Cancer and Metastasis Reviews

, Volume 27, Issue 3, pp 387–402 | Cite as

Clinical biomarkers of kinase activity: examples from EGFR inhibition trials

Article

Abstract

Introduction

Tumor response and duration of patient survival after treatment with inhibitors of the epidermal growth factor receptor (EGFR) varies considerably between different kinds of EGFR inhibitors, different combination schedules, but also between individual patients.

Discussion

Development and introduction of biomarkers into clinical practice is necessary to predict treatment response and thereby to individualize cancer therapy. Due to specific interactions of EGFR inhibitors with biological effects of irradiation, biomarkers are expected to differ for radiation oncology compared to application of the drugs alone or within chemotherapy treatment schedules and therefore need to be established and tested separately.

Objectives

The review summarizes the current status of potential predictors for the effect of EGFR inhibitors used as single agents or in combination with chemotherapy.

Conclusion

Based on this knowledge and on preclinical radiotherapy data, candidate biomarkers and further research strategies for radiation oncology are discussed.

Keywords

Radiotherapy Biomarker Prediction Prognosis EGFR inhibition Molecular targeting Tumour response Local tumour control Survival Radiosensitization Translational research 

Notes

Acknowledgements

The authors are supported by a grant of the German Research Council (BA 1433/6-1) within the research network “Mechanisms of the heterogeneity of the efficacy of EGFR inhibitors for radiotherapy of solid tumours” (DFG-PAK 190).

