Current Colorectal Cancer Reports

, Volume 8, Issue 1, pp 42–50 | Cite as

Clinical Implications and Quality Assurance of Molecular Testing for EGFR-Targeting Agents in Colorectal Cancer

  • Loredana Vecchione
  • Zenia Saridaki
  • Sabine Tejpar
Personalized Medicine in Colorectal Cancer (WA Messersmith, Section Editor)

Abstract

The introduction in clinical practice of anti-epidermal growth factor receptor (EGFR) antibodies has improved the clinical outcome of metastatic colorectal cancer (mCRC) patients. Nevertheless, only 10% of mCRC tumors respond to these treatments, thus rendering the efforts made to maximize their therapeutic index justified. Although several biomarkers have been identified, we do not know yet how to administer these drugs in colorectal cancer patients in a “personalized–targeted manner.” With this review we will try to demonstrate that we need to go beyond the assumption of a binary relationship between one genetic event and response or resistance to anti-EGFR drugs and that several factors can influence the response to these agents. Therefore, the introduction in future approaches of a holistic genomic discovery plan instead of an individual and specific identification of alterations is needed.

Keywords

Metastatic colorectal cancer EGFR dependency Anti-EGFR treatments Cetuximab Panitumumab Anti-EGFR moAbs Personalized cancer medicine Colorectal cancer subgroups Molecular subgroups KRAS BRAF PI3KCA NRAS PTEN Amphiregulin Epiregulin HER2 amplification Gene module Gene expression profile FcγRIIa FcγRIIΙa Let7 Anti-EGFR sensitivity Anti-EGFR resistance KRAS testing 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Vecchione L, Jacobs B, Normanno N, et al. EGFR-targeted therapy. Exp. Cell. Res. (2011), doi:10.1016/j.yexcr.2011.08.021.
  2. 2.
    Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525e32.Google Scholar
  3. 3.
    Pritchard CC, Grady WM. Colorectal cancer molecular biology moves into clinical practice. Gut 2011;60:116e129.Google Scholar
  4. 4.
    Rosen N. Molecular biology of gastrointestinal cancers. In: De Vita VTJ, Hellman S, Rosenberg SA, editors. Cancer—principles and practice of oncology, 5th edn. Lippincott Williams & Wilkins; 1997, p. 971–979.Google Scholar
  5. 5.
    Yarden Y: The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001 Sep;37 Suppl 4:S3-8.Google Scholar
  6. 6.
    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37. Review.Google Scholar
  7. 7.
    Fedor-Chaiken M, Hein PW, Stewart JC, et al. E-cadherin binding modulates EGF receptor activation. Cell Commun Adhes. 2003;10(2):105-18.Google Scholar
  8. 8.
    Morgillo F, Woo JK, Kim ES, et al. Heterodimerization of Insulin-like Growth Factor Receptor/Epidermal Growth Factor Receptor and Induction of Survivin Expression Counteract the Antitumor Action of Erlotinib. Ancer Res 2006;66(20):10100-11).Google Scholar
  9. 9.
    Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Eng J Med. 2008;358:1160–74.CrossRefGoogle Scholar
  10. 10.
    Fiske WH, Threadgill D, Coffey RJ. ERBBs in the gastrointestinal tract: recent progress and new perspectives. Exp Cell Res. 2009;315(4):583–601. Epub 2008 Nov 7.PubMedCrossRefGoogle Scholar
  11. 11.
    Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366(1):2–16.PubMedCrossRefGoogle Scholar
  12. 12.
    Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Sem Oncol. 2006;33:369–85.CrossRefGoogle Scholar
  13. 13.
    Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. JCO April 10, 2005 vol. 23 no. 11 2445-2459.Google Scholar
  14. 14.
    Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs. 2009;20(10):851–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Saltz LB, Meropol NJ, Loehrer Sr PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005;23:1803–10.PubMedCrossRefGoogle Scholar
  18. 18.
    Roberts RB, Min L, Washington MK, et al. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis, Proc. Natl. Acad. Sci. U.S.A. 99 (3) (Feb 5 2002) 513 1521–1526 (Epub 2002 Jan 29).Google Scholar
  19. 19.
    Hecht J, Mitchell E, Baranda J, et al. Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing low (1–9%) or negative (<1%) levels of epidermal growth factor receptor (EGFR). J. Clin. Oncol. 24 (2006) 157s (abstract).Google Scholar
  20. 20.
    Meropol NJ. Epidermal growth factor receptor inhibitors in colorectal cancer: it's time to get back on target. JCO Mar. 2005;20:1791–3.CrossRefGoogle Scholar
  21. 21.
    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;6:279–86.PubMedCrossRefGoogle Scholar
  22. 22.
