Advanced search

Vol 6, No 5 (2010)
Review paper
Published online: 2011-01-19

open access

View PDF (Polish) Download PDF file
Page views 1449
Article views/downloads 3766
Get Citation

Connect on Social Media

Connect on Social Media

The treatment interfering with EGFR in colorectal cancer patients

Marek Z. Wojtukiewicz, Piotr Tokajuk, Ewa Sierko
Onkol. Prak. Klin 2010;6(5):241-254.

Abstract

Over the last decade systemic treatment of colorectal cancer patients has changed considerably. New cytotoxics, such as oxaliplatin, irinotecan and capecitabine have been introduced to everyday clinical practice. More importantly, introduction of targeted therapy aimed at molecular targets present in cancer cells has substantially improved treatment outcomes. Currently, two major strategies of targeted therapy are used in colorectal cancer in routine clinical practice: blocking angiogenesis by using bevacizumab, a monoclonal antibody directed against VEGF and inhibition of the epidermal growth factor receptor (EGFR) by monoclonal antibodies — cetuximab and panitumumab. Results of the studies that evaluated association between histologic grade of malignancy and EGFR expression on colorectal cancer cells have been controversial. Interestingly, clinical studies reported in recent years have not showed unequivocally a significant association between EGFR expression and survival of colorectal cancer patients. Nevertheless, it has been demonstrated in several phase II and III clinical trials that the addition of monoclonal antibodies directed against EGFR to palliative chemotherapy in advanced colorectal cancer patients without a mutation in KRAS gene (wild-type KRAS) leads to significant improvements in response rates and significant prolongation of progression-free survival (and in some trials improvement of overall survival was documented, too). Intriguingly, it has been showed in several studies that using monoclonal antibodies directed against EGFR in combination with chemotherapy for advanced colorectal cancer patients with mutation in KRAS gene (mutant KRAS) has been associated with inferior treatment results. These observations have served as the scientific foundation for introduction of KRAS gene mutation analysis to clinical practice as the first biomarker in targeted therapy of advanced colorectal cancer patients. Results of phase III clinical trials were the basis of current indications of cetuximab and panitumumab. These antibodies are indicated for EGFR-expressing, KRAS wild-type metastatic colorectal cancer, in combination with first-line or second-line chemotherapy, or as a single agents in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to chemotherapy. Additionally, the activity of EGFR tyrosine kinase inhibitors has been evaluated in several phase I and II clinical trials. The aim of this paper is to review data from prospective randomised clinical trials that assessed targeted therapy directed against EGFR in the treatment of colorectal cancer patients.

Onkol. Prak. Klin. 2010; 6, 5: 241–254

Keywords: colorectal cancertargeted therapyEGFREGFR inhibitorscetuximabpanitumumabchemotherapypredictive factorsKRAS mutationBRAF mutation

