefGoogle Scholar
  10. 10.
    Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516PubMedCrossRefGoogle Scholar
  11. 11.
    Mendelson J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787–2799CrossRefGoogle Scholar
  12. 12.
    Hynes NH, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354PubMedCrossRefGoogle Scholar
  13. 13.
    Goldstein NS, Armin M (2001) 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 92:1331–1346PubMedCrossRefGoogle Scholar
  14. 14.
    Spano JP, Fagard R, Soria JC (2005) Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspective. Ann Oncol 16:189–194PubMedCrossRefGoogle Scholar
  15. 15.
    Ciardello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174CrossRefGoogle Scholar
  16. 16.
    Li S, Schmitz KR, Jeffrey PD et al (2005) Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7:301–311PubMedCrossRefGoogle Scholar
  17. 17.
    Saltz L, Meropol N, Loeherer P et al (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201–1208PubMedCrossRefGoogle Scholar
  18. 18.
    Lenz HJ, Van Cutsem E, Khambata-Ford S et al (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. J Clin Oncol 24:4914–4921PubMedCrossRefGoogle Scholar
  19. 19.
    Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan refractory metastatic colorectal cancer. N Engl J Med 351:337–345PubMedCrossRefGoogle Scholar
  20. 20.
    Eng C, Maurel J, Scheithauer W et al (2007) Impact of quality of life of adding cetuximab to irinotecan in patients who have failed prior oxaliplatin-based therapy: the EPIC trial. J Clin Oncol 25s:A4003Google Scholar
  21. 21.
    Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048PubMedCrossRefGoogle Scholar
  22. 22.
    Chung K, Shia J, Kemeny N et al (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810PubMedCrossRefGoogle Scholar
  23. 23.
    Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapyrefractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664PubMedCrossRefGoogle Scholar
  24. 24.
    Van Cutsem E, Siena S, Humblet Y et al (2008) An open-label, single arm study assessing safety and efficacy of panitumumab in patients with mCRC refractory to standard chemotherapy. Ann Oncol 19:92–98PubMedCrossRefGoogle Scholar
  25. 25.
    Folprecht G, Gruenberger T, Hartmann JT et al (2008) Randomized multicenter study of cetuximab plus FOLFOX or cetuximab plus FOLFIRI in neoadjuvant treatment of non-resectable colorectal liver metastases (CELIM-study). Ann Oncol 19:viii168 A510Google Scholar
  26. 26.
    Tabernero J, Van Cutsem E, Díaz-Rubio E et al (2007) Phase II trial of cetuximab in combination with fluorouracil, leucovorin and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 25:5225–5232PubMedCrossRefGoogle Scholar
  27. 27.
    Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417PubMedCrossRefGoogle Scholar
  28. 28.
    Andreyev HJ, Norman AR, Cunningham D et al (1998) Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst 90:675–684PubMedCrossRefGoogle Scholar
  29. 29.
    Kastrinakis WV, Ramchuren N, Maggard M et al (1995) KRAS status does not predict successful hepatic resection of colorectal cancer metastasis. Arch Surg 130:9–14PubMedGoogle Scholar
  30. 30.
    Petrowsky H, Sturm I, Graubitz O et al (2001) Relevance of Ki-67 antigen expression and KRAS mutation in colorectal liver metastases. Eur J Surg Oncol 27:80–87PubMedCrossRefGoogle Scholar
  31. 31.
    Lièvre A, Bachet JB, Le Corre D et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995PubMedCrossRefGoogle Scholar
  32. 32.
    Lièvre A, Bachet JB, Boige V et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379PubMedCrossRefGoogle Scholar
  33. 33.
    Khambata-Ford S, Garret C, Meropol N et al (2007) Expression of epiregulin and amphiregulin and KRAS mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230–3237PubMedCrossRefGoogle Scholar
  34. 34.
    Amado RG, Wolf M, Peeters M et al (2008) Wildtype KRAS is required for panitumumab efficacy in patients with metastatic cancer. J Clin Oncol 26:1626–1634PubMedCrossRefGoogle Scholar
  35. 35.