References

  1. 1.
    Salomon, D. S., Brandt, R., Ciardiello, F., & Normanno, N. (1995). Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Reviews in Oncology/Hematology, 19, 183–232.PubMedGoogle Scholar
  2. 2.
    Sartor, C. I. (2003). Epidermal growth factor family receptors and inhibitors: Radiation response modulators. Seminars in Radiation Oncology, 13, 22–30.PubMedGoogle Scholar
  3. 3.
    Baumann, M., Krause, M., Dikomey, E., Dittmann, K., Dorr, W., Kasten-Pisula, U., et al. (2007). EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms. Radiotherapy and Oncology, 83, 238–248.PubMedGoogle Scholar
  4. 4.
    Shepherd, F. A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E. H., Hirsh, V., Thongprasert, S., et al. (2005). Erlotinib in previously treated non-small-cell lung cancer. New England Journal of Medicine, 353, 123–132.PubMedGoogle Scholar
  5. 5.
    Thatcher, N., Chang, A., Parikh, P., Rodrigues Pereira, J., Ciuleanu, T., von Pawel, J., et al. (2005). Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 366, 1527–1537.PubMedGoogle Scholar
  6. 6.
    Giaccone, G., Herbst, R. S., Manegold, C., Scagliotti, G., Rosell, R., Miller, V., et al. (2004). Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. Journal of Clinical Oncology, 22, 777–784.PubMedGoogle Scholar
  7. 7.
    Herbst, R. S., Giaccone, G., Schiller, J. H., Natale, R. B., Miller, V., Manegold, C., et al. (2004). Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. Journal of Clinical Oncology, 22, 785–794.PubMedGoogle Scholar
  8. 8.
    Herbst, R. S., Prager, D., Hermann, R., Fehrenbacher, L., Johnson, B. E., Sandler, A., et al. (2005). TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. Journal of Clinical Oncology, 23, 5892–5899.PubMedGoogle Scholar
  9. 9.
    Gatzemeier, U., Pluzanska, A., Szczesna, A., Kaukel, E., Roubec, J., De Rosa, F., et al. (2007). Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: The Tarceva Lung Cancer Investigation Trial. Journal of Clinical Oncology, 25, 1545–1552.PubMedGoogle Scholar
  10. 10.
    Moore, M. J., Goldstein, D., Hamm, J., Figer, A., Hecht, J. R., Gallinger, S., et al. (2007). Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 25, 1960–1966.PubMedGoogle Scholar
  11. 11.
    Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., et al. (2004). Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine, 351, 337–345.PubMedGoogle Scholar
  12. 12.
    Burtness, B., Goldwasser, M. A., Flood, W., Mattar, B., & Forastiere, A. A. (2005). Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. Journal of Clinical Oncology, 23, 8646–8654.PubMedGoogle Scholar
  13. 13.
    Van Cutsem, E., Peeters, M., Siena, S., Humblet, Y., Hendlisz, A., Neyns, B., et al. (2007). 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. Journal of Clinical Oncology, 25, 1658–1664.PubMedGoogle Scholar
  14. 14.
    Bonner, J. A., Harari, P. M., Giralt, J., Azarnia, N., Shin, D. M., Cohen, R. B., et al. (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New England Journal of Medicine, 354, 567–578.PubMedGoogle Scholar
  15. 15.
    Dellas, K., Hipp, M., Arnold, D., Koelbl, O., Hänsgen, G., Liersch, T., et al. (2007). Cetuximab in Kombination mit Capecitabin und Oxaliplatin (CET-CAPOX) plus Standard-Radiatio als neoadjuvante Therapie des fortgeschrittenen Rektumkarzinoms. Ergebnisse einer Phase I/II-Studie. Experimentelle Strahlentherapie und klinische Strahlenbiologie, 16, 145–147.Google Scholar
  16. 16.
    Roedel, C., Arnold, D., Hipp, M., & Sauer, R. (2006). Cetuximab in combination with Capecitabine, Oxaliplatin and concomitant radiotherapy (Cet-Capox-RT) as preoperative therapy for rectal cancer. International Journal of Radiation Oncology, Biology, Physics, 66(Supplement), S82–S83.Google Scholar
  17. 17.
    Machiels, J. P., Sempoux, C., Scalliet, P., Coche, J. C., Humblet, Y., Van Cutsem, E., et al. (2007). Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Annals of Oncology, 18, 738–744.PubMedGoogle Scholar
  18. 18.
    Rodel, C., Grabenbauer, G. G., Papadopoulos, T., Hohenberger, W., Schmoll, H. J., & Sauer, R. (2003). Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. Journal of Clinical Oncology, 21, 3098–3104.PubMedGoogle Scholar
  19. 19.
    Rodel, C., & Sauer, R. (2007). Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlentherapie und Onkologie, 183, 227–235.PubMedGoogle Scholar
  20. 20.
    Krause, M., Schutze, C., Petersen, C., Pimentel, N., Hessel, F., Harstrick, A., et al. (2005). Different classes of EGFR inhibitors may have different potential to improve local tumour control after fractionated irradiation: A study on C225 in FaDu hSCC. Radiotherapy and Oncology, 74, 109–115.PubMedGoogle Scholar
  21. 21.
    Toulany, M., Dittmann, K., Baumann, M., & Rodemann, H. P. (2005). Radiosensitization of Ras-mutated human tumor cells in vitro by the specific EGF receptor antagonist BIBX1382BS. Radiotherapy and Oncology, 74, 117–129.PubMedGoogle Scholar
  22. 22.
    Burdak-Rothkamm, S., Rube, C. E., Nguyen, T. P., Ludwig, D., Feldmann, K., Wiegel, T., et al. (2005). Radiosensitivity of tumor cell lines after pretreatment with the EGFR tyrosine kinase inhibitor ZD1839 (IressaÒ). Strahlentherapie und Onkologie, 181, 197–204.PubMedGoogle Scholar
  23. 23.
    Begg, A. C., Haustermans, K., Hart, A. A., Dische, S., Saunders, M., Zackrisson, B., et al. (1999). The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: A multicenter analysis. Radiotherapy and Oncology, 50, 13–23.PubMedGoogle Scholar
  24. 24.
    Hermans, R., Van den Bogaert, W., Rijnders, A., Doornaert, P., & Baert, A. L. (1999). Predicting the local outcome of glottic squamous cell carcinoma after definitive radiation therapy: Value of computed tomography-determined tumour parameters. Radiotherapy and Oncology, 50, 39–46.PubMedGoogle Scholar
  25. 25.
