Targeted Oncology

, Volume 5, Issue 1, pp 19–28

Integrated molecular dissection of the epidermal growth factor receptor (EFGR) oncogenic pathway to predict response to EGFR-targeted monoclonal antibodies in metastatic colorectal cancer

  • Andrea Sartore-Bianchi
  • Katia Bencardino
  • Federica Di Nicolantonio
  • Federico Pozzi
  • Chiara Funaioli
  • Valentina Gambi
  • Sabrina Arena
  • Miriam Martini
  • Simona Lamba
  • Andrea Cassingena
  • Roberta Schiavo
  • Alberto Bardelli
  • Salvatore Siena
Review

Abstract

The introduction of KRAS testing as a diagnostic tool to select patients for epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies for metastatic colorectal cancer is widely regarded as a key advance in the field of personalized cancer medicine. Oncologists are now facing emerging issues in the treatment of metastatic colorectal cancer, including: (i) the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients; (ii) the explanation of rare cases of patients carrying KRAS-mutated tumors who have been reported to respond to either cetuximab or panitumumab and (iii) the discovery of mechanisms of secondary resistance to anti-EGFR antibody therapies. Here we discuss the potential role of comprehensive dissection of the key oncogenic nodes in the EGFR signaling cascade to predict resistance and sensitivity to EGFR monoclonal antibodies in metastatic colorectal cancer. Current data suggest that, together with KRAS mutations, the evaluation of BRAF and PIK3CA/PTEN alterations could also be useful for selecting patients with reduced chance to benefit from EGFR-targeted therapy. Furthermore, measuring EGFR gene copy number also appears relevant to positively identify responders. Up until now, each of these markers has been mainly assessed as a single event, often in retrospective analyses and patients’ series. As these molecular alterations display overlapping patterns of occurrence, this adds considerable complexity to the drawing of an algorithm suitable for clinical decision-making. We suggest that in the near future comprehensive molecular analysis of the entire oncogenic pathway triggered by the EGFR should be performed, thus enhancing the prediction ability of individual markers.