    Karapetis C, Khambata-Ford S, Jonker D et al (2008) KRAS mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765PubMedCrossRefGoogle Scholar
  36. 36.
    Di Fiore F, Van Cutsem E, Laurent-Puig P et al (2008) Role of KRAS mutation in predicting response, progression-free survival and overall survival in irinotecan-refractory patients with cetuximab plus irinotecan for a metastatic colorectal cancer: analysis of 281 individual data from published series. J Clin Oncol 26s:A4035Google Scholar
  37. 37.
    De Roock W, Piessevaux H, De Schutter J et al (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
  38. 38.
    Bokemeyer C, Bondarenko I, Hartmann J et al (2008) KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer with FOLFOX with or without cetuximab: the OPUS experience. J Clin Oncol 26s:A4000Google Scholar
  39. 39.
    Bokemeyer C, Bondarenko I, Makhson A et al (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
  40. 40.
    Folprecht G, Lutz MP, Schöffski P et al (2006) Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 17:450–456PubMedCrossRefGoogle Scholar
  41. 41.
    Hecht JR, Mitchell E, Chidiac T et al (2009) A randomized phase IIIB trial of chemotherapy, bevacizumab and panitumumab compared with chemotherapy and bevacizumab alone in metastatic colorectal cancer. J Clin Oncol 27:672–680PubMedCrossRefGoogle Scholar
  42. 42.
    Punt CJ, Tol J, Rodenburg CJ et al (2008) Randomized phase III study of capecitabine, oxaliplatin and bevacizumab with or without cetuximab in advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 26s:A4011Google Scholar
  43. 43.
    Tol J, Koopman M, Cats A et al (2009) Chemotherapy, bevacizumab and cetuximab in metastatic colorectal cancer. N Engl J Med 360:563–572PubMedCrossRefGoogle Scholar
  44. 44.
    Blanke CD (2009) Dual-antibody therapy in advanced colorectal cancer: gather ye rosebuds while ye may. J Clin Oncol 27:655–658PubMedCrossRefGoogle Scholar
  45. 45.
    Mayer RJ (2009) Targeted therapy for advancer colorectal cancer. More is not always better. N Engl J Med 360:623–625PubMedCrossRefGoogle Scholar
  46. 46.
    Van Krieken JHJM, Jung A, Kirchner T et al (2008) KRAS mutation testing for predicting response to antiEGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch 453:417–431PubMedCrossRefGoogle Scholar
  47. 47.
    Wong R, Cunningham D (2008) Using predictive biomarkers to select patients with advanced colorectal cancer for treatment with epidermal growth factor receptor antibodies. J Clin Oncol 26:5668–5670PubMedCrossRefGoogle Scholar
  48. 48.
    Baselga J, Rosen N (2008) Determinants of RA-Sistance to Anti-Epidermal growth factor receptor agents. J Clin Oncol 26:1582–1584PubMedCrossRefGoogle Scholar
  49. 49.
    Ramos FJ, Tabernero J (2008) Biomarkers in colorectal cancer. Cancer Chemother Rev 4:194–204Google Scholar
  50. 50.
    Arribas J, Baselga J (2005) Who will benefit from treatment against EGFR? Lancet Oncol 6:257–258PubMedCrossRefGoogle Scholar
  51. 51.
    Tejpar S, Peeters M, Humblet Y et al (2007) Phase I/II study of cetuximab doseescalation in patients with metastatic colorectal cancer with no or slight skin reactions on cetuximab Standard dose treatment (EVEREST): Pharmacokinetic, pharmacodynamic and efficacy data. J Clin Oncol 25s:A4037Google Scholar
  52. 52.
    Tejpar S, Peeters M, Humblet Y et al (2008) Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer, treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): The EVEREST experience (preliminary data). J Clin Oncol 26s:A4001Google Scholar
  53. 53.
    O’Callaghan CJO, Tu D, Karapetis S et al (2008) The relationship between the development of rash and clinical and quality of life outcomes in colorectal cancer patients treated with cetuximab in NCIC CTG CO.17. J Clin Oncol 26s:A4130Google Scholar
  54. 54.