    Baumann, M., Krause, M., Zips, D., Eicheler, W., Dörfler, A., Ahrens, J., et al. (2003). Selective inhibition of the epidermal growth factor tyrosine kinase by BIBX1382BS improves growth delay but not local control after fractionated irradiation in human FaDu squamous cell carcinoma in nude mice. International Journal of Radiation Biology, 79, 547–559.PubMedGoogle Scholar
  26. 26.
    Krause, M., Hessel, F., Zips, D., Hilberg, F., & Baumann, M. (2004). Adjuvant inhibition of the epidermal growth factor receptor after fractionated irradiation of FaDu human squamous cell carcinoma. Radiotherapy and Oncology, 72, 95–101.PubMedGoogle Scholar
  27. 27.
    Krause, M., Prager, J., Zhou, X., Yaromina, A., Dorfler, A., Eicheler, W., et al. (2007). EGFR-TK inhibition before radiotherapy reduces tumour volume but does not improve local control: Differential response of cancer stem cells and nontumourigenic cells? Radiotherapy and Oncology, 83, 316–325.PubMedGoogle Scholar
  28. 28.
    Kummermehr, J., & Trott, K. R. (1997). Tumour stem cells. In C. S. Potten (Ed.) Stem cells (pp. 363–400). London: Academic Press Limited.Google Scholar
  29. 29.
    Krause, M., Zips, D., Thames, H. D., Kummermehr, J., & Baumann, M. (2006). Preclinical evaluation of molecular-targeted anticancer agents for radiotherapy. Radiotherapy and Oncology, 80, 112–122.PubMedGoogle Scholar
  30. 30.
    Toulany, M., Dittmann, K., Kruger, M., Baumann, M., & Rodemann, H. P. (2005). Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway. Radiotherapy and Oncology, 76, 143–150.PubMedGoogle Scholar
  31. 31.
    Schmidt-Ullrich, R. K., Mikkelsen, R. B., Dent, P., Todd, D. G., Valerie, K., Kavanagh, B. D., et al. (1997). Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene, 15, 1191–1197.PubMedGoogle Scholar
  32. 32.
    Dent, P., Reardon, D. B., Park, J. S., Bowers, G., Logsdon, C., Valerie, K., et al. (1999). Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Molecular Biology of the Cell, 10, 2493–2506.PubMedGoogle Scholar
  33. 33.
    Bandyopadhyay, D., Mandal, M., Adam, L., Mendelsohn, J., & Kumar, R. (1998). Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells. Journal of Biological Chemistry, 273, 1568–1573.PubMedGoogle Scholar
  34. 34.
    Huang, S. M., & Harari, P. M. (2000). Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: Inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clinical Cancer Research, 6, 2166–2174.PubMedGoogle Scholar
  35. 35.
    Dittmann, K., Mayer, C., Fehrenbacher, B., Schaller, M., Raju, U., Milas, L., et al. (2005). Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. Journal of Biological Chemistry, 280, 31182–31189.PubMedGoogle Scholar
  36. 36.
    Krause, M., Ostermann, G., Petersen, C., Yaromina, A., Hessel, F., Harstrick, A., et al. (2005). Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation. Radiotherapy and Oncology, 76, 162–167.PubMedGoogle Scholar
  37. 37.
    Eriksen, J. G., Steiniche, T., & Overgaard, J. (2005). The influence of epidermal growth factor receptor and tumor differentiation on the response to accelerated radiotherapy of squamous cell carcinomas of the head and neck in the randomized DAHANCA 6 and 7 study. Radiotherapy and Oncology, 74, 93–100.PubMedGoogle Scholar
  38. 38.
    Bentzen, S. M., Atasoy, B. M., Daley, F. M., Dische, S., Richman, P. I., Saunders, M. I., et al. (2005). Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. Journal of Clinical Oncology, 23, 5560–5567.PubMedGoogle Scholar
  39. 39.
    Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 350, 2129–2139.PubMedGoogle Scholar
  40. 40.
    Paez, J. G., Janne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., et al. (2004). EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science, 304, 1497–1500.PubMedGoogle Scholar
  41. 41.
    Pao, W., & Miller, V. A. (2005). Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: Current knowledge and future directions. Journal of Clinical Oncology, 23, 2556–2568.PubMedGoogle Scholar
  42. 42.
    Sequist, L. V., Bell, D. W., Lynch, T. J., & Haber, D. A. (2007). Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. Journal of Clinical Oncology, 25, 587–595.PubMedGoogle Scholar
  43. 43.
    Uramoto, H., & Mitsudomi, T. (2007). Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer? British Journal of Cancer, 96, 857–863.PubMedGoogle Scholar
  44. 44.
    Johnson, B. E., & Janne, P. A. (2005). Epidermal growth factor receptor mutations in patients with non-small cell lung cancer. Cancer Research, 65, 7525–7529.PubMedGoogle Scholar
  45. 45.
    Sordella, R., Bell, D. W., Haber, D. A., & Settleman, J. (2004). Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science, 305, 1163–1167.PubMedGoogle Scholar
  46. 46.
    Eberhard, D. A., Johnson, B. E., Amler, L. C., Goddard, A. D., Heldens, S. L., Herbst, R. S., et al. (2005). Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of Clinical Oncology, 23, 5900–5909.PubMedGoogle Scholar
  47. 47.
    Bell, D. W., Lynch, T. J., Haserlat, S. M., Harris, P. L., Okimoto, R. A., Brannigan, B. W., et al. (2005). Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. Journal of Clinical Oncology, 23, 8081–8092.PubMedGoogle Scholar
  48. 48.
    Cappuzzo, F., Hirsch, F. R., Rossi, E., Bartolini, S., Ceresoli, G. L., Bemis, L., et al. (2005). Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. Journal of the National Cancer Institute, 97, 643–655.PubMedGoogle Scholar
  49. 49.
    Hirsch, F. R., & Witta, S. (2005). Biomarkers for prediction of sensitivity to EGFR inhibitors in non-small cell lung cancer. Current Opinion in Oncology, 17, 118–122.PubMedGoogle Scholar
  50. 50.
    Sasaki, H., Endo, K., Konishi, A., Takada, M., Kawahara, M., Iuchi, K., et al. (2005). EGFR Mutation status in Japanese lung cancer patients: Genotyping analysis using LightCycler. Clinical Cancer Research, 11, 2924–2929.PubMedGoogle Scholar
