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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5437-5439 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.917
Predicting the Future From Trials of the Past: Epidermal Growth Factor Receptor Expression and Outcome of Fractionated Radiation Therapy TrialsDepartments of Radiation Oncology and Dermatology, Thomas Jefferson University, Philadelphia, PA The epidermal growth factor receptor (EGFR; HER 1; ErbB1) has been at the center of an explosion of translational research over the past 20 years. The EGFR is expressed or overexpressed in a large number of malignancies, including non–small-cell lung (NSCLC), head and neck, esophageal, gastric, colorectal, breast, prostate, bladder, renal, pancreatic, and ovarian cancers.1,2 EGFR expression is often found in association with increased expression of its ligands, most notably epidermal growth factor (EGF), tumor growth factor-alpha, or amphiregulin.3 EGFR activation and signaling affects many aspects of cell biology relevant to malignant transformation, including cell cycle progression, migration and invasion, differentiation, and cell survival. The antiapoptotic effects of EGFR activation may be particularly relevant to the assessment of treatment outcomes in patients afflicted with EGFR expressing tumors have been ascribed to regulation of Bcl-2 family members.4-10 In this issue, Bentzen et al11 examine EGFR expression status in 304 patients with available pretreatment tumor biopsy material among 918 patients randomized to Continuous Hyperfractionated Accelerated Radiotherapy (CHART) versus conventionally fractionated radiotherapy. The EGFR index was defined as the proportion of tumor cells with EGFR membrane staining. Significant benefit in locoregional tumor control from CHART was seen in patients with head and neck squamous cell carcinoma with high EGFR expression (2P = .010) but not in patients with low EGFR expression (2P = .85). By contrast, EGFR expression status was not linked to patient survival or rate of distant metastases. Bentzen et al11 used immunohistochemical analysis to assess EGFR expression levels, which raises some technical concerns. First, manual methods of immunohistochemical scoring of antigen expression as used in this report are fraught with variability. This variability may explain the lack of association of EGFR expression with other biomarkers evaluated in this study (Ki-67 index, Ki-67 pattern, p53 index, p53 intensity, bcl-2 expression, or cyclin D1 index). Another concern centers on the retrospective analysis of archived tissue stored for different periods of time. The CHART head and neck phase III trial accrued patients over 5 years from March 1990 to April 1995. During this extended period, oxidation of antigens/DNA/RNA may have occurred. A recent editorial in the Journal of Clinical Oncology by Meropol12 refers to work by Atkins et al13 in support of the notion that extended storage of tissue sections over time affects the sensitivity of EGFR immunostaining. However, despite these concerns, the study by Bentzen et al11 provides an interesting new perspective on intratumoral EGFR expression as a variable with obvious relevance to the design of fractionated radiotherapy. Several reports have illuminated molecular mechanisms leading to enhanced expression of the EGFR in epithelial malignancies. In addition to gene amplification, sequence analysis has revealed polymorphisms of intron 1 of the EGFR gene characterized by (CA)n dinucleotide repeats of different lengths that regulate transcription rates of the EGFR in cell lines and in tumor tissues in patients.14-17 The length of the (CA)n dinucleotide repeat tract is inversely correlated with the transcriptional activity of the EGFR gene. Further investigation of EGFR sequences expressed by tumor cells has also revealed alterations that primarily affect the activation state of the receptor rather than the expression levels. For example, in patients with colorectal cancer, a polymorphic variant of the EGFR gene (HER-1 R497K) has been identified that is associated with higher receptor kinase activity.18 Interestingly, expression of the constitutively active HER-1 R497K variant is associated with pelvic tumor recurrences. It remains to be investigated whether this EGFR variant is expressed at normal or increased levels in tumor cells. Other studies revealed somatic mutations representing small deletions, mutations, or missense point mutations in the tyrosine kinase domain of EGFR gene, which greatly affect sensitivity of these tumors to EGFR inhibitors and ionizing radiation.19-22 These mutations result not only in constitutive activity of the EGFR and enhanced long-term activation by its ligands but also in exceptional sensitivity toward EGFR inhibitors such as gefinitib (IRESSA).23-27 Although these tyrosine kinase domain mutations are best characterized in NSCLC they may be relevant for other cancers, as described recently for colorectal tumors28 and head and neck cancer.29 Collectively, these results raise the important issue of whether determining EGFR expression levels alone should guide future radiotherapy trials in patients afflicted with head and neck squamous cell carcinomas. The experience with gefinitib clearly suggests that screens for EGFR mutations should complement assessment of EGFR expression status to identify select groups of patients that may benefit from different radiation therapy modalities. Two major developments since the CHART