    Lenz HJ, Mayer RJ, Gold PJ et al (2004) Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. J Clin Oncol 23s:A3510Google Scholar
  55. 55.
    Saltz L (2005) Epidermal growth factor receptornegative colorectal cancer: Is there truly such and entity? Clin Colorectal Cancer 5s:98–100CrossRefGoogle Scholar
  56. 56.
    Meropol NJ (2005) Epidermal growth factor receptor inhibitors in colorectal cancer: it’s time to get back on target. J Clin Oncol 23:1791–1793PubMedCrossRefGoogle Scholar
  57. 57.
    Valentini AM, Pirelli M, Carusso ML (2008) EGFR-targeted therapy in colorectal cancer: does immunohistochemistry deserve a role in predicting the response to cetuximab? Curr Opin Mol Ther 10:124–131PubMedGoogle Scholar
  58. 58.
    Penault-Llorca F, Cayre A, Arnauld L et al (2006) Is there an immunohistochemical technique definitively valid in epidermal growth factor receptor assessment? Oncol Rep 16:1173–1179PubMedGoogle Scholar
  59. 59.
    Francoual M, Etienne-Grimaldi MC, Fomento JL et al (2006) EGFR in colorectal cancer: more than a simple receptor. Ann Oncol 17:962–967PubMedCrossRefGoogle Scholar
  60. 60.
    Hecht J, Mitcell E, Baranda J et al (2006) Panitumumab antitumor activity in patients with metastatic colorectal cancer expressing low (1–9%) or negative (<1%) levels of epidermal growth factor receptor (EGFR). J Clin Oncol 24s:A3547Google Scholar
  61. 61.
    Van Schaeybroeck S, Karaiskou-MacCaul A, Kelly D et al (2005) Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin Cancer Res 11:7480–7489PubMedCrossRefGoogle Scholar
  62. 62.
    Personeni N, Hendlisz A, Gallez J et al (2005) Correlation between the response to cetuximab alone or in combination with irinotecan and the activated/phosphorylated epidermal growth factor receptor in metastatic colorectal cancer. Semin Oncol 32s:59–62CrossRefGoogle Scholar
  63. 63.
    Janne PA, Engelman JA, Johnson BE (2005) Epidermal growth factor receptor mutations in nonsmall-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 23:3227–3234PubMedCrossRefGoogle Scholar
  64. 64.
    Tsuchihashi Z, Khambata-Frd S, Hanna N et al (2005) Responsiveness to cetuximab without mutations in EGFR. N Engl J Med 353:208–209PubMedCrossRefGoogle Scholar
  65. 65.
    Moroni M, Veronese S, Benevenuti S et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti-EGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286PubMedCrossRefGoogle Scholar
  66. 66.
    Sartore-Bianchi A, Moroni M, Veronese S et al (2007) Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with Panitumumab. J Clin Oncol 25:3238–3245PubMedCrossRefGoogle Scholar
  67. 67.
    Personeni N, Fieuws S, Piessevaux H et al (2008) Clinical usefulness of EGFR copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 14:5869–5876PubMedCrossRefGoogle Scholar
  68. 68.
    Personeni N, Piessevaux H, Fieuws S et al (2008) Association between EGFR gene copy number and KRAS status and impact on outcome prediction in colorectal cancer patients treated with cetuximab. J Clin Oncol 26s:A11093Google Scholar
  69. 69.
    Capuzzo F, Finocchiaro G, Rossi E et al (2008) EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 19:717–723CrossRefGoogle Scholar
  70. 70.
    Capuzzo F, Varela-Garcia M, Finocchiaro G et al (2008) Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 99:83–89CrossRefGoogle Scholar
  71. 71.
    Mancuso A, Leone L, Vigna F et al (2008) EGFR, DCC and KRAS mutations as predictive factors for cetuximab sensitivity in metastatic colorectal cancer. J Clin Oncol 26S:A4128Google Scholar
  72. 72.
    Italiano A, Follana P, Caroli FX et al (2008) Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number. Ann Surg Oncol 15:649–654PubMedCrossRefGoogle Scholar
  73. 73.