  51. 51.
    Pan, Q., Pao, W., & Ladanyi, M. (2005). Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. Journal of Molecular Diagnostics, 7, 396–403.PubMedGoogle Scholar
  52. 52.
    Janne, P. A., Borras, A. M., Kuang, Y., Rogers, A. M., Joshi, V. A., Liyanage, H., et al. (2006). A rapid and sensitive enzymatic method for epidermal growth factor receptor mutation screening. Clinical Cancer Research, 12, 751–758.PubMedGoogle Scholar
  53. 53.
    Ang, K., Berkey, B. A., Tu, X., Zhang, H. Z., Katz, R., Hammond, E. H., et al. (2002). Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Research, 62, 7350–7356.PubMedGoogle Scholar
  54. 54.
    Dassonville, O., Formento, J. L., Francoual, M., Ramaioli, A., Santini, J., Schneider, M., et al. (1993). Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. Journal of Clinical Oncology, 11, 1873–1878.PubMedGoogle Scholar
  55. 55.
    Nicholson, R. I., Gee, J. M., & Harper, M. E. (2001). EGFR and cancer prognosis. European Journal of Cancer, 37(Suppl 4), S9–S15.PubMedGoogle Scholar
  56. 56.
    Tsao, M. S., Sakurada, A., Cutz, J. C., Zhu, C. Q., Kamel-Reid, S., Squire, J., et al. (2005). Erlotinib in lung cancer - molecular and clinical predictors of outcome. New England Journal of Medicine, 353, 133–144.PubMedGoogle Scholar
  57. 57.
    Hirsch, F. R., Varella-Garcia, M., Bunn Jr., P. A., Franklin, W. A., Dziadziuszko, R., Thatcher, N., et al. (2006). Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. Journal of Clinical Oncology, 24, 5034–5042.PubMedGoogle Scholar
  58. 58.
    Hirsch, F. R., Varella-Garcia, M., Bunn Jr., P. A., Di Maria, M. V., Veve, R., Bremmes, R. M., et al. (2003). Epidermal growth factor receptor in non-small-cell lung carcinomas: Correlation between gene copy number and protein expression and impact on prognosis. Journal of Clinical Oncology, 21, 3798–3807.PubMedGoogle Scholar
  59. 59.
    Jeon, Y. K., Sung, S. W., Chung, J. H., Park, W. S., Seo, J. W., Kim, C. W., et al. (2006). Clinicopathologic features and prognostic implications of epidermal growth factor receptor (EGFR) gene copy number and protein expression in non-small cell lung cancer. Lung Cancer, 54, 387–398.PubMedGoogle Scholar
  60. 60.
    Temam, S., Kawaguchi, H., El-Naggar, A. K., Jelinek, J., Tang, H., Liu, D. D., et al. (2007). Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. Journal of Clinical Oncology, 25, 2164–2170.PubMedGoogle Scholar
  61. 61.
    Takano, T., Ohe, Y., Sakamoto, H., Tsuta, K., Matsuno, Y., Tateishi, U., et al. (2005). Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. Journal of Clinical Oncology, 23, 6829–6837.PubMedGoogle Scholar
  62. 62.
    Amann, J., Kalyankrishna, S., Massion, P. P., Ohm, J. E., Girard, L., Shigematsu, H., et al. (2005). Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Research, 65, 226–235.PubMedGoogle Scholar
  63. 63.
    Johnson, B. E., & Janne, P. A. (2005). Selecting patients for epidermal growth factor receptor inhibitor treatment: A FISH story or a tale of mutations? Journal of Clinical Oncology, 23, 6813–6816.PubMedGoogle Scholar
  64. 64.
    Dziadziuszko, R., Witta, S. E., Cappuzzo, F., Park, S., Tanaka, K., Danenberg, P. V., et al. (2006). Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer. Clinical Cancer Research, 12, 3078–3084.PubMedGoogle Scholar
  65. 65.
    Hirsch, F. R., Varella-Garcia, M., Cappuzzo, F., McCoy, J., Bemis, L., Xavier, A. C., et al. (2007). Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Annals of Oncology, 18, 752–760.PubMedGoogle Scholar
  66. 66.
    Varella-Garcia, M. (2006). Stratification of non-small cell lung cancer patients for therapy with epidermal growth factor receptor inhibitors: The EGFR fluorescence in situ hybridization assay. Diagnostic Pathology, 1, 19.PubMedGoogle Scholar
  67. 67.
    Chakravarti, A., Chakladar, A., Delaney, M. A., Latham, D. E., & Loeffler, J. S. (2002). The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner. Cancer Research, 62, 4307–4315.PubMedGoogle Scholar
  68. 68.
    Bernhard, E. J., Stanbridge, E. J., Gupta, S., Gupta, A. K., Soto, D., Bakanauskas, V. J., et al. (2000). Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines. Cancer Research, 60, 6597–6600.PubMedGoogle Scholar
  69. 69.
    Marchetti, A., Martella, C., Felicioni, L., Barassi, F., Salvatore, S., Chella, A., et al. (2005). EGFR mutations in non-small-cell lung cancer: Analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. Journal of Clinical Oncology, 23, 857–865.PubMedGoogle Scholar
  70. 70.
    Pao, W., Wang, T. Y., Riely, G. J., Miller, V. A., Pan, Q., Ladanyi, M., et al. (2005). KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med, 2, e17.PubMedGoogle Scholar
  71. 71.
    van Zandwijk, N., Mathy, A., Boerrigter, L., Ruijter, H., Tielen, I., de Jong, D., et al. (2007). EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: Retro- and prospective observations in non-small-cell lung cancer. Annals of Oncology, 18, 99–103.PubMedGoogle Scholar
  72. 72.
    Massarelli, E., Varella-Garcia, M., Tang, X., Xavier, A. C., Ozburn, N. C., Liu, D. D., et al. (2007). KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clinical Cancer Research, 13, 2890–2896.PubMedGoogle Scholar
  73. 73.
    Ogino, S., Kawasaki, T., Brahmandam, M., Yan, L., Cantor, M., Namgyal, C., et al. (2005). Sensitive sequencing method for KRAS mutation detection by Pyrosequencing. Journal of Molecular Diagnostics, 7, 413–421.PubMedGoogle Scholar
  74. 74.
    Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., et al. (2004). EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proceedings of the National Academy of Sciences of the United States of America, 101, 13306–13311.PubMedGoogle Scholar
  75. 75.
    Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., et al. (2005). Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. Journal of the National Cancer Institute, 97, 339–346.PubMedGoogle Scholar
  76. 76.
    Mu, X. L., Li, L. Y., Zhang, X. T., Wang, M. Z., Feng, R. E., Cui, Q. C., et al. (2005). Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in Chinese patients with non-small cell lung cancer. Clinical Cancer Research, 11, 4289–4294.PubMedGoogle Scholar
  77. 77.
    Pham, D., Kris, M. G., Riely, G. J., Sarkaria, I. S., McDonough, T., Chuai, S., et al. (2006). Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. Journal of Clinical Oncology, 24, 1700–1704.PubMedGoogle Scholar
  78. 78.
    Ahrendt, S. A., Decker, P. A., Alawi, E. A., Zhu Yr, Y. R., Sanchez-Cespedes, M., Yang, S. C., et al. (2001). Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer, 92, 1525–1530.PubMedGoogle Scholar
  79. 79.
    Nakagawa, K., Tamura, T., Negoro, S., Kudoh, S., Yamamoto, N., Takeda, K., et al. (2003). Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumors. Annals of Oncology, 14, 922–930.PubMedGoogle Scholar
  80. 80.
    Chang, A., Parikh, P., Thongprasert, S., Tan, E. H., Perng, R. P., Ganzon, D., et al. (2006). Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: Subset analysis from the ISEL study. Journal of Thoracic Oncology, 1, 847–855.PubMedGoogle Scholar
  81. 81.
    Chou, T. Y., Chiu, C. H., Li, L. H., Hsiao, C. Y., Tzen, C. Y., Chang, K. T., et al. (2005). Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clinical Cancer Research, 11, 3750–3757.PubMedGoogle Scholar
  82. 82.
    Cappuzzo, F., Varella-Garcia, M., Shigematsu, H., Domenichini, I., Bartolini, S., Ceresoli, G. L., et al. (2005). Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. Journal of Clinical Oncology, 23, 5007–5018.PubMedGoogle Scholar
  83. 83.
    Cappuzzo, F., Ligorio, C., Janne, P. A., Toschi, L., Rossi, E., Trisolini, R., et al. (2007). Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: The ONCOBELL trial. Journal of Clinical Oncology, 25, 2248–2255.PubMedGoogle Scholar
  84. 84.
    Rajput, A., Koterba, A. P., Kreisberg, J. I., Foster, J. M., Willson, J. K., & Brattain, M. G. (2007). A novel mechanism of resistance to epidermal growth factor receptor antagonism in vivo. Cancer Research, 67, 665–673.PubMedGoogle Scholar
  85. 85.
    Erjala, K., Sundvall, M., Junttila, T. T., Zhang, N., Savisalo, M., Mali, P., et al. (2006). Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clinical Cancer Research, 12, 4103–4111.PubMedGoogle Scholar
  86. 86.
    Saltz, L. B., Meropol, N. J., Loehrer Sr., P. J., Needle, M. N., Kopit, J., & Mayer, R. J. (2004). Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. Journal of Clinical Oncology, 22, 1201–1208.PubMedGoogle Scholar
  87. 87.
    Chung, K. Y., Shia, J., Kemeny, N. E., Shah, M., Schwartz, G. K., Tse, A., et al. (2005). Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. Journal of Clinical Oncology, 23, 1803–1810.PubMedGoogle Scholar
  88. 88.
    Baselga, J. (2005). Does epidermal growth factor receptor status predict activity of cetuximab in colorectal cancer patients? Nature Clinical Practice Oncology, 2, 284–285.PubMedGoogle Scholar
  89. 89.
    Mukohara, T., Engelman, J. A., Hanna, N. H., Yeap, B. Y., Kobayashi, S., Lindeman, N., et al. (2005). Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. Journal of the National Cancer Institute, 97, 1185–1194.PubMedGoogle Scholar
  90. 90.
    Cohen, E. E., Lingen, M. W., Martin, L. E., Harris, P. L., Brannigan, B. W., Haserlat, S. M., et al. (2005). Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR. Clinical Cancer Research, 11, 8105–8108.PubMedGoogle Scholar
  91. 91.
    Kwak, E. L., Jankowski, J., Thayer, S. P., Lauwers, G. Y., Brannigan, B. W., Harris, P. L., et al. (2006). Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clinical Cancer Research, 12, 4283–4287.PubMedGoogle Scholar
  92. 92.
    Sudo, T., Mimori, K., Nagahara, H., Utsunomiya, T., Fujita, H., Tanaka, Y., et al. (2007). Identification of EGFR mutations in esophageal cancer. European Journal of Surgical Oncology, 33, 44–48.PubMedGoogle Scholar
  93. 93.
    Nagahara, H., Mimori, K., Ohta, M., Utsunomiya, T., Inoue, H., Barnard, G. F., et al. (2005). Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clinical Cancer Research, 11, 1368–1371.PubMedGoogle Scholar
  94. 94.
    Janmaat, M. L., Gallegos-Ruiz, M. I., Rodriguez, J. A., Meijer, G. A., Vervenne, W. L., Richel, D. J., et al. (2006). Predictive factors for outcome in a phase II study of gefitinib in second-line treatment of advanced esophageal cancer patients. Journal of Clinical Oncology, 24, 1612–1619.PubMedGoogle Scholar
  95. 95.
    Mellinghoff, I. K., Wang, M. Y., Vivanco, I., Haas-Kogan, D. A., Zhu, S., Dia, E. Q., et al. (2005). Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. New England Journal of Medicine, 353, 2012–2024.PubMedGoogle Scholar
  96. 96.
    Lee, J. W., Soung, Y. H., Kim, S. Y., Nam, H. K., Park, W. S., Nam, S. W., et al. (2005). Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clinical Cancer Research, 11, 2879–2882.PubMedGoogle Scholar
  97. 97.
    Na, I. I., Kang, H. J., Cho, S. Y., Koh, J. S., Lee, J. K., Lee, B. C., et al. (2007). EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil. European Journal of Cancer, 43, 520–526.PubMedGoogle Scholar
  98. 98.
    Loeffler-Ragg, J., Skvortsov, S., Sarg, B., Skvortsova, I., Witsch-Baumgartner, M., Mueller, D., et al. (2005). Gefitinib-responsive EGFR-positive colorectal cancers have different proteome profiles from non-responsive cell lines. European Journal of Cancer, 41, 2338–2346.PubMedGoogle Scholar
  99. 99.
    Loeffler-Ragg, J., Witsch-Baumgartner, M., Tzankov, A., Hilbe, W., Schwentner, I., Sprinzl, G. M., et al. (2006). Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. European Journal of Cancer, 42, 109–111.PubMedGoogle Scholar