trial are the use of chemotherapy and the EGFR antagonistic monoclonal antibody cetuximab in head and neck malignancies. Several trials have shown the benefit of chemotherapy delivered concurrently with radiotherapy, which primarily improves the local or locoregional effect(s) of radiotherapy.30 Furthermore, multiple reports support the view that EGFR blockade radiosensitizes carcinoma cells in both in vitro and in vivo settings.31-38 The international phase III trial report by Bonner et al39 demonstrated that addition of an anti-EGFR antibody to radiation yielded an improvement in locoregional tumor control and overall survival without increasing mucositis and dysphagia compared with radiation alone. These studies raise the issue of whether EGFR expression and mutational status can be used to identify patients with head and neck cancer who would benefit from different radiation treatment modalities perhaps in combination with EGFR inhibitors. In summary, the report by Bentzen et al11 suggests that more aggressive radiation therapy may be useful to treat biologically aggressive head and neck squamous cell carcinomas. This work underscores the importance of retrospective biomarker research to guide hypothesis-driven prospective clinical trials. It is likely that future studies will include analysis of the mutational or activation status of the EGFR in tumor tissues. This will provide a sound basis for future research efforts aimed at integrating cutting-edge therapies in the treatment of head and neck cancer. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Bunn PA Jr, Franklin W: Epidermal growth factor receptor expression, signal pathway, and inhibitors in non-small cell lung cancer. Semin Oncol 29:38-44, 2002 2. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995[Medline]
3. Baselga J: Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 7:2-8, 2002 (suppl 4)
4. Bill HM, Knudsen B, Moores SL, et al: Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells. Mol Cell Biol 24:8586-8599, 2004 5. Reginato MJ, Mills KR, Paulus JK, et al: Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 5:733-740, 2003[CrossRef][Medline] 6. Jost M, Class R, Kari C, et al: A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. J Invest Dermatol 112:443-449, 1999[CrossRef][Medline]
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8. Jost M, Huggett TM, Kari C, et al: Epidermal growth factor receptor-dependent control of keratinocyte survival and Bcl-xL expression through a MEK-dependent pathway. J Biol Chem 276:6320-6326, 2001 9. Mahoney MG, Simpson A, Jost M, et al: Metastasis-associated protein (MTA)1 enhances migration, invasion, and anchorage-independent survival of immortalized human keratinocytes. Oncogene 21:2161-2170, 2002[CrossRef][Medline]
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12. Meropol NJ: Epidermal growth factor receptor inhibitors in colorectal cancer: It's time to get back on target. J Clin Oncol 23:1791-1793, 2005
13. Atkins D, Reiffen KA, Tegtmeier CL, et al: Immunohistochemical detection of EGFR in paraffin-embedded tumor tissues: Variation in staining intensity due to choice of fixative and storage time of tissue sections. J Histochem Cytochem 52:893-901, 2004 14. Gebhardt F, Zanker KS, Brandt B: Differential expression of alternatively spliced c-erbB-2 mRNA in primary tumors, lymph node metastases, and bone marrow micrometastases from breast cancer patients. Biochem Biophys Res Commun 247:319-323, 1998[CrossRef][Medline]
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23. Kosaka T, Yatabe Y, Endoh H, et al: Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res 64:8919-8923, 2004
24. Marchetti A, Martella C, Felicioni L, et al: 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. J Clin Oncol 23:857-865, 2005
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27. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004
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29. Lee J, Soung Y, Kim S, et al: Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res 11:2879-2882, 2005 30. Cooper JS, Ang KK: Concomitant chemotherapy and radiation therapy certainly improves local control. Int J Radiat Oncol Biol Phys 61:7-9, 2005[CrossRef][Medline] 31. Raben D, Bianco C, Helfrich B, et al: Interference with EGFR signaling: Paradigm for improving radiation response in cancer treatment. Expert Rev Anticancer Ther 2:461-471, 2002[CrossRef][Medline]
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34. Huang SM, Harari PM: Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: Inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res 6:2166-2174, 2000
35. Harari PM, Huang SM: Modulation of molecular targets to enhance radiation. Clin Cancer Res 6:323-325, 2000 36. Reardon DB, Contessa JN, Mikkelsen RB, et al: Dominant negative EGFR-CD533 and inhibition of MAPK modify JNK1 activation and enhance radiation toxicity of human mammary carcinoma cells. Oncogene 18:4756-4766, 1999[CrossRef][Medline] 37. Nakata E, Hunter N, Mason K, et al: C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy. Int J Radiat Oncol Biol Phys 59:1163-1173, 2004[CrossRef][Medline]
38. Milas L, Mason K, Hunter N, et al: In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6:701-708, 2000 39. Bonner J, Giralt J, Harari P, et al: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. Proc Am Soc Clin Oncol 23:489, 2004 (abstr 5507) Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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