Article available in PDF format

View PDF (Polish) Download PDF file

References

  1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001; 2(2): 127–137.
    CrossRefPubMed
  2. Gullick W. The epidermal growth factor system of ligands and receptors in cancer. European Journal of Cancer. 2009; 45(supl. 1): 205–210.
    CrossRef
  3. Lockhart AC, Lockhart C, Berlin JD. The epidermal growth factor receptor as a target for colorectal cancer therapy. Semin Oncol. 2005; 32(1): 52–60.
    CrossRefPubMed
  4. Radinsky R, Risin S, Fan D, et al. Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res. 1995; 1(1): 19–31.
    PubMed
  5. Kluftinger AM, Robinson BW, Quenville NF, et al. Correlation of epidermal growth factor receptor and c-erbB2 oncogene product to known prognostic indicators of colorectal cancer. Surg Oncol. 1992; 1(1): 97–105.
    PubMed
  6. 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): 1331–1346.
    PubMed
  7. McKay JA, Murray LJ, Curran S, et al. Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases. Eur J Cancer. 2002; 38(17): 2258–2264.
    PubMed
  8. Wan CW, McKnight MK, Brattain DE, et al. Different epidermal growth factor growth responses and receptor levels in human colon carcinoma cell lines. Cancer Lett. 1988; 43(1-2): 139–143.
    PubMed
  9. 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(4): 337–345.
    CrossRefPubMed
  10. Gross ME, Zorbas MA, Danels YJ, et al. Cellular growth response to epidermal growth factor in colon carcinoma cells with an amplified epidermal growth factor receptor derived from a familial adenomatous polyposis patient. Cancer Res. 1991; 51(5): 1452–1459.
    PubMed
  11. Karameris A, Kanavaros P, Aninos D, et al. Expression of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) in gastric and colorectal carcinomas. An immunohistological study of 63 cases. Pathol Res Pract. 1993; 189(2): 133–137.
    PubMed
  12. Radinsky R. Modulation of tumor cell gene expression and phenotype by the organ-specific metastatic environment. Cancer Metastasis Rev. 1995; 14(4): 323–338.
    PubMed
  13. Spano JP, Lagorce C, Atlan D, et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol. 2005; 16(1): 102–108.
    CrossRefPubMed
  14. Al-Mulla F, Keith WN, Pickford IR, et al. Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases. Genes Chromosomes Cancer. 1999; 24(4): 306–314.
    PubMed
  15. Paredes-Zaglul A, Kang JJ, Essig YP, et al. Analysis of colorectal cancer by comparative genomic hybridization: evidence for induction of the metastatic phenotype by loss of tumor suppressor genes. Clin Cancer Res. 1998; 4(4): 879–886.
    PubMed
  16. Steele RJ, Kelly P, Ellul B, et al. Epidermal growth factor receptor expression in colorectal cancer. Br J Surg. 1990; 77(12): 1352–1354.
    PubMed
  17. Steele RJ, Kelly P, Ellul B, et al. Immunohistochemical detection of epidermal growth factor receptors on human colonic carcinomas. Br J Cancer. 1990; 61(2): 325–326.
    PubMed
  18. Koretz K, Schlag P, Möller P. Expression of epidermal growth factor receptor in normal colorectal mucosa, adenoma, and carcinoma. Virchows Arch A Pathol Anat Histopathol. 1990; 416(4): 343–349.
    PubMed
  19. Moorghen M, Ince P, Finney KJ, et al. Epidermal growth factor receptors in colorectal carcinoma. Anticancer Res. 1990; 10(3): 605–611.
    PubMed
  20. Mayer A, Takimoto M, Fritz E, et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer. 1993; 71(8): 2454–2460.
    PubMed
  21. Barbacid M. ras genes. Annu Rev Biochem. 1987; 56: 779–827.
    CrossRefPubMed
  22. Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989; 49(17): 4682–4689.
    PubMed
  23. Lowy D, Willumsen B. Function and Regulation of Ras. Annual Review of Biochemistry. 1993; 62(1): 851–891.
    CrossRef
  24. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007; 7(4): 295–308.
    CrossRefPubMed
  25. Blick SKA, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs. 2007; 67(17): 2585–2607.
    PubMed
  26. Weber J, McCormack PL. Panitumumab: in metastatic colorectal cancer with wild-type KRAS. BioDrugs. 2008; 22(6): 403–411.
    PubMed
  27. Hecht JR, Peeters M, Van Cu, et al. Safety and tolerability of panitumumab, a fully human monoclonal antibody (mab), in patients (pts) with metastatic colorectal cancer (mCRC). . Ann. Oncol. 2006; 17(supl. 9): ix124 abstr. 361P.
  28. Perkins G, Lièvre A, Ramacci C, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006; 66(8): 3992–3995.
    CrossRefPubMed
  29. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007; 67(6): 2643–2648.
    CrossRefPubMed
  30. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008; 19(3): 508–515.
    CrossRefPubMed
  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(8): 1166–1169.
    CrossRefPubMed
  32. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007; 25(22): 3230–3237.
    CrossRefPubMed
  33. Lambrechts D, De Ro, Prenen H, et al. The role of KRAS, BRAF, NRAS, and PIK3CA mutations as markers of resistance to cetuximab in chemorefractory metastatic colorectal cancer. . J. Clin. Oncol. 2009; 27(supl.): 15 abstr. 4020.
  34. Ruzzo A, Cremolini C, Loupakis F, et al. Association of BRAF mutations and EGFR Intron-1 L/L genotype with resistance to cetuximab plus irinotecan treatment in KRAS wild-type metastatic colorectal cancer patients. J. Clin. Oncol. 2009; 27(supl.): 15.
  35. Sartore-Bianchi A, Bencardino K, Di Nicolantonio F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008; 26(35): 5705–5712.
    CrossRefPubMed
  36. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360(14): 1408–1417.
    CrossRefPubMed
  37. 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(5): 663–671.
    CrossRefPubMed
  38. Bokemeyer C, Kohne C, Rougier P, et al. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. Journal of Clinical Oncology. 2010; 28(15_suppl): 3506.
    CrossRef
  39. Maughan TS, Adams R, Smith CG, et al. Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): Mature results of the MRC COIN trial. . J. Clin. Oncol. 2010; 28(supl.): 15, abstr. 3502.