  100. 100.
    Chung, C. H., Ely, K., McGavran, L., Varella-Garcia, M., Parker, J., Parker, N., et al. (2006). Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. Journal of Clinical Oncology, 24, 4170–4176.PubMedGoogle Scholar
  101. 101.
    Agulnik, M., da Cunha Santos, G., Hedley, D., Nicklee, T., Dos Reis, P. P., Ho, J., et al. (2007). Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. Journal of Clinical Oncology, 24, 2184–2190.Google Scholar
  102. 102.
    Moroni, M., Veronese, S., Benvenuti, S., Marrapese, G., Sartore-Bianchi, A., Di Nicolantonio, F., 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 Oncology, 6, 279–286.PubMedGoogle Scholar
  103. 103.
    Benvenuti, S., Sartore-Bianchi, A., Di Nicolantonio, F., Zanon, C., Moroni, M., Veronese, S., 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 Research, 67, 2643–2648.PubMedGoogle Scholar
  104. 104.
    Lievre, A., Bachet, J. B., Le Corre, D., Boige, V., Landi, B., Emile, J. F., et al. (2006). KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Research, 66, 3992–3995.PubMedGoogle Scholar
  105. 105.
    Di Fiore, F., Blanchard, F., Charbonnier, F., Le Pessot, F., Lamy, A., Galais, M. P., et al. (2007). Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. British Journal of Cancer, 96, 1166–1169.PubMedGoogle Scholar
  106. 106.
    Lee, J., Jang, K. T., Ki, C. S., Lim, T., Park, Y. S., Lim, H. Y., et al. (2007). Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer, 109, 1561–1569.PubMedGoogle Scholar
  107. 107.
    Eke, I., Sandfort, V., Mischkus, A., Baumann, M., & Cordes, N. (2006). Antiproliferative effects of EGFR tyrosine kinase inhibition and radiation-induced genotoxic injury are attenuated by adhesion to fibronectin. Radiotherapy and Oncology, 80, 178–184.PubMedGoogle Scholar
  108. 108.
    Toulany, M., Kasten-Pisula, U., Brammer, I., Wang, S., Chen, J., Dittmann, K., et al. (2006). Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clinical Cancer Research, 12, 4119–4126.PubMedGoogle Scholar
  109. 109.
    Das, A. K., Sato, M., Story, M. D., Peyton, M., Graves, R., Redpath, S., et al. (2006). Non-small cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Research, 66, 9601–9608.PubMedGoogle Scholar
  110. 110.
    Olive, P. L., Banath, J. P., & Sinnott, L. T. (2004). Phosphorylated histone H2AX in spheroids, tumors, and tissues of mice exposed to etoposide and 3-amino-1,2,4-benzotriazine-1,3-dioxide. Cancer Research, 64, 5363–5369.PubMedGoogle Scholar
  111. 111.
    Klokov, D., MacPhail, S. M., Banath, J. P., Byrne, J. P., & Olive, P. L. (2006). Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays. Radiotherapy and Oncology, 80, 223–229.PubMedGoogle Scholar
  112. 112.
    Taneja, N., Davis, M., Choy, J. S., Beckett, M. A., Singh, R., Kron, S. J., et al. (2004). Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy. Journal of Biological Chemistry, 279, 2273–2280.PubMedGoogle Scholar
  113. 113.
    Das, A. K., Chen, B. P., Story, M. D., Sato, M., Minna, J. D., Chen, D. J., et al. (2007). Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma. Cancer Research, 67, 5267–5274.PubMedGoogle Scholar
  114. 114.
    Soung, Y. H., Lee, J. W., Kim, S. Y., Seo, S. H., Park, W. S., Nam, S. W., et al. (2005). Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Archiv, 446, 483–488.PubMedGoogle Scholar
  115. 115.
    Cho, N. Y., Choi, M., Kim, B. H., Cho, Y. M., Moon, K. C., & Kang, G. H. (2006). BRAF and KRAS mutations in prostatic adenocarcinoma. International Journal of Cancer, 119, 1858–1862.Google Scholar
  116. 116.
    Graziano, S. L., Gamble, G. P., Newman, N. B., Abbott, L. Z., Rooney, M., Mookherjee, S., et al. (1999). Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. Journal of Clinical Oncology, 17, 668–675.PubMedGoogle Scholar
  117. 117.
    Hoa, M., Davis, S. L., Ames, S. J., & Spanjaard, R. A. (2002). Amplification of wild-type K-ras promotes growth of head and neck squamous cell carcinoma. Cancer Research, 62, 7154–7156.PubMedGoogle Scholar
  118. 118.
    Yarbrough, W. G., Shores, C., Witsell, D. L., Weissler, M. C., Fidler, M. E., & Gilmer, T. M. (1994). ras mutations and expression in head and neck squamous cell carcinomas. Laryngoscope, 104, 1337–1347.PubMedGoogle Scholar
  119. 119.
    Matsuda, H., Konishi, N., Hiasa, Y., Hayashi, I., Tsuzuki, T., Tao, M., et al. (1996). Alterations of p16/CDKN2, p53 and ras genes in oral squamous cell carcinomas and premalignant lesions. Journal of Oral Pathology & Medicine, 25, 232–238.Google Scholar
  120. 120.
    Brunner, T. B., Cengel, K. A., Hahn, S. M., Wu, J., Fraker, D. L., McKenna, W. G., et al. (2005). Pancreatic cancer cell radiation survival and prenyltransferase inhibition: The role of K-Ras. Cancer Research, 65, 8433–8441.PubMedGoogle Scholar
  121. 121.
    Cengel, K. A., Voong, K. R., Chandrasekaran, S., Maggiorella, L., Brunner, T. B., Stanbridge, E., et al. (2007). Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells. Neoplasia, 9, 341–348.PubMedGoogle Scholar
  122. 122.
    Dittmann, K., Mayer, C., & Rodemann, H. P. (2005). Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity. Radiotherapy and Oncology, 76, 157–161.PubMedGoogle Scholar
  123. 123.
    Ang, K. K., Andratschke, N. H., & Milas, L. (2004). Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy. International Journal of Radiation Oncology, Biology, Physics, 58, 959–965.PubMedGoogle Scholar
  124. 124.
    Moeller, B. J., Richardson, R. A., & Dewhirst, M. W. (2007). Hypoxia and radiotherapy: Opportunities for improved outcomes in cancer treatment. Cancer and Metastasis Reviews, 26, 241–248.PubMedGoogle Scholar
  125. 125.
    Vaupel, P., & Mayer, A. (2007). Hypoxia in cancer: Significance and impact on clinical outcome. Cancer and Metastasis Reviews, 26, 225–239.PubMedGoogle Scholar
