The Potential of EGFR-Targeted Agents in Cancer Prevention

  • Steven D. Averbuch
  • Fadlo R. Khuri
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The prevention of cancer and its recurrence in high-risk individuals has become an increasingly realistic goal with the introduction of targeted therapies. Like other therapies intended to prevent morbidity and mortality in populations at risk, such as lipid-lowering agents and antihypertensives, cancer-prevention agents are intended for use in generally healthy individuals, and therefore must be well-tolerated. Other challenges associated with the use of agents in cancer prevention, rather than treatment, include the identification of an appropriate dose (the optimal biological dose for advanced disease may not be the optimal dose for early disease or for use in chemoprevention); similarly, the most appropriate schedule and form of administration must be determined. For example, preclinical models of lung cancer chemoprevention suggest that the use of inhaled formulations of retinoids may reduce the systemic side effects associated with chronic oral administration (1).


Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Expression Beta Carotene Growth Factor Receptor Tyrosine Kinase Epidermal Growth Factor Receptor Family 
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  1. 1.
    Dahl AR, Grossi IM, Houchens DP, et al. Inhaled isotretinoin (13-cis retinoic acid) is an effective lung cancer chemopreventive agent in A/J mice at low doses: a pilot study. Clin Cancer Res 2000;6:3015–3024.PubMedGoogle Scholar
  2. 2.
    King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 2001;86:2251–2256.CrossRefGoogle Scholar
  3. 3.
    Salih AK, Fentiman IS. 14. Breast cancer prevention. Int J Clin Pract 2002;56:267–271.PubMedGoogle Scholar
  4. 4.
    Baselga J. New technologies in epidermal growth factor receptor-targeted cancer therapy. Signal 2000;1:12–21.Google Scholar
  5. 5.
    Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999;82:241–250.PubMedCrossRefGoogle Scholar
  6. 6.
    Clarke K, Smith K, Gullick WJ, Harris AL. Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathway. Br J Cancer 2001;84:1322–1329.PubMedCrossRefGoogle Scholar
  7. 7.
    Maity A, Pore N, Lee J, et al. Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3’-kinase and distinct from that induced by hypoxia. Cancer Res 2000:60:5879–5886.PubMedGoogle Scholar
  8. 8.
    Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000;19:3159–3167.PubMedCrossRefGoogle Scholar
  9. 9.
    Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.PubMedCrossRefGoogle Scholar
  10. 10.
    Fontanini G, Vignati S, Bigini D, et al. Epidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer 1995;31A:178–183.PubMedCrossRefGoogle Scholar
  11. 11.
    Mukaida H, Toi M, Hirai T, et al. Clinical significance of the expression of epidermal growth factor and its receptor in esophageal cancer. Cancer 1991;68:142–148.PubMedCrossRefGoogle Scholar
  12. 12.
    Neal DE, Mellon K. Epidermal growth factor receptor and bladder cancer: a review. Urol Int 1992;48:365–371.PubMedCrossRefGoogle Scholar
  13. 13.
    Sainsbury JR, Farndon JR, Needham GK, et al. Epidermal-growth-factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet 1987;1:1398–1402.PubMedGoogle Scholar
  14. 14.
    Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 1997;8:1197–1206.PubMedCrossRefGoogle Scholar
  15. 15.
    Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995;55:5536–5539.PubMedGoogle Scholar
  16. 16.
    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–137.PubMedCrossRefGoogle Scholar
  17. 17.
    Carpenter G. Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways. J Cell Biol 1999;146:697–702.PubMedCrossRefGoogle Scholar
  18. 18.
    Albanell J, Rojo F, Averbuch S, et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 2002;20:110–124.PubMedCrossRefGoogle Scholar
  19. 19.
    Goss GD, Stewart DJ, Hirte H, et al. Initial results of Part 2 of a Phase I/II pharmacokinetic (PK), pharmacodynamic (PD) and biological activity study of ZD1839 (Iressa): NCIC CTG IND.122. Proc Am Soc Clin Oncol 2002;21:16a, abst 59.Google Scholar
  20. 20.
    Rowinsky EK. The pursuit of optimal outcomes in cancer therapy in a new age of rationally designed target-based anticancer agents. Drugs 2000;60 (Suppl 1):1–14.PubMedCrossRefGoogle Scholar
  21. 21.
    Herbst RS, Maddox A-M, Rothenberg ML, et al. The selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (‘Iressa’) 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;20:3815–3825.PubMedCrossRefGoogle Scholar
  22. 22.
    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;20:2240–2250.PubMedCrossRefGoogle Scholar
  23. 23.
    Fukuoka M, Yano S, Giaccone G, et al. Final results from a Phase II trial of ZD1839 (‘Iressa’) for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol 2002;21:298a, abst 1188.Google Scholar
  24. 24.
    Kris MG, Natale RB, Herbst RS, et al. A Phase II trial of ZD1839 (‘Iressa’) in advanced non-small-cell lung cancer (NSCLC) patients who had failed platinum- and docetaxelbased regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002;21:292a, abst 1166.Google Scholar
  25. 25.