    Cappuzzo F, Finocchiaro G, Rossi E, et al. EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol. 19 (2008) 717–723.Google Scholar
  23. 23.
    Personeni N, Fieuws S, Piessevaux H, et al. 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. 2008;14:5869–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Sartore-Bianchi A, Moroni M, Veronese S, et al. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. JCO August 1, 2007 vol. 25 no. 22 3238-3245.Google Scholar
  25. 25.
    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;25:3230–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Barber TD. Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med. 2004;351:2883.PubMedCrossRefGoogle Scholar
  27. 27.
    Tsuchihashi Z. Responsiveness to Cetuximab without Mutations in EGFR. N Engl J Med. 2005;353:208–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Samowitz WS, Curtin K, Schaffer D, et al. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiol Biomarkers Prev. 2000;9(11):1193–7.PubMedGoogle Scholar
  29. 29.
    Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer. 2001;85(5):692–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Lièvre A, Bachet JB, Le Corre D, et al. KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer Cancer Res April 15, 2006 66; 3992.Google Scholar
  31. 31.
    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;96:1166–9.PubMedCrossRefGoogle Scholar
  32. 32.
    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;26:1626–34.PubMedCrossRefGoogle Scholar
  33. 33.
    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;19:508–15.PubMedCrossRefGoogle Scholar
  34. 34.
    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;26:374–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Karapetis CS, Khambata-Ford S, Jonker DK, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 360 (2009) 1408–1417. 629.Google Scholar
  38. 38.
    Douillard J, Siena S, Cassidy J, et al. Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as 1st-line treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial. Eur J Cancer. 7 (2009) S6 (suppl; abstr 10LBA).Google Scholar
  39. 39.
    Allegra CJ, Jessup JM, Somerfield MR, 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. 2009;27(12):2091–6.PubMedCrossRefGoogle Scholar
  40. 40.
    • De Roock W, Claes B, Bernasconiet D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemo-refractory metastatic colorectal cancer: a retrospective Consortium analysis, Lancet Oncol. 2010;11 (8):753–762. By introducing the evaluation of other alterations involved in genes belonging to the EGFR pathway (other than KRAS), the authors improve the selection of patients that will benefit from anti-EGFR moAbs. Google Scholar
  41. 41.
    • De Roock W, Jonker DJ, Di Nicolantonio F, 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):1812–1820. The authors introduce the concept of different mutations in a singular gene occurring in mCRC as responsible for different response to anti-EGFR moAbs. Google Scholar
  42. 42.
    Janakiraman M, Vakiani E, Zeng Z, et al. Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res. 2010;70:5901–11.PubMedCrossRefGoogle Scholar
  43. 43.
    Edkins S, O'Meara S, Parker A, et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006;5:928–32.PubMedCrossRefGoogle Scholar
  44. 44.
    Feig LA, Cooper GM. Relationship among guanine nucleotide exchange, GTP hydrolysis, and transforming potential of mutated ras proteins. Mol Cell Biol. 1988;8:2472–8.PubMedGoogle Scholar
  45. 45.
    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;26:5705–12.PubMedCrossRefGoogle Scholar
  46. 46.
    Loupakis F, Ruzzo A, Cremolini C, 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;101:715–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS Metastatic Colon Cancer JCO December 10, 2009 vol. 27 no. 35 5924-5930.Google Scholar
  48. 48.
    Saridaki Z, Tzardi M, Papadaki C, et al. Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥2nd line cetuximab-based therapy of colorectal cancer patients. PLoS One. 2011;6(1):e15980.PubMedCrossRefGoogle Scholar
  49. 49.
    Souglakos J, Philips J, Wang R, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009;101(3):465–72.PubMedCrossRefGoogle Scholar
  50. 50.
    Prenen H, De Schutter J, Jacobs B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009;15:3184–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Perrone F, Lampis A, Orsenigo M, et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009;20:84–90.PubMedCrossRefGoogle Scholar
  52. 52.
    Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69:5. 1851-7.Google Scholar
  53. 53.
    Frattini M, Saletti P, Romagnani E, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97:1139–45.PubMedCrossRefGoogle Scholar
  54. 54.
    Loupakis F, Pollina L, Stasi I, et al. 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. JCO June 1, 2009 vol. 27 no. 16 2622-2629.Google Scholar
  55. 55.
    Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discovery Published OnlineFirst September 2, 2011; doi:10.1158/2159-8290.CD-11-0109.
  56. 56.
    Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86.Google Scholar
  57. 57.
    Personeni N, Fieuws S, Piessevaux H, et al. 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 September 15, 2008 14; 5869.Google Scholar
  58. 58.
    Jacobs B, De Roock W, Piessevaux H, et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2009;27:5068–74.PubMedCrossRefGoogle Scholar
  59. 59.
  60. 60.
  61. 61.
    Tabernero J, Cervantes A, Rivera F, et al. Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study. J Clin Oncol. 2010;28:1181–9.Google Scholar
  62. 62.
    •• Baker JB, Dutta D, Watson D, et al. Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. BJC 104 (2011) 488–495. The authors show that the evaluation of a gene classifier compared with a single gene study improves the specificity and the positive predictive value of cetuximab benefit. Google Scholar
  63. 63.
    •• Rhodes DR, Lockwood Banka W, Chinnaiyan AM. Gene Expression Modules Associated with Cetuximab Response in Metastatic Colorectal Cancer Predict Additional Patient Populations Likely to Respond. AACR Translation of the Cancer Genome, 7-10 FEB 2009, Boston, MA, USA. The authors show that gene modules better predict the response to targeted agents than single gene alterations and that it is even possible to predict gene mutation by gene expression profile.Google Scholar
  64. 64.
    •• Tejpar S, Popovici V, Delorenzi M, et al. Mutant KRAS and BRAF gene expression profiles in colorectal cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial, J. Clin. Oncol. 28 (2010) 15s (suppl; abstr 3505). The authors show that a single gene mutation is not homogeneous at its molecular level (eg, at gene expression profile), thus underlying the concept of a single gene mutation occurring in different CRC subgroups and not specific for a singular phenotype.Google Scholar
  65. 65.
    Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor– expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007;25:3712–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Bibeau F, Lopez-Crapez E, Di Fiore F, et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with Cetuximab Plus Irinotecan. JCO March 1, 2009 vol. 27 no. 7 1122-1129.Google Scholar
  67. 67.
    Graziano F, Ruzzo A, Loupakis F, et al. Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer. JCO March 20, 2008 vol. 26 no. 9 1427-1434.Google Scholar
  68. 68.
    Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120(5):635–47.PubMedCrossRefGoogle Scholar
  69. 69.
    Graziano F, Canestrari E, Loupakis F, et al. Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan. Pharmacogenomics J. 2010;10(5):458–64.PubMedCrossRefGoogle Scholar
  70. 70.
    Zhang W, Winder T, Ning YHJ, et al. A let-7 microRNA-binding site polymorphism in 3#-untranslated region of KRAS gene predicts response in wildtype KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy. Ann Oncol. 2011;22:104–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Santini D, Loupakis F, Vincenzi B, et al. High concordance of Kras status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist. 2008;13:1270–5.PubMedCrossRefGoogle Scholar
  72. 72.
    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;26:4217–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Bellon E, Ligtenberg MJL, Tejpar S, et al. External quality assessment for KRAS testing is needed: Setup of a European Program and Report of the First Joined Regional Quality Assessment Rounds. The Oncologist April 2011 vol. 16 no. 4 467-478.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Loredana Vecchione
    • 1
    • 2
    • 3
  • Zenia Saridaki
    • 1
    • 2
  • Sabine Tejpar
    • 1
    • 2
  1. 1.Digestive Oncology UnitUniversity Hospital GasthuisbergLeuvenBelgium
  2. 2.Center for Human GeneticsKatholieke Universiteit LeuvenLeuvenBelgium
  3. 3.Division of Medical Oncology, Department of Experimental and Clinical Medicine and Surgery “F. Magrassi and A. Lanzara,”Second University of NaplesNaplesItaly

Personalised recommendations