  126. 126.
    Storch, T. G., & Talley, G. D. (1988). Oxygen concentration regulates the proliferative response of human fibroblasts to serum and growth factors. Experimental Cell Research, 175, 317–325.PubMedGoogle Scholar
  127. 127.
    Wing, D. A., Talley, G. D., & Storch, T. G. (1988). Oxygen concentration regulates EGF-induced proliferation and EGF-receptor down regulation. Biochemical and Biophysical Research Communications, 153, 952–958.PubMedGoogle Scholar
  128. 128.
    Laderoute, K. R., Grant, T. D., Murphy, B. J., & Sutherland, R. M. (1992). Enhanced epidermal growth factor receptor synthesis in human squamous carcinoma cells exposed to low levels of oxygen. International Journal of Cancer, 52, 428–432.Google Scholar
  129. 129.
    Sorensen, B. S., Hao, J., Overgaard, J., Vorum, H., Honore, B., Alsner, J., et al. (2005). Influence of oxygen concentration and pH on expression of hypoxia induced genes. Radiotherapy and Oncology, 76, 187–193.PubMedGoogle Scholar
  130. 130.
    Kaplan, O., Jaroszewski, J. W., Faustino, P. J., Zugmaier, G., Ennis, B. W., Lippman, M., et al. (1990). Toxicity and effects of epidermal growth factor on glucose metabolism of MDA-468 human breast cancer cells. Journal of Biological Chemistry, 265, 13641–13649.PubMedGoogle Scholar
  131. 131.
    Steinbach, J. P., Klumpp, A., Wolburg, H., & Weller, M. (2004). Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. Cancer Research, 64, 1575–1578.PubMedGoogle Scholar
  132. 132.
    Perrotte, P., Matsumoto, T., Inoue, K., Kuniyasu, H., Eve, B. Y., Hicklin, D. J., et al. (1999). Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clinical Cancer Research, 5, 257–265.PubMedGoogle Scholar
  133. 133.
    Petit, A. M., Rak, J., Hung, M. C., Rockwell, P., Goldstein, N., Fendly, B., et al. (1997). Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: Angiogenic implications for signal transduction therapy of solid tumors. American Journal of Pathology, 151, 1523–1530.PubMedGoogle Scholar
  134. 134.
    Ciardiello, F., Caputo, R., Bianco, R., Damiano, V., Fontanini, G., Cuccato, S., et al. (2001). Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clinical Cancer Research, 7, 1459–1465.PubMedGoogle Scholar
  135. 135.
    Huang, S. M., Li, J., Armstrong, E. A., & Harari, P. M. (2002). Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Research, 62, 4300–4306.PubMedGoogle Scholar
  136. 136.
    Luwor, R. B., Lu, Y., Li, X., Mendelsohn, J., & Fan, Z. (2005). The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene, 24, 4433–4441.PubMedGoogle Scholar
  137. 137.
    Arsham, A. M., Plas, D. R., Thompson, C. B., & Simon, M. C. (2004). Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Research, 64, 3500–3507.PubMedGoogle Scholar
  138. 138.
    Mizukami, Y., Li, J., Zhang, X., Zimmer, M. A., Iliopoulos, O., & Chung, D. C. (2004). Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Research, 64, 1765–1772.PubMedGoogle Scholar
  139. 139.
    Bussink, J., Kaanders, J. H., & van der Kogel, A. J. (2007). Microenvironmental transformations by VEGF- and EGF-receptor inhibition and potential implications for responsiveness to radiotherapy. Radiotherapy and Oncology, 82, 10–17.PubMedGoogle Scholar
  140. 140.
    Bruns, C. J., Harbison, M. T., Davis, D. W., Portera, C. A., Tsan, R., McConkey, D. J., et al. (2000). Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clinical Cancer Research, 6, 1936–1948.PubMedGoogle Scholar
  141. 141.
    Zips, D., & Baumann, M. (2003). Anti-VEGF strategies in combination with radiotherapy. In C. Nieder, L. Milas, & K. Ang (Eds.) Modification of radiation response (pp. 179–188). Berlin: Springer.Google Scholar
  142. 142.
    Solomon, B., Binns, D., Roselt, P., Weibe, L. I., McArthur, G. A., Cullinane, C., et al. (2005). Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging. Molecular Cancer Therapeutics, 4, 1417–1422.PubMedGoogle Scholar
  143. 143.
    Iyer, R., Thames, H. D., Tealer, J. R., Mason, K. A., & Evans, S. C. (2004). Effect of reduced EGFR function on the radiosensitivity and proliferative capacity of mouse jejunal crypt clonogens. Radiotherapy and Oncology, 72, 283–289.PubMedGoogle Scholar
  144. 144.
    Epstein, J. B., Gorsky, M., Guglietta, A., Le, N., & Sonis, S. T. (2000). The correlation between epidermal growth factor levels in saliva and the severity of oral mucositis during oropharyngeal radiation therapy. Cancer, 89, 2258–2265.PubMedGoogle Scholar
  145. 145.
    Lee, S. W., Jung, K. I., Kim, Y. W., Jung, H. D., Kim, H. S., & Hong, J. P. (2007). Effect of epidermal growth factor against radiotherapy-induced oral mucositis in rats. International Journal of Radiation Oncology, Biology, Physics, 67, 1172–1178.PubMedGoogle Scholar
  146. 146.
    Yano, S., Kondo, K., Yamaguchi, M., Richmond, G., Hutchison, M., Wakeling, A., et al. (2003). Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. Anticancer Research, 23, 3639–3650.PubMedGoogle Scholar
  147. 147.
    Ando, M., Okamoto, I., Yamamoto, N., Takeda, K., Tamura, K., Seto, T., et al. (2006). Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. Journal of Clinical Oncology, 24, 2549–2556.PubMedGoogle Scholar
  148. 148.
    Czito, B. G., Willett, C. G., Bendell, J. C., Morse, M. A., Tyler, D. S., Fernando, N. H., et al. (2006). Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: Phase I trial results. Journal of Clinical Oncology, 24, 656–662.PubMedGoogle Scholar
  149. 149.
    Eicheler, W., Krause, M., Hessel, F., Zips, D., & Baumann, M. (2005). Kinetics of EGFR expression during fractionated irradiation varies between different human squamous cell carcinoma lines in nude mice. Radiotherapy and Oncology, 76, 151–156.PubMedGoogle Scholar
  150. 150.