    Perez-Soler R, Chachoua A, Huberman M, et al. A Phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced, EGFR-expressing, non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;20:310a, abst 1235.Google Scholar
  26. 26.
    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;19:3267–3279.PubMedGoogle Scholar
  27. 27.
    Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. IARC Cancer Base No. 5. Lyon, FR: IARC Press, 2001. Limited version available from 2001; last updated 03/02/2001.Google Scholar
  28. 28.
    Ries LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review 1973–1999 Bethesda, MD: National Cancer Institute, 2002.–1999/, 2002.Google Scholar
  29. 29.
    Lippman SM, Lee JJ, Karp DD, et al. Randomized Phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 2001;93:605–618.PubMedCrossRefGoogle Scholar
  30. 30.
    Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–1149.PubMedCrossRefGoogle Scholar
  31. 31.
    Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–1155.PubMedCrossRefGoogle Scholar
  32. 32.
    The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029–1035.CrossRefGoogle Scholar
  33. 33.
    Rusch V, Klimstra D, Venkatraman E, et al. Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clin Cancer Res 1997;3:515–522.PubMedGoogle Scholar
  34. 34.
    Fontanini G, De Laurentiis M, Vignati S, et al. Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I–IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res 1998;4:241–249.PubMedGoogle Scholar
  35. 35.
    Rusch V, Baselga J, Cordon-Cardo C, et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53 (10 Suppl):2379–2385.PubMedGoogle Scholar
  36. 36.
    Ohsaki Y, Tanno S, Fujita Y, et al. Epidermal growth factor receptor expression correlates with poor prognosis in nonsmall cell lung cancer patients with p53 overexpression. Oncol Rep 2000;7:603–607.PubMedGoogle Scholar
  37. 37.
    Brabender J, Danenberg KD, Metzger R, et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival. Clin Cancer Res 2001;7:1850–1855.PubMedGoogle Scholar
  38. 38.
    Kurie JM, Shin HJ, Lee JS, et al. Increased epidermal growth factor receptor expression in metaplastic bronchial epithelium. Clin Cancer Res 1996;2:1787–1793.PubMedGoogle Scholar
  39. 39.
    Rusch V, Klimstra D, Linkov I, Dmitrovsky E. Aberrant expression of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. Cancer Res 1995;55:1365–1372.PubMedGoogle Scholar
  40. 40.
    Hsieh ET, Shepherd FA, Tsao MS. Co-expression of epidermal growth factor receptor and transforming growth factor-alpha is independent of ras mutations in lung adenocarcinoma. Lung Cancer 2000;29:151–157.PubMedCrossRefGoogle Scholar
  41. 41.
    Lonardo F, Dragnev KH, Freemantle SJ, et al. Evidence for the epidermal growth factor receptor as a target for lung cancer prevention. Clin Cancer Res 2002;8:54–60.PubMedGoogle Scholar
  42. 42.
    Averbuch SD. Lung cancer prevention: retinoids and the epidermal growth factor receptor-a phoenix rising? Clin Cancer Res 2002;8:1–3.PubMedGoogle Scholar
  43. 43.
    Langenfeld J, Kiyokawa H, Sekula D, et al. Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. Proc Natl Acad Sci USA 1997;94:12,070–12,074.CrossRefGoogle Scholar
  44. 44.
    Boyle JO, Langenfeld J, Lonardo F, et al. Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells. J Natl Cancer Inst 1999;91:373–379.PubMedCrossRefGoogle Scholar
  45. 45.
    Price P, Sinnett HD, Gusterson B, et al. Duct carcinoma in situ: predictors of local recurrence and progression in patients treated by surgery alone. Br J Cancer 1990;61:869–872.PubMedCrossRefGoogle Scholar
  46. 46.
    Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–1388.PubMedCrossRefGoogle Scholar
  47. 47.
    Cuzick J. Update on new studies in Europe. Eur J Cancer 2002;38 (Suppl 3):abst 20.Google Scholar
  48. 48.
    Normanno N, Ciardiello F. EGF-related peptides in the pathophysiology of the mammary gland. J Mammary Gland Biol Neoplasia 1997;2:143–151.PubMedCrossRefGoogle Scholar
  49. 49.
    Klijn JG, Berns PM, Schmitz PI, Foekens JA. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev 1992;13:3–17.PubMedGoogle Scholar
  50. 50.
    Suo Z, Risberg B, Kalsson MG, et al. EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival. J Pathol 2002;196:17–25.PubMedCrossRefGoogle Scholar
  51. 51.
    Suo Z, Bjaamer A, Ottestad L, Nesland JM. Expression of EGFR family and steroid hormone receptors in ductal carcinoma in situ of the breast. Ultrastruct Pathol 2001;25:349–356.PubMedCrossRefGoogle Scholar
  52. 52.
    Pedersen MW, Meltorn M, Damstrup L, Poulsen HS. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol 2001;12:745–760.PubMedCrossRefGoogle Scholar
  53. 53.
    Lenferink AE, Simpson JF, Shawver LK, et al. Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice. Proc Nall Acad Sci USA 2000;97:9609–9614.CrossRefGoogle Scholar
  54. 54.
    Chan KC, Knox WF, Gee JM, et al. Effect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast. Cancer Res 2002;62:122–128.PubMedGoogle Scholar
  55. 55.
    Chan KC, Knox WF, Gandhi A, et al. Blockade of growth factor receptors in ductal carcinoma in situ inhibits epithelial proliferation. Br J Surg 2001;88:412–418.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Steven D. Averbuch
  • Fadlo R. Khuri

There are no affiliations available

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