Keywords

Colorectal cancer Biomarkers EGFR Monoclonal antibodies 

References

  1. 1.
    Winer E, Gralow J, Diller L et al (2008) American Society of Clinical Oncology. 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 27:812–826CrossRefPubMedGoogle Scholar
  2. 2.
    Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765CrossRefPubMedGoogle Scholar
  3. 3.
    Linardou H, Dahabreh IJ, Kanaloupiti D et al (2008) Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 9:962–972CrossRefPubMedGoogle Scholar
  4. 4.
    Moroni M, Veronese S, Benvenuti S et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286CrossRefPubMedGoogle Scholar
  5. 5.
    Bos JL (1989) RAS oncogenes in human cancer: a review. Cancer Res 49:4682–4689PubMedGoogle Scholar
  6. 6.
    Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137CrossRefPubMedGoogle Scholar
  7. 7.
    McCubrey JA, Steelman LS, Abrams SL, Lee JT et al (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 46:249–279CrossRefPubMedGoogle Scholar
  8. 8.
    Tan YH, Liu Y, Eu KW et al (2008) Detection of B-RAF V600E mutation by pyrosequencing. Pathology 40:295–298CrossRefPubMedGoogle Scholar
  9. 9.
    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 204:484–488CrossRefPubMedGoogle Scholar
  10. 10.
    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 122:2255–2259CrossRefPubMedGoogle Scholar
  11. 11.
    Rajagopalan H, Bardelli A, Lengauer C et al (2002) Tumorigenesis: RAF/RAS oncogenes and mismatchrepair status. Nature 418:934CrossRefPubMedGoogle Scholar
  12. 12.
    Di Nicolantonio F, Martini M, Molinari F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712CrossRefPubMedGoogle Scholar
  13. 13.
    Loupakis F, Ruzzo A, Cremolini C et al (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 18:715–721CrossRefGoogle Scholar
  14. 14.
    Van Cutsem E, Lang Y, Folprecht G et al (2010) Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer—the influence of KRAS and BRAF biomarkers on outcome: update data from the CRYSTAL trial. Proceedings of the 2010 Gastrointestinal Cancers Symposium. Abstract no. 281Google Scholar
  15. 15.
    Tol J, Nagtegaal ID, Punt CJ (2009) BRAF mutation in metastatic colorectal cancer. N Engl J Med 361:98–99CrossRefPubMedGoogle Scholar
  16. 16.
    Souglakos J, Philips J, Wang R, Marwah S et al (2009) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 101:465–472CrossRefPubMedGoogle Scholar
  17. 17.
    Roth AD, Tejpar S, Delorenzi M et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 28:466–474CrossRefPubMedGoogle Scholar
  18. 18.
    Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA (1998) Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. Natl Cancer Inst 90:675–684CrossRefGoogle Scholar
  19. 19.
    Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634CrossRefPubMedGoogle Scholar
  20. 20.
    Nagata Y, Lan KH, Zhou X et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127CrossRefPubMedGoogle Scholar
  21. 21.
    Mellinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024CrossRefPubMedGoogle Scholar
  22. 22.
    Velho S, Oliveira C, Ferreira A et al (2005) The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 41:1649–1654CrossRefPubMedGoogle Scholar
  23. 23.
    Frattini M, Saletti P, Romagnani E et al (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145CrossRefPubMedGoogle Scholar
  24. 24.
    Loupakis F, Pollina L, Stasi I et al (2009) PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 27:2622–2629CrossRefPubMedGoogle Scholar
  25. 25.
    Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M et al (2009) Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 4:e7287CrossRefPubMedGoogle Scholar
  26. 26.
    Laurent-Puig P, Cayre A, Manceau G et al (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27:5924–5930CrossRefPubMedGoogle Scholar
  27. 27.
    Jhawer M, Goel S, Wilson AJ et al (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961CrossRefPubMedGoogle Scholar
  28. 28.
    Lievre A, Bachet JB, Le Corre D et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995CrossRefPubMedGoogle Scholar
  29. 29.
    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 20:84–90CrossRefPubMedGoogle Scholar
  30. 30.
    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 69:1851–1857CrossRefPubMedGoogle Scholar
  31. 31.
    Prenen H, De Schutter J, Jacobs B et al (2009) PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 15:3184–3188CrossRefPubMedGoogle Scholar
  32. 32.
    Ogino S, Nosho K, Kirkner GJ et al (2009) PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 27:1477–1484CrossRefPubMedGoogle Scholar
  33. 33.
    Razis E, Briasoulis E, Vrettou E et al (2008) Potential value of PTEN in predicting cetuximab response in colorectal cancer. An exploratory study. BMC Cancer 8:234CrossRefPubMedGoogle Scholar
  34. 34.
    Zhao L, Vogt PK (2008) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A 105:2652–2657CrossRefPubMedGoogle Scholar
  35. 35.
    Goel A, Arnold C, Niedzwiecki D et al (2004) Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 64:3014–3021CrossRefPubMedGoogle Scholar
  36. 36.
    Bardelli A, Siena S (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 28(7):1254–1261CrossRefPubMedGoogle Scholar
  37. 37.
    Ooi A, Takehana T, Li X et al (2004) Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study. Mod Pathol 17:895–904CrossRefPubMedGoogle Scholar
  38. 38.
    Shia J, Klimstra DS, Li AR et al (2005) Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study. Mod Pathol 18:1350–1356CrossRefPubMedGoogle Scholar
  39. 39.
    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 24:4914–4921CrossRefPubMedGoogle Scholar
  40. 40.
    Vallböhmer D, Zhang W, Gordon M et al (2005) Molecular determinants of cetuximab efficacy. J Clin Oncol 23:3536–3544CrossRefPubMedGoogle Scholar
  41. 41.
    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 25:3238–3245CrossRefPubMedGoogle Scholar
  42. 42.
    Scartozzi M, Bearzi I, Mandolesi A et al (2009) Epidermal growth factor receptor (EGFR) gene copy number (GCN) correlates with clinical activity of irinotecan-cetuximab in K-RAS wild-type colorectal cancer: a fluorescence in situ (FISH) and chromogenic in situ hybridization (CISH) analysis. BMC Cancer 9:303CrossRefPubMedGoogle Scholar
  43. 43.
    Hirsch FR, Herbst RS, Olsen C et al (2008) Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 26:3351–3357CrossRefPubMedGoogle Scholar
  44. 44.
    Personeni N, Fieuws S, Piessevaux H et al (2008) Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 14:5869–5876CrossRefPubMedGoogle Scholar
  45. 45.
    Cappuzzo F, Finocchiaro G, Rossi E et al (2008) EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 19:717–723CrossRefPubMedGoogle Scholar
  46. 46.
    Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al (2007) 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 67:2643–2648CrossRefPubMedGoogle Scholar
  47. 47.
    De Roock W, Claes B, Fountzilas G et al (2009) PIK3CA, BRAF and KRAS mutations and outcome prediction in chemorefractory metastatic colorectal cancer (mCRC) patients treated with EGFR targeting monoclonal antibodies (MoAbs): Results of a European Consortium. Eur J Cancer 7:302s (abstract 6005)Google Scholar
  48. 48.
    Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboüé 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(8):1166–1169CrossRefPubMedGoogle Scholar
  49. 49.
    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(22):3230–3237CrossRefPubMedGoogle Scholar
  50. 50.
    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(5):663–671CrossRefPubMedGoogle Scholar
  51. 51.
    Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pintér 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(14):1408–1417CrossRefPubMedGoogle Scholar
  52. 52.
    Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, Humblet Y, Pénault-Llorca F, De Hertogh G, Laurent-Puig P, Van Cutsem E, Tejpar S (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 27(30):5068–5074CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Andrea Sartore-Bianchi
    • 1
  • Katia Bencardino
    • 1
  • Federica Di Nicolantonio
    • 2
  • Federico Pozzi
    • 1
  • Chiara Funaioli
    • 1
  • Valentina Gambi
    • 1
  • Sabrina Arena
    • 2
  • Miriam Martini
    • 2
  • Simona Lamba
    • 2
  • Andrea Cassingena
    • 1
  • Roberta Schiavo
    • 1
  • Alberto Bardelli
    • 2
    • 3
  • Salvatore Siena
    • 1
  1. 1.The Falck Division of Medical OncologyOspedale Niguarda Ca’ GrandaMilanItaly
  2. 2.Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment (IRCC)University of Torino Medical SchoolTurinItaly
  3. 3.FIRC Institute of Molecular OncologyMilanItaly

Personalised recommendations