    Petersen, C., Eicheler, W., Frömmel, A., Krause, M., Balschukat, S., Zips, D., et al. (2003). Proliferation and micromilieu during fractionated irradiation of human FaDu squamous cell carcinoma in nude mice. International Journal of Radiation Biology, 79, 469–477.PubMedGoogle Scholar
  151. 151.
    Scartozzi, M., Bearzi, I., Berardi, R., Mandolesi, A., Fabris, G., & Cascinu, S. (2004). Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: Implications for treatment with EGFR-targeted monoclonal antibodies. Journal of Clinical Oncology, 22, 4772–4778.PubMedGoogle Scholar
  152. 152.
    McKay, J. A., Murray, L. J., Curran, S., Ross, V. G., Clark, C., Murray, G. I., et al. (2002). Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases. European Journal of Cancer, 38, 2258–2264.PubMedGoogle Scholar
  153. 153.
    Cai, W., Chen, K., He, L., Cao, Q., Koong, A., & Chen, X. (2007). Quantitative PET of EGFR expression in xenograft-bearing mice using (64)Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody. European Journal of Nuclear Medicine and Molecular Imaging, 34, 850–858.PubMedGoogle Scholar
  154. 154.
    Goldenberg, A., Masui, H., Divgi, C., Kamrath, H., Pentlow, K., & Mendelsohn, J. (1989). Imaging of human tumor xenografts with an indium-111-labeled anti-epidermal growth factor receptor monoclonal antibody. Journal of the National Cancer Institute, 81, 1616–1625.PubMedGoogle Scholar
  155. 155.
    Masui, H., Kawamoto, T., Sato, J. D., Wolf, B., Sato, G., & Mendelsohn, J. (1984). Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Research, 44, 1002–1007.PubMedGoogle Scholar
  156. 156.
    Divgi, C. R., Welt, S., Kris, M., Real, F. X., Yeh, S. D., Gralla, R., et al. (1991). Phase I and imaging trial of indium 111-labeled anti-epidermal growth factor receptor monoclonal antibody 225 in patients with squamous cell lung carcinoma. Journal of the National Cancer Institute, 83, 97–104.PubMedGoogle Scholar
  157. 157.
    Perk, L. R., Visser, G. W., Vosjan, M. J., Stigter-van Walsum, M., Tijink, B. M., Leemans, C. R., et al. (2005). (89)Zr as a PET surrogate radioisotope for scouting biodistribution of the therapeutic radiometals (90)Y and (177)Lu in tumor-bearing nude mice after coupling to the internalizing antibody cetuximab. Journal of Nuclear Medicine, 46, 1898–1906.PubMedGoogle Scholar
  158. 158.
    Pnwar, P., Iznaga-Escobar, N., Mishra, P., Srivastava, V., Sharma, R. K., Chandra, R., et al. (2005). Radiolabeling and biological evaluation of DOTA-Ph-Al derivative conjugated to anti-EGFR antibody or egf/r3 for targeted tumor imaging and therapy. Cancer Biology and Therapy, 4, 854–860.PubMedCrossRefGoogle Scholar
  159. 159.
    Schechter, N. R., Yang, D. J., Azhdarinia, A., Kohanim, S., Wendt 3rd, R., Oh, C. S., et al. (2003). Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody. Anticancer Drugs, 14, 49–56.PubMedGoogle Scholar
  160. 160.
    Schechter, N. R., Wendt 3rd, R. E., Yang, D. J., Azhdarinia, A., Erwin, W. D., Stachowiak, A. M., et al. (2004). Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck. Journal of Nuclear Medicine, 45, 1683–1687.PubMedGoogle Scholar
  161. 161.
    Bonasera, T. A., Ortu, G., Rozen, Y., Krais, R., Freedman, N. M., Chisin, R., et al. (2001). Potential (18)F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase. Nuclear Medicine and Biology, 28, 359–374.PubMedGoogle Scholar
  162. 162.
    Mishani, E., Abourbeh, G., Jacobson, O., Dissoki, S., Ben Daniel, R., Rozen, Y., et al. (2005). High-affinity epidermal growth factor receptor (EGFR) irreversible inhibitors with diminished chemical reactivities as positron emission tomography (PET)-imaging agent candidates of EGFR overexpressing tumors. Journal of Medicinal Chemistry, 48, 5337–5348.PubMedGoogle Scholar
  163. 163.
    Ortu, G., Ben-David, I., Rozen, Y., Freedman, N. M., Chisin, R., Levitzki, A., et al. (2002). Labeled EGFr-TK irreversible inhibitor (ML03): In vitro and in vivo properties, potential as PET biomarker for cancer and feasibility as anticancer drug. International Journal of Cancer, 101, 360–370.Google Scholar
  164. 164.
    Velikyan, I., Sundberg, A. L., Lindhe, O., Hoglund, A. U., Eriksson, O., Werner, E., et al. (2005). Preparation and evaluation of (68)Ga-DOTA-hEGF for visualization of EGFR expression in malignant tumors. Journal of Nuclear Medicine, 46, 1881–1888.PubMedGoogle Scholar
  165. 165.
    Kimura, H., Kasahara, K., Kawaishi, M., Kunitoh, H., Tamura, T., Holloway, B., et al. (2006). Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non-small-cell lung cancer. Clinical Cancer Research, 12, 3915–3921.PubMedGoogle Scholar
  166. 166.
    Bell, D. W., & Haber, D. A. (2006). A blood-based test for epidermal growth factor receptor mutations in lung cancer. Clinical Cancer Research, 12, 3875–3877.PubMedGoogle Scholar
  167. 167.
    Taguchi, F., Solomon, B., Gregorc, V., Roder, H., Gray, R., Kasahara, K., et al. (2007). Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: A multicohort cross-institutional study. Journal of the National Cancer Institute, 99, 838–846.PubMedGoogle Scholar
  168. 168.
    Gatzemeier, U., Heller, A., Foernzler, D., Moecks, J., Ward, C., de Rosa, F., et al. (2005). Exploratory analyses EGFR, KRAS mutations and other molecular markers in tumors of NSCLC patients (pts) treated with chemotherapy +/− erlotinib (TALENT). Journal of Clinical Oncology, 23(supplement), 7028.Google Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Radiation Oncology, Medical Faculty Carl Gustav CarusTechnische Universität DresdenDresdenGermany
  2. 2.OncoRay Center for Radiation Research in Oncology, Medical Faculty Carl Gustav CarusTechnische Universität DresdenDresdenGermany
  3. 3.Experimental Center, Medical Faculty and University Hospital Carl Gustav CarusTechnische Universität DresdenDresdenGermany

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