  40. Mekenkamp LJM, Tol J, Dijkstra JR, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009; 360(6): 563–572.
    CrossRefPubMed
  41. Punt CJA, Tol J. More is less -- combining targeted therapies in metastatic colorectal cancer. Nat Rev Clin Oncol. 2009; 6(12): 731–733.
    CrossRefPubMed
  42. Scartozzi M, Galizia E, Chiorrini S, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol. 2009; 20(2): 227–230.
    CrossRefPubMed
  43. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26(14): 2311–2319.
    CrossRefPubMed
  44. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007; 357(20): 2040–2048.
    CrossRefPubMed
  45. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010; 11(1): 38–47.
    CrossRefPubMed
  46. Douillard JY, Siena S, Cassidy J, 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. 2010; 28(31): 4697–4705.
    CrossRefPubMed
  47. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009; 27(5): 672–680.
    CrossRefPubMed
  48. Peeters M, Oliner KS, Price TJ, 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. 2010; 28(31): 4706–4713.
    CrossRefPubMed
  49. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 25(13): 1658–1664.
    CrossRefPubMed
  50. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26(10): 1626–1634.
    CrossRefPubMed
  51. Baselga J, Rischin D, Ranson M, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol. 2002; 20(21): 4292–4302.
    CrossRefPubMed
  52. Herbst RS, Maddox AM, Rothenberg ML, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol. 2002; 20(18): 3815–3825.
    CrossRefPubMed
  53. Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol. 2002; 20(9): 2240–2250.
    CrossRefPubMed
  54. Rothenberg ML, LaFleur B, Levy DE, et al. Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol. 2005; 23(36): 9265–9274.
    CrossRefPubMed
  55. Hartmann JT, Kroening H, Bokemeyer C, et al. Phase I study of gefitinib in combination with oxaliplatin and weekly 5-FU/FA (FUFOX) for second-/third-line treatment in patients (pts) with metastatic colorectal cancer (CRC). Journal of Clinical Oncology. 2005; 23(16_suppl): 16s, abstr. 3154.
    CrossRef
  56. Kuo T, Cho CD, Halsey J, et al. Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer. J Clin Oncol. 2005; 23(24): 5613–5619.
    CrossRefPubMed
  57. Fisher GA, Kuo T, Ramsey M, et al. A phase II study of gefitinib, 5-fluorouracil, leucovorin, and oxaliplatin in previously untreated patients with metastatic colorectal cancer. Clin Cancer Res. 2008; 14(21): 7074–7079.
    CrossRefPubMed
  58. Arnold D, Constantin C, Seufferlein T, et al. Phase I study of gefitinib in combination with capecitabine and irinotecan for 2ndand/or 3rd-line treatment in patients with metastatic colorectal cancer. . J. Clin. Oncol. 2005; 23(supl.): 16s, abstr. 3691.
  59. Veronese ML, Sun W, Giantonio B, et al. A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer. Br J Cancer. 2005; 92(10): 1846–1849.
    CrossRefPubMed
  60. Meyerhardt J, Clark J, Supko J, et al. Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer. Cancer Chemotherapy and Pharmacology. 2007; 60(5): 661–670.
    CrossRef
  61. Hochhaus A, Hofheinz R, Heike M, et al. Phase I study of gefitinib in combination with FOLFIRI as 2 nd -/3 rd -line treatment in patients with metastatic colorectal cancer. . J. Clin. Oncol. 2005; 23(supl.): 16s, abstr. 3674.
  62. Wolpin BM, Clark JW, Meyerhardt JA, et al. Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2006; 6(3): 208–213.
    CrossRefPubMed
  63. Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001; 19(13): 3267–3279.
    CrossRefPubMed
  64. Keilholz U, Arnold D, Niederle N, et al. Erlotinib as 2 nd and 3 rd line monotherapy in patients with metastatic colorectal cancer. Results of a multicenter two-cohort phase II trial. . J. Clin. Oncol. 2005; 23(supl.): 16s, abstr. 3575.
  65. Meyerhardt JA, Stuart K, Fuchs CS, et al. Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer. Ann Oncol. 2007; 18(7): 1185–1189.
    CrossRefPubMed
  66. Goldberg RM, Sargent DJ, Thibodeau SN, et al. Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147. Journal of Clinical Oncology. 2010; 28(suppl.): abstr. 3508.
    CrossRef
  67. Alberts SR, Sargent DJ, Smyrk TC, et al. Adjuvant mFOLFOX6 with or without cetuxiumab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): results from NCCTG Intergroup Phase III Trial N0147. . J. Clin. Oncol. 2010; 28(supl.): 15s, abstr. CRA3507.
  68. Douillard J, Cassidy J, Jassem J, et al. Randomized, open-label, phase III study of panitumumab (pmab) with FOLFOX4 versus FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): efficacy by skin toxicity (ST). . J. Clin. Oncol. 2010; 28(supl.): 15s, abstr. 3528.
  69. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010; 28(8): 1351–1357.
    CrossRefPubMed
  70. Lynch TJ, Kim EdS, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007; 12(5): 610–621.
    CrossRefPubMed
  71. Tan EH, Chan A. Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Ann Pharmacother. 2009; 43(10): 1658–1666.
    CrossRefPubMed

About cookies

Necessary cookies

Allways active

These cookies are necessary for the proper display and operation of the website. Blocking them may cause the website to malfunction.

Analytical cookies

As part of our website, we use analytical tools, such as Google Analytics, that allow us to verify website traffic. These tools may require the use of cookies.

Community cookies

These are cookies associated with the social networks we use. Accepting them will allow us to associate your visit to the site with our social media profiles.

Marketing cookies

These are cookies responsible for carrying out advertising and marketing activities - consenting to their use will allow us to target you with advertisements based on your previous activities within our website.

Oncology in Clinical Practice

About Via Medica Advertising
Bookstore (Ikamed) TVMed
News
Copyright © 2023 Via Medica Regulations Cookie policy Privacy policy Legal Notice