    Milano G, Etienne-Grimaldi MC, Dahan L et al (2008) Epidermal growth factor receptor (EGFR) status and KRAS mutations in colorectal cancer. Ann Oncol 19:2033–2038PubMedCrossRefGoogle Scholar
  74. 74.
    Goncalvez A, Esteyries S, Taylor-Smedra B et al (2008) A polymorphism of EGFR domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximabbased treatment. BMJ Cancer 8:1–11CrossRefGoogle Scholar
  75. 75.
    Liu W, Wu X, Zhang W et al (2007) Relationship of EGFR mutations, expression, amplification and polymorphisms to epidermal growth receptor inhibitors in the NC160 cell lines. Clin Cancer Res 15:6788–6795CrossRefGoogle Scholar
  76. 76.
    Puyo S, Le Morvan V, Robert J (2008) Impact of EGFR gene polymorphisms on anticancer drug cytotoxicity in vitro. Mol Diagn Ther 12:225–234PubMedGoogle Scholar
  77. 77.
    Carcereny E, Castellvi-Bel S, Alonso V et al (2008) EGFR polymorphisms as predictors of clinical outcome in patients with advanced colorectal cancer treated with cetuximab and panitumumab. J Clin Oncol 26s:A4124Google Scholar
  78. 78.
    Nishimura T, Andoh A, Inatomi O et al (2008) Amphiregulin and epiregulin expression in neoplastic and inflammatory lesions in the colon. Oncol Rep 19:105–110PubMedGoogle Scholar
  79. 79.
    Yotsumoto F, Yagi H, Suzuki SO et al (2008) Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun 365:555–561PubMedCrossRefGoogle Scholar
  80. 80.
    Tejpar S, De Roock W, Biesmans B et al (2008) High amphiregulin and epiregulin expression in KRAS wild type colorectal primaries predicts response and survival benefit after treatment with cetuximab and irinotecan for metastatic disease. ASCO Gastrointestinal Cancers Symposium a411Google Scholar
  81. 81.
    Baker JB, Dutta D, Watson T et al (2008) Evaluation of tumor gene expression and KRAS mutations in FFPE tumor tissue as predictors of response to cetuximab in metastatic colorectal cancer. J Clin Oncol 26s:A3512Google Scholar
  82. 82.
    Barault L, Veyrie N, Jooste V et al (2008) Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer 122:2255–2259PubMedCrossRefGoogle Scholar
  83. 83.
    Tan YH, Liu Y, Eu KW et al (2008) Detection of B-RAF V600E mutation by pyrosequencing. Pathology 40:295–298PubMedCrossRefGoogle Scholar
  84. 84.
    Calistri D, Rengucci C, Seymour I et al (2005) Mutation analysis of p53, KRAS and B-RAF genes in colorectal cancer progression. J Cell Physiol 204:484–488PubMedCrossRefGoogle Scholar
  85. 85.
    Oliveira C, Pinto M, Duval A et al (2003) B-RAF mutations characterize colon but no gastric cancer with mismatch repair deficiency. Oncogene 22:9192–9196PubMedCrossRefGoogle Scholar
  86. 86.
    Ogino S, cantor M, Kawasaki T et al (2006) CpG island methylator phenotype (CIMP) of colorectal cancer is best characterized by quantitative DNA methylation analysis and prospective cohort studies. Gut 55:1000–1006PubMedCrossRefGoogle Scholar
  87. 87.
    Perrone F, Lampis A, Orsenigo M et al (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 20:84–90PubMedCrossRefGoogle Scholar
  88. 88.
    Finocchiaro G, Capuzzo F, Rossi E et al (2008) Insulin-like growth factor receptor-1 (IGFR-1), MET, and B-RAF and primary resistance to cetuximab therapy in colorectal cancer patients. J Clin Oncol 26s:A4135Google Scholar
  89. 89.
    Artale S, Sartore-Bianchi A, Veronese S et al (2008) Mutations of KRAS and B-RAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol 26:4217–4219PubMedCrossRefGoogle Scholar
  90. 90.
    Di Nicolantonio F, Martini M, Molinari F et al (2008) Wild-type B-RAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712PubMedCrossRefGoogle Scholar
  91. 91.
    Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al (2007) Oncogenic activation of the RAS/RAF signaling pathways impairs the response of metastatic colorectal cancer to anti-epidermal growth factor receptor antibodies therapies. Cancer Res 67:2643–2648PubMedCrossRefGoogle Scholar
  92. 92.
    Jhawer M, Goel S, Wilson AJ et al (2008) PIK3-CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961PubMedCrossRefGoogle Scholar
  93. 93.
    Vehlo S, Oliveira C, Ferreira A et al (2005) The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 41:1649–1654CrossRefGoogle Scholar
  94. 94.
    Ogino S, Nosho K, Kirkner GJ et al (2009) PIK3-CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 27:1477–1484PubMedCrossRefGoogle Scholar
  95. 95.
    Sartore-Bianchi A, Martini M, Molinari F et al (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69:1851–1857PubMedCrossRefGoogle Scholar
  96. 96.
    Blanco-Aparicio C, Renner O, Leal J, Carnero A (2007) PTEN, more than the AKT pathway. Carcinogenesis 28:1379–1386PubMedCrossRefGoogle Scholar
  97. 97.
    Carnero A, Blanco-Aparicio C, Renner O et al (2008) The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 8:187–198PubMedCrossRefGoogle Scholar
  98. 98.
    Bing-Hua J, Ling-Zhi L (2008) PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta 1784:150–158Google Scholar
  99. 99.
    Nassif NT, Lobo GP, Wu X et al (2004) PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene 23:617–628PubMedCrossRefGoogle Scholar
  100. 100.
    Frattini M, Saletti P, Romagnani E et al (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145PubMedCrossRefGoogle Scholar
  101. 101.
    Loupakis F, Pollina L, Stasi I et al (2008) Evaluation of PTEN expression in colorectal cancer metastases and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment. J Clin Oncol 26s:A4003Google Scholar
  102. 102.
    Bardier A, Golmard J, Domont J et al (2008) Coexpression of EGFR, pEGFR, VEGF, pVEGF, PTEN, pAKT and p21 in colorectal cancer patients can have IHC variability between metastases and primary tumors and for EGFR.targeted therapies, p21 and VEGF appear reliably as predictive factors of response. J Clin Oncol 26s:A22074Google Scholar
  103. 103.
    Colakoglu T, Yildirim S, Kayaselcuk F et al (2008) Clinicopathological significance of PTEN loss and the phosphoinositide 3-kinase/Akt pathway in sporadic colorectal neoplasms: is PTEN loss predictor of local recurrence? Am J Surg 195:719–725PubMedCrossRefGoogle Scholar
  104. 104.
    Merlin JL, Perkins G, Lievre A et al (2008) Additional value of EGFR downstream signaling phosphoprotein expression to KRAS mutation for response prediction to cetuximab in colorectal cancer. J Clin Oncol 26s:A4126Google Scholar
  105. 105.
    Bleeker FE, Felicioni L, Buttitta F et al (2008) AKT1(E17K) in human solid tumours. Oncogene [Epub ahead of print] PMID:18504432Google Scholar
  106. 106.
    Kim MS, Jeong EG, Yoo NJ, Lee SH (2008) Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukemias. Br J Cancer 98:1553–1555Google Scholar
  107. 107.
    Saletti P, Molinari F, Martin V et al (2008) Analysis of epidermal growth factor receptor (EGFR) downstream proteins in metastatic colorectal cancer patients: Comparison between primary tumor and related metastatic sites. J Clin Oncol 26s:A11075Google Scholar

Copyright information

© Feseo 2009

Authors and Affiliations

  • Jose A. García-Sáenz
    • 1
  • Javier Sastre
    • 1
  • Eduardo Díaz-Rubio García
    • 1
  1. 1.Servicio de Oncología MédicaHospital Clínico Universitario San CarlosMadridSpain

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